TW202434726A - Evolved adenine deaminases and rna-guided nuclease fusion proteins with internal insertion sites and methods of use - Google Patents

Abstract

Compositions and methods comprising deaminases for targeted editing of nucleic acids are provided. Also provided are compositions and methods for localizing a heterologous polypeptide to a target DNA molecule and for targeted editing of nucleic acids are provided. Fusion proteins comprising an RNA-guided nuclease (RGN) and at least one heterologous polypeptide inserted therein and fusion proteins comprising a DNA-binding polypeptide and a deaminase are provided. The heterologous polypeptide can be a prime editing polypeptide or a base-editing polypeptide. Compositions also include nucleic acid molecules encoding the deaminases or the fusion proteins. Vectors and host cells comprising the nucleic acid molecules encoding the deaminases or fusion proteins are also provided.

Description

Fusion protein with internal insertion site, evolved adenine deamination and RNA-guided nuclease and method of use thereof

Cross-references between related applications

This application claims priority to U.S. Provisional Patent Application No. 63/382,344 filed on November 4, 2022 and U.S. Provisional Patent Application No. 63/485,642 filed on February 17, 2023, each of which is fully incorporated herein by reference. Reference to Sequence Listing Submitted Electronically as an XML File

This application contains a sequence listing that has been filed in xml format by the USPTO Patent Center and is hereby incorporated by reference in its entirety. The xml copy created on November 5, 2023 is named L103438_1330TW_Seq_List.xml and is 1154 KB in size.

The invention is related to the fields of molecular biology and gene editing.

Targeted genome editing or modification is rapidly becoming an important tool for basic and applied research. Initial approaches involved engineered nucleases such as meganucleases, zinc finger fusion proteins or TALENs, which require the generation of chimeric nucleases with engineered, programmable, sequence-specific DNA binding domains specific for each particular target sequence. RNA-guided nucleases (RGNs) (e.g., CRISPR-Cas proteins of the CRISPR-associated (Cas) bacterial system) allow for the targeting of specific sequences by complexing the nuclease with a guide RNA that specifically hybridizes to a particular target sequence. It is less expensive and more efficient to generate target-specific guide RNAs than to generate chimeric nucleases for each target sequence. Such RNA-guided nucleases can be used to edit the genome via the introduction of sequence-specific, double-strand breaks that are repaired via error-prone non-homologous end joining (NHEJ) to introduce mutations at specific genomic locations.

In addition, RGNs are useful for targeted DNA editing methods. Targeted editing of nucleic acid sequences that allow for the introduction of specific modifications into genomic DNA (e.g., targeted splicing) enables a more nuanced approach to studying gene function and gene expression. RGNs can also be used to generate chimeric proteins that utilize the RNA-guided activity of RGNs in conjunction with DNA-modifying enzymes (e.g., deaminases) for targeted base editing. Targeted editing can be used to target human genetic diseases or to introduce agronomically beneficial mutations into the genomes of crop plants. The development of genome editing tools provides new approaches to mammalian therapeutics and agricultural biotechnology based on gene editing.

Compositions and methods for locating a heterologous polynucleotide to a target DNA molecule and modifying the target DNA molecule are provided. The composition provided includes a deaminase polypeptide and a fusion protein, the fusion protein including an RNA-guided nuclease (RGN) and at least one heterologous polypeptide (e.g., a deaminase) inserted therein. The heterologous polypeptide can be a lead editing polypeptide or an alkaline editing polypeptide. Fusion proteins including alkaline editing polypeptides are also referred to herein as alkaline editors. Therefore, in some embodiments, the alkaline editor includes a nucleic acid molecule binding polypeptide (e.g., a DNA binding polypeptide) and a deaminase polypeptide. In some embodiments, the alkaline editor includes an RGN into which a deaminase is inserted. In some embodiments, the base editor comprising the RGN into which the deaminase polypeptide is inserted exhibits improved editing activity and/or a shifted editing window compared to the parent base editor. In some embodiments, the parent base editor comprises a deaminase fused to the amino terminus of the RGN. Also provided are nucleic acid molecules encoding the disclosed deaminase polypeptides and fusion proteins, vectors comprising the nucleic acid molecules, and cells comprising the deaminase polypeptides or fusion proteins, nucleic acid molecules, or vectors.

Provided are a system comprising the disclosed fusion protein (or a nucleic acid molecule encoding the fusion protein) and one or more guide RNAs (or one or more nucleic acid molecules encoding the guide RNA) for localizing a heterologous polypeptide or deaminase to a target DNA molecule, and a cell comprising the system. A method for localizing a heterologous polypeptide or deaminase and/or modifying a target DNA molecule comprises delivering the disclosed system to a target DNA molecule or a cell comprising the target DNA molecule.

A pharmaceutical composition is provided, the pharmaceutical composition comprising a deaminase and a fusion protein disclosed herein, a nucleic acid molecule encoding the deaminase and the fusion protein (or a vector or a cell comprising the nucleic acid molecule), or a system (or a cell comprising the system). A method for treating an individual suffering from a disease, disorder, or symptom or at risk of developing a disease, disorder, or symptom comprises administering to the individual a fusion protein disclosed herein, a nucleic acid molecule encoding the fusion protein (or a vector or a cell comprising the nucleic acid molecule), a system (or a cell comprising the system), or a pharmaceutical composition. In some embodiments, the disease, disorder, or symptom is associated with a causal mutation and treatment comprises correction of the causal mutation.

Many modifications and other embodiments of the invention described herein will come to mind to one having ordinary skill in the art having the benefit of the teachings presented in the foregoing description. Therefore, it should be understood that the invention is not limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended patent applications. Although specific terms are employed herein, these terms are used in a generic and descriptive sense only and not for purposes of limitation. I. Overview

The present disclosure provides fusion proteins including nucleic acid molecule binding polypeptides such as DNA binding polypeptides and deaminase polypeptides, and deaminase. In certain embodiments, the DNA binding polypeptide is a sequence-specific DNA binding polypeptide because the DNA binding polypeptide binds to the target sequence at a higher frequency than to a random background sequence. In some embodiments, the DNA binding polypeptide is or is derived from a meganuclease, a zinc finger fusion protein, or a TALEN. In some embodiments, the fusion protein includes an RNA-guided DNA binding polypeptide and a deaminase polypeptide. In some embodiments, the RNA-guided DNA binding polypeptide is an RNA-guided nuclease (RGN), such as a CRISPR-Cas (e.g., Cas9) polypeptide bound to a guide RNA (also called a gRNA), which in turn binds to a target nucleic acid sequence via strand hybridization.

The present disclosure also provides fusion proteins comprising an RGN and at least one heterologous polypeptide inserted into the RGN (as well as nucleic acid molecules encoding the fusion proteins). The heterologous polypeptide can be inserted within a surface location of the RGN (e.g., immediately after an amino acid residue on the surface of the RGN). The presently disclosed fusion proteins can include RGNs with a base editing polypeptide or a lead editing polypeptide, some of which exhibit improved editing activity and/or a shifted editing window compared to end-to-end fusion proteins.

The terms "protein", "peptide" and "polypeptide" are used interchangeably herein and refer to polymers of amino acid residues linked together by peptide (amide) bonds. The terms refer to proteins, peptides or polypeptides of any size, structure or function. Typically, a protein, peptide or polypeptide will be at least three amino acids long. A protein, peptide or polypeptide may refer to an individual protein or an aggregation of proteins. For example, one or more amino acids in a protein, peptide or polypeptide may be modified by the addition of chemical entities such as carbohydrate groups, hydroxyl groups, phosphate groups, farnesyl groups, isofarnesyl groups, fatty acid groups, linkers for conjugation, functionalization, or other modifications, and the like. A protein, peptide or polypeptide may also be a single molecule, or may be a multimolecular complex. The protein, peptide or polypeptide may be only a fragment of a naturally occurring protein or peptide. The protein, peptide or polypeptide may be naturally occurring, recombinant or synthetic, or any combination thereof.

As used herein, the term "fusion protein" refers to a hybrid polypeptide comprising protein domains from at least two different proteins. A fusion protein may include more than one different domain, for example, a RGN and a deaminase. The fusion proteins of the present invention include a deaminase disclosed herein and a nucleic acid molecule-binding polypeptide or a heterologous protein (e.g., a deaminase) inserted into the amino acid sequence of the RGN, which in some cases can disrupt the domain within the RGN protein. In some embodiments, the fusion protein is in a complex with a nucleic acid (e.g., RNA) or is conjugated to a nucleic acid (e.g., RNA).

The heterologous polypeptide inserted into the RGN according to the present invention can be an abase editing polypeptide, such as a deaminase polypeptide or an active variant or fragment thereof, which directly chemically modifies (e.g., deaminates) a nucleobase, resulting in conversion from one nucleobase to another. The deamination of a nucleobase by a deaminase can result in a point mutation at the respective residue, which is referred to herein as "nucleobase editing," or "base editing." Fusion proteins comprising RNA-guided nuclease (RGN) polypeptides and deaminases can therefore be used for targeted editing of nucleic acid sequences.

The fusion proteins disclosed herein may include an RGN fused to a lead editing polypeptide. Lead editing is a versatile and precise genome editing method that uses a nucleic acid programmable DNA binding protein that acts in association with a polymerase to directly write new genetic information into a specified DNA site (described in, e.g., US 11,447,770B1; WO2021072328; WO2021226558; WO2020156575; WO2021042047; US11193123; each of which is incorporated herein by reference in its entirety). The lead editing system uses an RGN that is a nickase, and the system is programmed with a lead editing (PE) guide RNA ("PEgRNA").

The fusion proteins disclosed herein can be used for targeted editing of DNA in vitro, for example, for generating genetically modified cells. These genetically modified cells can be plant cells or animal cells. Such fusion proteins can also be used, for example, to introduce targeted mutations in cells obtained from an individual (which are subsequently reintroduced into the same or another individual), for example, for correcting genetic defects in mammalian cells in vitro; and for introducing targeted mutations, for example, correction of genetic defects, or introduction of deactivating mutations in disease-related genes in mammalian individuals. Such fusion proteins can also be used to introduce targeted mutations in plant cells, for example, for introducing beneficial or agronomically valuable traits or alleles.

Any fusion protein provided herein can be produced by any method known in the art. For example, the proteins provided herein can be produced by recombinant protein expression and purification, which is particularly suitable for use with fusion proteins that include a peptide linker. Methods for recombinant protein expression and purification are well known and include those described in Green and Sambrook , Molecular Cloning: A Laboratory Manual (4th edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York (2012)), which is incorporated herein by reference in its entirety. II. Nucleic Acid Molecules Binding to Polypeptides

Some aspects of the disclosure provide fusion proteins comprising a nucleic acid molecule binding polypeptide and a deaminase polypeptide. Although the present invention contemplates binding to RNA molecules and targeted editing of RNA molecules, in some embodiments, the nucleic acid molecule binding polypeptide of the fusion protein is a DNA binding polypeptide. Such fusion proteins are useful for targeted editing of DNA in vitro, ex vivo or in vivo. These fusion proteins are active in mammalian cells and are useful for targeted editing of DNA molecules.

In some embodiments, the presently disclosed fusion proteins include a DNA binding polypeptide. As used herein, the term "DNA binding polypeptide" refers to any polypeptide capable of binding to DNA. In certain embodiments, the DNA binding polypeptide portion of the presently disclosed fusion proteins binds to double-stranded DNA. In some embodiments, the DNA binding polypeptide binds to DNA in a sequence-specific manner. As used herein, the term "sequence specificity" or "sequence-specific manner" refers to a selective interaction with a specific nucleotide sequence.

Two polynucleotide sequences are considered to be substantially complementary when they hybridize to each other under strict conditions. Similarly, a DNA binding polypeptide is considered to bind to a specific target sequence in a sequence-specific manner if it binds to its sequence under strict conditions. "Strict conditions" or "strict hybridization conditions" are intended to refer to conditions under which two polynucleotide sequences (or polypeptides that bind to their specific target sequences) will bind to each other to a detectable degree greater than other sequences (e.g., at least 2-fold greater than background). Strict conditions are sequence-dependent and will be different in different circumstances. Typically, stringent conditions will be those in which: the salt concentration is less than 1.5 M Na ion, typically about 0.01 to 1.0 M Na ion concentration (or other salts) at pH 7.0 to 8.3, and the temperature is at least 30° C. for short sequences (e.g., 10 to 50 nucleotides) and at least 60° C. for long sequences (e.g., greater than 50 nucleotides). Stringent conditions can also be achieved by adding destabilizing agents such as formamide. Exemplary low stringency conditions include hybridization with a buffer solution of 30 to 35% formamide, 1 M NaCl, 1% SDS (sodium dodecyl sulfate) at 37°C, and washing with 1X to 2X SSC (20X SSC = 3.0 M NaCl/0.3 M trisodium citrate) at 50 to 55°C. Exemplary moderate stringency conditions include hybridization in 40 to 45% formamide, 1.0 M NaCl, 1% SDS at 37°C, and washing with 0.5X to 1X SSC at 55 to 60°C. Exemplary high stringency conditions include hybridization in 50% formamide, 1 M NaCl, 1% SDS at 37°C, and washing in 0.1X SSC at 60 to 65°C. Alternatively, the wash buffer may include about 0.1% to about 1% SDS. The hybridization duration is generally less than about 24 hours, typically about 4 to about 12 hours. The duration of the wash time is at least a length of time sufficient to achieve equilibrium.

Tm is the temperature (under defined ionic strength and pH) at which 50% of the complementary sequence hybridizes with the perfectly matching sequence. For DNA-DNA hybrids, Tm can be roughly estimated from the equation of Meinkoth and Wahl (1984) Anal. Biochem. 138:267-284: Tm = 81.5°C + 16.6 (log M) + 0.41 (%GC) - 0.61 (% formamide (% form)) - 500/L; where M is the molar concentration of monovalent cations, %GC is the percentage of guanosine and cytosine nucleotides in the DNA, % formamide is the percentage of formamide in the hybrid solution, and L is the length of the hybrid in base pairs. Generally, stringent conditions are selected to be about 5°C below the thermal melting point (Tm) of the specific sequence and its complement at a defined ionic strength and pH. However, extremely stringent conditions may employ hybridization and/or washing at 1, 2, 3, or 4°C below the thermal melting point (Tm); moderately stringent conditions may employ hybridization and/or washing at 6, 7, 8, 9, or 10°C below the thermal melting point (Tm); and low stringency conditions may employ hybridization and/or washing at 11, 12, 13, 14, 15, or 20°C below the thermal melting point (Tm). Those of ordinary skill in the art will appreciate that, using the equation, hybridization and wash compositions, and desired Tm, variations in the stringency of the hybridization and/or wash solutions are inherently described. An extensive guide to nucleic acid hybridization is available in Tijssen (1993) Laboratory Techniques in Biochemistry and Molecular Biology—Hybridization with Nucleic Acid Probes, Part I, Chapter 2 (Elsevier, New York); and Ausubel et al., eds. (1995) Current Protocols in Molecular Biology, Chapter 2 (Greene Publishing and Wiley-Interscience, New York). See Sambrook et al. (1989) Molecular Cloning: A Laboratory Manual (2nd ed., Cold Spring Harbor Laboratory Press, Plainview, New York).

In certain embodiments, the sequence-specific DNA binding polypeptide is an RNA-guided DNA binding polypeptide (RGDBP). As used herein, the terms "RNA-guided DNA binding polypeptide" and "RGDBP" refer to a polypeptide that can bind to DNA via hybridization of an associated RNA molecule with a target DNA sequence.

In some embodiments, the DNA binding polypeptide of the fusion protein is a nuclease, e.g., a sequence-specific nuclease. As used herein, the term "nuclease" refers to an enzyme that catalyzes the cleavage of phosphodiester bonds between nucleotides in a nucleic acid molecule. In some embodiments, the DNA binding polypeptide is an endonuclease, which is capable of cleaving phosphodiester bonds between nucleotides within a nucleic acid molecule, and in certain embodiments, the DNA binding polypeptide is an exonuclease, which is capable of cleaving nucleotides at either end (5' or 3') of a nucleic acid molecule. In some embodiments, the sequence-specific nuclease is selected from the group consisting of a meganuclease, a zinc finger nuclease, a TAL effector DNA binding domain nuclease fusion protein (TALEN), and an RNA-guided nuclease (RGN) or a variant thereof in which the nuclease activity has been reduced or inhibited.

As used herein, the term "meganuclease" or "nesting endonuclease" refers to an endonuclease that binds to a recognition site of 12 to 40 bp in length within double-stranded DNA. Non-limiting examples of meganucleases are those belonging to the LAGLIDADG family that includes the conserved amino acid motif LAGLIDADG (SEQ ID NO: 700). The term "meganuclease" may refer to a dimeric or single-chain meganuclease.

As used herein, the term "zinc finger nuclease" or "ZFN" refers to a chimeric protein that includes a zinc finger DNA binding domain and a nuclease domain.

As used herein, the term "TAL effector DNA binding domain nuclease fusion protein" or "TALEN" refers to a chimeric protein comprising a TAL effector DNA binding domain and a nuclease domain.

In certain embodiments, the DNA-binding polypeptide is a DNA-binding polypeptide capable of generating a single-stranded region within a double-stranded DNA molecule. An example of a single-stranded region is a single-stranded loop included within an R-loop, which is a three-stranded nucleic acid structure that includes a region of single-stranded DNA that is formed within a double-stranded DNA molecule resulting from hybridization of complementary strands with a single-stranded RNA or DNA molecule. Adenine within the single-stranded region of the R-loop or adenine adjacent to the single-stranded region of the R-loop can be deaminated by an adenine deaminase that is active on single-stranded nucleic acids (e.g., ssDNA). In some of these embodiments, the DNA-binding polypeptide capable of generating an R-loop within a double-stranded DNA molecule is an RNA-guided DNA-binding polypeptide or an RGN nuclease. As used herein, the term "RNA-guided nuclease" or "RGN" refers to an RNA-guided DNA-binding polypeptide having nuclease activity. RGNs are considered "RNA-guided" because the guide RNA forms a complex with the RNA-guided nuclease to direct the RNA-guided nuclease to bind to a target sequence and, in some embodiments, introduce a single-stranded or double-stranded break at the target sequence.

Although RGNs are capable of cleaving a target sequence immediately upon binding, the term RGN also encompasses RGNs that are capable of binding to but not cleaving a target sequence without nuclease activity. The term "cleave" or "cleavage" refers to the hydrolysis of at least one phosphodiester bond within the backbone of one or both strands of a double-stranded target sequence (e.g., a target DNA sequence) (which can result in single-strand or double-strand breaks within the target DNA sequence). Cleavage of a target sequence by an RGN can result in single-strand or double-strand breaks. RGNs that are only capable of cleaving a single strand of a double-stranded target nucleic acid molecule are referred to herein as nickases. Such RGNs have a single functional nuclease domain. The RGN nickase may be an RGN protein that naturally cleaves both strands of a double-stranded nucleic acid molecule or a naturally occurring nickase that has been mutated in one or more nuclease domains such that the nuclease activity of the mutated domains is reduced or eliminated to become a nickase.

RNA-guided nucleases (RGNs) allow targeted manipulation at a single site within the genome and are useful in therapeutic and research applications in the context of gene targeting. RNA-guided nucleases have been used for genome engineering in various organisms, including mammals, by stimulating nonhomologous end joining or homologous recombination. RGNs include CRISPR-Cas proteins, which are RNA-guided nucleases that are directed to a target sequence by a guide RNA (gRNA) as part of the clustered regularly interspaced short palindromic repeat (CRISPR) RNA-guided nuclease system, or active variants or fragments thereof.

Some aspects of this disclosure provide fusion proteins comprising an RNA-guided DNA-binding polypeptide and a deaminase polypeptide (e.g., an adenine deaminase polypeptide). In some embodiments, the RNA-guided DNA-binding polypeptide is an RNA-guided nuclease (RGN). In other embodiments, the RNA-guided nuclease is a naturally occurring CRISPR-Cas protein or an active variant or fragment thereof. CRISPR-Cas systems are classified as either Class 1 or Class 2 systems. Class 2 systems include single effector nucleases and include Types II, V, and VI. Class 1 and Class 2 systems are subdivided into types (Type I, II, III, IV, V, VI), and some types are further subdivided into subtypes (e.g., Type II-A, Type II-B, Type II-C, Type V-A, Type V-B).

In certain embodiments, the RGN is a naturally occurring type II CRISPR-Cas protein or an active variant or fragment thereof. As used herein, the term "type II CRISPR-Cas protein", "type II CRISPR-Cas effector protein" or "type II RNA-guided nuclease" refers to an RGN that requires a trans-activating RNA (tracrRNA) and includes two nuclease domains (i.e., RuvC and HNH), each of which is responsible for cleaving a single strand of a double-stranded DNA molecule. In some embodiments, the present invention provides a fusion protein comprising a currently disclosed deaminase (whose sequence is shown in SEQ ID NO: 415) fused to a Cas9 protein (e.g., Streptococcus pyocyaneus Cas9 (SpCas9)), or a SpCas9 nickase, which is described in U.S. Patent Nos. 10,000,772 and 8,697,359, each of which is incorporated herein by reference in its entirety. In some embodiments, the present invention provides a fusion protein comprising a currently disclosed deaminase (whose sequence is shown in SEQ ID NO: 701) fused to Streptococcus thermophilus Cas9 (StCas9), or a StCas9 nickase, which is disclosed in U.S. Patent No. 10,113,167, which is incorporated herein by reference in its entirety. In some embodiments, the present invention provides a fusion protein comprising the presently disclosed deaminase (as shown in SEQ ID NO: 702) fused to Staphylococcus aureus Cas9 (SaCas9), or SaCas9 nickase, which is disclosed in U.S. Patent No. 9,752,132, which is incorporated herein by reference in its entirety.

In some embodiments, the CRISPR-Cas protein is a naturally occurring type V CRISPR-Cas protein or an active variant or fragment thereof. As used herein, the term "V-type CRISPR-Cas protein", "V-type CRISPR-Cas effector protein" or "V-type RNA-guided nuclease" refers to an RGN that cleaves dsDNA and includes a single RuvC nuclease domain or a segmented RuvC nuclease domain and lacks an HNH domain (Zetsche et al. 2015, Cell doi:10.1016/j.cell.2015.09.038; Shmakov et al. 2017, Nat Rev Microbiol doi:10.1038/nrmicro.2016.184; Yan et al. 2018, Science doi:10.1126/science.aav7271; Harrington et al. 2018, Science doi:10.1126/science.aav4294). In some embodiments, the fusion protein disclosed herein includes Cas12 (e.g., Cas12a). It should be noted that Cas12a is also known as Cpf1 and does not require tracrRNA, although other V-type CRISPR-Cas proteins such as Cas12b do require tracrRNA. Most V-type effectors can also target ssDNA (single-stranded DNA), often without the requirement for a PAM (Zetsche et al. 2015; Yan et al. 2018; Harrington et al. 2018). The terms "V-type CRISPR-Cas protein" and "V-type RGN" encompass unique RGNs that include a segmented RuvC nuclease domain, such as those disclosed in WO 2021/138247, the contents of each application are incorporated herein by reference in their entirety. In some embodiments, the present invention provides a fusion protein comprising a presently disclosed deaminase fused to Francisella novicida Cas12a (FnCas12a) (whose sequence is shown in SEQ ID NO: 703 and disclosed in U.S. Patent No. 9,790,490, which is incorporated herein by reference in its entirety) or any of the nuclease-inactive mutants of FnCas12a disclosed in U.S. Patent No. 9,790,490.

In some embodiments, the CRISPR-Cas protein is a naturally occurring Type VI CRISPR-Cas protein or an active variant or fragment thereof. As used herein, the term "Type VI CRISPR-Cas protein", "Type VI CRISPR-Cas effector protein" or "Type VI RGN" refers to a CRISPR-Cas effector protein that does not require tracrRNA and includes two HEPN domains that cleave RNA. In some embodiments, the present invention provides a fusion protein comprising a currently disclosed deaminase fused to Cas13.

In some embodiments, the fusion proteins currently disclosed include RGN, or a nickase or nuclease-inactive variant thereof, as disclosed in International Application Publication Nos. WO 2019/236566, WO 2020/139783, WO 2021/030344, WO 2021/138247, WO 2021/231437, or WO 2021/217002, or International Application No. PCT/IB2023/058160 filed on August 12, 2023, each of which is incorporated herein by reference in its entirety.

In some embodiments, the presently disclosed fusion proteins include RGNs listed in Table 1 and/or as shown in SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699 or nickases, or variants thereof without nuclease activity. Guide RNA sequences (crRNA repeats and tracrRNA sequences) and common PAM sequences that can be used with each RGN in Table 1 are also provided. In certain embodiments, the fusion proteins include active variants (active variants capable of binding to nucleic acid molecules in an RNA-guided manner) of RGNs listed in Table 1 and/or as shown in SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699, which are active variants that are incompatible with RGNs listed in Table 1 and/or as shown in SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699. Any of the amino acid sequences shown in NOs: 1-4, 49-162, 435, 575, 576, 698, and 699 has between 80% and 99% or higher sequence identity (including but not limited to about or more than about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more). In some embodiments, the fusion protein comprises an RGN having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity to the RGN amino acid sequences disclosed in Table 1 and/or as set forth in SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699. In other embodiments, the fusion protein comprises a fragment of the RGN listed in Table 1, such as a fragment that differs by as few as 1-15 amino acid residues, as few as 1-10 (e.g., 6-10), as few as 5, as few as 4, as few as 3, as few as 2, or as few as 1 amino acid residue. In specific embodiments, the RGN comprises an N-terminal or C-terminal truncation, which may include at least a deletion of 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 amino acids or more from the N-terminus or C-terminus of the polypeptide. In some embodiments, the RGN comprises an internal deletion, which may include at least a deletion of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60 amino acids or more. Table 1. Non-limiting examples of RNA-guided nucleases RGN Name RGN SEQ ID NO: crRNA repeat sequence tracrRNA PAM APG05083.1 60 432 433 434 APG07433.1 1 416 417 418 APG07513.1 435 436 437 438 APG08290.1 57 439 440 441 APG05459.1 58 442 443 444 APG04583.1 61 445 446 447 APG01688.1 62 448 449 450 APG00969 63 451 452 453 APG03128 64 454 455 456 APG09748 140 457 458 459 APG00771 65 460 461 462 APG02789 141 463 464 465 APG09106 142 466 467 468 APG05733.1 66 469 470 471 APG06207.1 67 472 473 474 APG01647.1 68 475 476 477 APG08032.1 69 478 479 480 APG05712.1 70 481 482 483 APG01658.1 71 484 485 486 APG06498.1 72 487 488 489 APG09106.1 142 466 467 468 APG09882.1 73 493 494 495 APG02675.1 74 496 497 498 APG01405.1 75 499 500 501 APG06250.1 76 502 503 504 APG06877.1 77 505 506 507 APG09053.1 78 508 509 510 APG04293.1 79 511 512 513 APG01308.1 80 514 515 516 APG06646.1 81 517 518 519 APG09624 144 520 521 ND APG05405 146 522 523 ND APG06622 82 524 525 526 APG02787 83 527 528 529 APG06248 84 530 531 532 APG06007 85 533 534 535 APG02874 86 536 537 538 APG03850 87 539 540 541 APG07553 88 542 543 544 APG03031 89 545 546 547 APG09208 90 548 549 550 APG05586 2 419 420 421 APG08770 91 551 552 553 APG08167 92 554 555 556 APG01604 3 422 423 424 APG03021 93 557 558 559 APG06015 94 560 561 562 APG09344 95 563 564 565 APG07991 96 566 567 568 APG01868 97 569 570 571 APG02998 98 572 573 574 APG09298 99 419 420 421 APG06251 100 419 420 421 APG03066 101 419 420 421 APG01560 102 419 420 421 APG02777 103 419 420 421 APG05761 104 419 420 421 APG02479 105 419 420 421 APG08385 106 419 420 421 APG09217 107 419 420 421 APG06657 108 419 420 421 APG05586 171 419 420 421 APG07433.1 deletion variant 575 416 417 418 APG08290.1 deletion variant 576 439 440 441 LPG10134 109 163 175 NGG LPG10136 110 164 176 NNNNCC LPG10138 111 165 177 NNNNC LPG10139 112 166 178 NNNNC LPG10141 113 167 179 NGGNR LPG10145 4 168 180 NNGG LPG10146 114 169 181 NNRNNAY LPG10147 115 170 182 NNAAT LPG10150 116 171 183 NNRRW LPG10155 117 172 184 NNAAT LPG10159 118 173 185 NRAAR LPG10160 119 174 186 NAAT LPG10165 120 187 208 nnnnGRRA LPG10166 121 188 209 nnnAAC, nnnAAA, nnnCAC, nnnnCAC LPG10167 122 189 210 CC LPG10168 123 190 211 CC LPG10169 124 191 212 nnGAA LPG10171 125 192 213 nnnnGnnA LPG10186 126 193 214 nV LPG10190 127 194 215 nnnnCCD、nnnnCTG LPG10191 128 195 216 nAHAAY LPG10194 129 196 217 VGG LPG10195 130 197 218 NNRA LPG10196 131 198 219 NNNYTT LPG10197 132 199 220 nv LPG10198 133 200 221 nnnnCMAA LPG10200 134 201 222 nG LPG10203 135 202 223 nnnnGGG LPG10204 136 203 224 nnnnGTG, nnnnGCGA LPG10205 137 204 or 205 225 or 226 nnnnGTG, nnnnGCGA LPG10207 138 206 227 CC LPG10208 139 207 228 nnnnGTG, nnnnGCGA *ND: Not Determined

The RGN composition of the fusion protein disclosed in the present invention can be APG07433.1 (disclosed in International Patent Publication No. WO 2019/236566, which is incorporated herein by reference in its entirety; and as shown in SEQ ID NO: 1), APG05586 (disclosed in International Patent Publication No. WO 2021/217002, which is incorporated herein by reference in its entirety; and as shown in SEQ ID NO: 2), APG01604 (disclosed in International Patent Publication No. WO 2021/217002, which is incorporated herein by reference in its entirety; and as shown in SEQ ID NO: 3), LPG10145 (disclosed in International Patent Publication No. WO 2023/139557, which is incorporated herein by reference in its entirety; and as shown in SEQ ID NO: 4), LPG10196 (disclosed in international application No. PCT/IB2023/058160 filed on August 12, 2023, which is incorporated herein by reference in its entirety; and as shown in SEQ ID NO: 131); or an active fragment or variant thereof (capable of binding to a nucleic acid molecule in an RNA-guided manner), such as a nickase variant thereof.

The RGN can have between 80% and 99% or more sequence identity (retaining RGN activity) to any of SEQ NOS: 1, 2, 3, 4, and 131, including but not limited to at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more. In certain embodiments, the fusion protein includes an RGN having 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more sequence identity (retaining RGN activity) to any of SEQ NOS: 1, 2, 3, 4, and 131. The fusion protein may include an active fragment of an RGN as set forth in any one of SEQ ID NOs: 1, 2, 3, 4, and 131, such as an active fragment that differs from any one of SEQ ID NOs: 1, 2, 3, 4, and 131 by as few as 1-15 amino acid residues, as few as 1-10 (e.g., 6-10), as few as 5, as few as 4, as few as 3, as few as 2, or as few as 1 amino acid residue. In certain embodiments, the active RGN fragment includes an N-terminal or C-terminal truncation, which may include at least a deletion of 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 amino acids or more from the N-terminus or C-terminus of the polypeptide set forth in any one of SEQ ID NOs: 1, 2, 3, 4, and 131. In some embodiments, the active RGN variant or fragment comprises an internal deletion, which internal deletion may include at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60 amino acids or more of any one of SEQ ID NOs: 1, 2, 3, 4, and 131. The active fragment of RGN may include at least 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050 or more consecutive amino acid residues of the amino acid sequence shown in any one of SEQ ID NOs: 1, 2, 3, 4, and 131.

In some embodiments, the RGN of the fusion protein is an RGN nickase that includes a mutation (e.g., a D10A mutation, wherein the amino acid numbering is based on the Streptococcus pyocyaneus Cas9 sequence as set forth in SEQ ID NO: 415) that enables the RGN to cleave only the non-base-edited target strand of the nucleic acid duplex (the strand that includes the PAM and base-pairs with the gRNA). The nickase that includes the D10A mutation, or an equivalent mutation, has an inactive RuvC nuclease domain and cleaves the targeted strand. The D10A nickase is unable to cleave the non-target strand of the DNA, i.e., the strand where base editing is desired. In these embodiments, the RGN nicks the target strand, while the complementary non-target strand is modified by the deaminase. Using the modified non-target strand as a template, the cell's DNA repair machinery repairs the nicked target strand, thereby introducing the mutation into the DNA.

Thus, in some embodiments, the nickase includes an inactive RuvC domain. The RuvC domain has an RNase H fold structure (see, e.g., Nishimasu et al. (2014) Cell 156(5):935-949, which is incorporated by reference in its entirety). The RuvC domain of an RGN is often a segmented RuvC domain that includes two or more non-adjacent regions in a linear amino acid sequence. For example, the RuvC domain of Streptococcus pyocyaneus Cas9 includes amino acid residues 1-59, 718-769, and 909-1098 of SEQ ID NO: 415. A non-limiting example of a mutation within the RuvC domain that does not activate its nuclease activity is the D10A mutation, which mutates the first aspartate residue in the segmented RuvC nuclease domain. nAPG07433.1 (as shown in SEQ ID NO: 49) is a nickase variant (with an inactive RuvC domain) of APG07433.1 as shown in SEQ ID NO: 1 and described in WO 2019/236566 (incorporated herein by reference in its entirety). nAPG05586 (as shown in SEQ ID NO: 50) is a nickase variant (with an inactive RuvC domain) of APG05586 (as shown in SEQ ID NO: 2). nAPG01604 (as shown in SEQ ID NO: 51) is a nickase variant of APG01604 (as shown in SEQ ID NO: 3) (with an inactive RuvC domain). nLPG10145 (as shown in SEQ ID NO: 52) is a nickase variant of LPG10145 (as shown in SEQ ID NO: 4) (with an inactive RuvC domain). nLPG10196 (as shown in SEQ ID NO: 698) is a nickase variant of LPG10196 (as shown in SEQ ID NO: 131) (with an inactive RuvC domain).

In some embodiments, the RGN of the fusion protein is an RGN nickase that includes a mutation (e.g., an H840A mutation, where the amino acid numbering is based on the Streptococcus pyogenes Cas9 sequence as set forth in SEQ ID NO: 415) that enables the RGN to cleave only the non-target strand (the strand that does not include a PAM and does not base pair with a gRNA) of a nucleic acid duplex. In some of these embodiments, the nickase includes an inactive HNH nuclease domain. The HNH nuclease domain of the RGN has a ββα metallo-fold (see, e.g., Nishimasu et al. 2014). For example, the HNH nuclease domain of the Streptococcus pyogenes Cas9 includes amino acid residues 775-908 of SEQ ID NO: 415. A non-limiting example of a mutation in the HNH domain that does not activate its nuclease activity is the H840A mutation that mutates the first histidine of the HNH nuclease domain. RGNs with inactive HNH domains act on non-target strands. nAPG07433.1 (as shown in SEQ ID NO: 56) is a nickase variant (with an inactive HNH domain) of APG07433.1 as shown in SEQ ID NO: 1 and described in WO 2019/236566 (incorporated herein by reference in its entirety). nAPG05586 (as shown in SEQ ID NO: 53) is a nickase variant (with an inactive HNH domain) of APG05586 (as shown in SEQ ID NO: 2). nAPG01604 (as shown in SEQ ID NO: 54) is a nickase variant of APG01604 (as shown in SEQ ID NO: 3) (with an inactive HNH domain). nLPG10145 (as shown in SEQ ID NO: 55) is a nickase variant of LPG10145 (as shown in SEQ ID NO: 4) (with an inactive HNH domain). nLPG10196 (as shown in SEQ ID NO: 699) is a nickase variant of LPG10196 (as shown in SEQ ID NO: 131) (with an inactive HNH domain).

Methods for inactivating the RuvC and/or HNH domains of RGNs are known in the art and generally include mutating the first aspartic acid in a segmented RuvC domain and/or the first histidine in a HNH domain. Generally, the aspartic acid residue or the histidine residue is mutated to an alanine. Other amino acid residues in the RuvC domain that can be mutated to inactivate the nuclease activity of the domain include Glu762, His983, and Asp986 (generally alanine), where the amino acid numbering is based on the Streptococcus pyogenes Cas9 sequence as set forth in SEQ ID NO: 415. Other amino acid residues in the HNH domain that can be mutated include D839 and N863 (generally alanine), where the amino acid numbering is based on the Streptococcus pyogenes Cas9 sequence as set forth in SEQ ID NO: 415.

Unless otherwise stated, when the nomenclature "n" is used followed by the name of the nuclease, this refers to a nickase in which the RuvC domain has been inactivated (e.g., with a D10A mutation).

In some embodiments, the fusion protein comprises an RGN nickase that retains nickase activity, the RGN nickase comprising an amino acid sequence having about 60% to about 99.5% identity to any one of SEQ ID NOs: 49-56, 698, and 699. In some embodiments, the RGN nickase that retains nickase activity comprises an amino acid sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identity to any one of SEQ ID NOs: 49-56, 698, and 699.

In some embodiments, the fusion protein comprises an RGN nickase comprising an amino acid sequence having between 80% and 99% or more (including but not limited to at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more) sequence identity to any one of SEQ ID NOs: 49-56, 698, and 699.

In some embodiments, the RGN of the fusion protein is nuclease-inactive. As used herein, an RGN protein that has been mutated to become nuclease-inactive or "inactive" with a nuclease may be referred to as an RNA-guided DNA-binding polypeptide or a nuclease-inactive RGN or a nuclease-inactive RGN. Methods for generating nuclease-inactive RGNs are known in the art and generally include mutating a sole nuclease domain or all nuclease domains of the RGN to render the nuclease domain(s) inactive. In those embodiments where the RGN includes only a single nuclease domain (e.g., a RuvC domain), the nuclease-inactive variant will have at least one mutation within the RuvC domain that renders the RuvC nuclease domain inactive. In those embodiments where the RGN comprises more than one nuclease domain (e.g., a RuvC domain and a HNH domain), at least one mutation in each of the RuvC domain and the HNH domain inactivates the nuclease domains of both.

An exemplary suitable nuclease-inactive RGN is the D10A/H840A Cas9 mutant (see, e.g., Qi et al., Cell . 2013; 152(5): 1173-83, the entire contents of which are incorporated herein by reference). In addition, suitable nuclease-inactive variants of other known RNA-guided nucleases (RGNs) can be determined.

Other exemplary suitable nuclease-inactive RGN variants include, but are not limited to, D10A/D839A/H840A, and D10A/D839A/H840A/N863A mutant domains (see, e.g., Mali et al., Nature Biotechnology . 2013; 31(9):833-838, the entire contents of which are incorporated herein by reference).

Based on the present disclosure and the knowledge in the art, other suitable RGN proteins that are mutated into nickases or inactive nucleases will be apparent to one of ordinary skill in the art (such as, for example, the RGNs disclosed in PCT Publication No. WO 2019/236566, which is incorporated herein by reference in its entirety) and are within the scope of this disclosure.

Any method known in the art for introducing mutations into amino acid sequences (e.g., PCR-mediated mutagenesis and site-directed mutagenesis) can be used to generate nickase or nuclease-inactive RGNs. See, e.g., U.S. Publication No. 2014/0068797 and U.S. Patent No. 9,790,490; each of which is incorporated herein by reference in its entirety.

Fusion proteins of the present invention including RGNs utilize a guide RNA that is composed of an RGN that binds to the fusion protein and guides the fusion protein to a target sequence. The term "guide RNA" refers to a nucleotide sequence that is sufficiently complementary to a target nucleotide sequence to hybridize with the target sequence and guide the sequence-specific binding of an associated RGN to the target nucleotide sequence. More specifically, when the target nucleotide sequence is double-stranded, such as in the case of DNA, the target nucleotide sequence is composed of a target strand (which includes a PAM sequence) and a non-target strand. In these embodiments, the guide RNA is sufficiently complementary to the non-target strand of a double-stranded target sequence (e.g., a target DNA sequence) such that the guide RNA hybridizes with the non-target strand and guides the sequence-specific binding of an associated RGN-guided nuclease (RGN) to a target sequence (e.g., a target DNA sequence). Thus, in some embodiments, the guide RNA comprises a spacer that is identical to the sequence of the target strand, except that uracil (U) is substituted for thymidine (T) in the guide RNA.

A guide RNA is one or more RNA molecules (typically, one or two) that can bind to an RGN and guide the RGN to bind to a specific target nucleotide sequence, and in those examples where the RGN has nickase or nuclease activity, also cleave the target nucleotide sequence. Guide RNAs include CRISPR RNA (crRNA) and in some embodiments include transactivated CRISPR RNA (tracrRNA). In some embodiments, a portion of the guide RNA includes DNA nucleotides. In certain embodiments, the guide RNA includes artificial, non-naturally occurring nucleotide analogs or one or more nucleotides are chemically modified (including modifications described in International Application No. PCT/IB2023/058418, filed on August 25, 2023, which is incorporated herein by reference in its entirety).

CRISPR RNA includes a spacer sequence and a CRISPR repeat sequence. A "spacer sequence" is a nucleotide sequence that directly hybridizes with a non-target strand of a target sequence of interest. The spacer sequence is engineered to fully or partially complement the target sequence of interest. In various embodiments, the spacer sequence includes about 8 nucleotides to about 30 nucleotides or more nucleotides. For example, the length of the spacer sequence can be about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, or more nucleotides. In some embodiments, the length of the spacer sequence is 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more nucleotides. In some embodiments, the length of the spacer sequence is about 10 to about 26 nucleotides, or about 12 to about 30 nucleotides in length. In some embodiments, the length of the spacer sequence is about 30 nucleotides. In some embodiments, the length of the spacer sequence is 30 nucleotides. In some embodiments, the degree of complementarity between a spacer sequence and its corresponding target sequence, when optimally aligned using a suitable alignment algorithm, is between 50% and 99% or higher, including but not limited to about or greater than about 50%, about 60%, about 70%, about 75%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or more. In some embodiments, the degree of complementarity between a spacer sequence and its corresponding target sequence when optimally aligned using a suitable alignment algorithm is 50%, 60%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more. In some embodiments, the intervening sequence contains no secondary structure predictable using any suitable polynucleotide folding algorithm known in the art, including but not limited to mFold (see, e.g., Zuker and Stiegler (1981) Nucleic Acids Res . 9:133-148) and RNAfold (see, e.g., Gruber et al. (2008) Cell 106(1):23-24).

The CRISPR RNA repeat sequence comprises a nucleotide sequence that forms a structure recognized by the RGN molecule alone or in combination with a hybridized tracrRNA. In various embodiments, the CRISPR RNA repeat sequence comprises about 8 nucleotides to about 30 nucleotides or more. In some embodiments, the CRISPR RNA repeat sequence comprises 8 nucleotides to 30 nucleotides or more. For example, the length of the CRISPR repeat sequence can be about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, or more nucleotides. In some embodiments, the CRISPR repeat sequence is 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more nucleotides in length. In some embodiments, the degree of complementarity between a CRISPR repeat sequence and its corresponding tracrRNA sequence, when optimally aligned using a suitable alignment algorithm, is between 50% and 99% or higher, including but not limited to about or greater than about 50%, about 60%, about 70%, about 75%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more. In some embodiments, the degree of complementarity between a CRISPR repeat sequence and its corresponding tracrRNA sequence is 50%, 60%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more.

In some embodiments, the guide RNA further comprises a tracrRNA molecule. The transactivated CRISPR RNA or tracrRNA molecule comprises a nucleotide sequence comprising a region having sufficient complementarity to hybridize with the CRISPR repeat sequence of the crRNA, which is referred to herein as an anti-repeat region. In some embodiments, the tracrRNA molecule further comprises a region having a secondary structure (e.g., stem-loop), or forms a secondary structure when hybridized with the crRNA corresponding thereto. In some embodiments, the region of the tracrRNA that is fully or partially complementary to the CRISPR repeat sequence comprises a secondary structure at the 5' end of the molecule and the 3' end of the tracrRNA. This secondary structure region generally comprises several hairpin structures found adjacent to the anti-repeat sequence, including a nexus hairpin. There is often a terminal hairpin at the 3' end of the tracrRNA, which varies in structure and number, but often includes a GC-rich Rho-independent transcriptional terminator hairpin followed by a run of U's at the 3' end. See, e.g., Briner et al. (2014) Molecular Cell 56:333-339, Briner and Barrangou (2016) Cold Spring Harb Protoc ; doi: 10.1101/pdb.top090902, and U.S. Publication No. 2017/0275648, each of which is incorporated herein by reference in its entirety.

In various embodiments, the anti-repeat region of the tracrRNA that is fully or partially complementary to the CRISPR repeat sequence comprises about 6 nucleotides to about 30 nucleotides or more nucleotides. For example, the length of the base pairing region between the tracrRNA anti-repeat sequence and the CRISPR repeat sequence can be about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, or more nucleotides. In some embodiments, the length of the base pairing region between the tracrRNA anti-repeat sequence and the CRISPR repeat sequence can be 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more nucleotides. In some embodiments, the length of the anti-repeat region of the tracrRNA that fully or partially complements the CRISPR repeat sequence is about 10 nucleotides. In some embodiments, the length of the anti-repeat region of the tracrRNA that fully or partially complements the CRISPR repeat sequence is 10 nucleotides. In some embodiments, the degree of complementarity between a CRISPR repeat sequence and its corresponding tracrRNA anti-repeat sequence, when optimally aligned using a suitable alignment algorithm, is between about 50% and about 99%, including but not limited to about or greater than about 50%, about 60%, about 70%, about 75%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more. In some embodiments, the degree of complementarity between a CRISPR repeat sequence and its corresponding tracrRNA anti-repeat sequence when optimally aligned using a suitable alignment algorithm is at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more.

In various embodiments, the entire tracrRNA includes about 60 nucleotides to more than about 210 nucleotides. In some embodiments, the entire tracrRNA includes 60 nucleotides to more than 210 nucleotides. For example, the length of tracrRNA can be about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210 or more nucleotides. In some embodiments, the length of tracrRNA is 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 150, 160, 170, 180, 190, 200, 210 or more nucleotides. In some embodiments, the length of tracrRNA is about 100 to about 200 nucleotides, including about 95, about 96, about 97, about 98, about 99, about 100, about 105, about 106, about 107, about 108, about 109, and about 100 nucleotides. In some embodiments, the tracrRNA is 100 to 110 nucleotides in length, including 95, 96, 97, 98, 99, 100, 105, 106, 107, 108, 109, and 110 nucleotides in length.

The guide RNA forms a complex with an RNA-guided DNA-binding polypeptide or an RNA-guided nuclease, or a fusion protein including the foregoing, to guide the RNA-guided nuclease, or a fusion protein including the foregoing, to bind to the target sequence. If the guide RNA is complexed with the RGN, the bound RGN introduces a single-stranded or double-stranded break at the target sequence. After the target sequence has been sheared, the break can be repaired so that the DNA sequence of the target sequence is modified during the repair process. Provided herein are methods for modifying a target sequence in the DNA of a host cell using a mutant variant of an RNA-guided nuclease (linked to an alkali editing polypeptide (e.g., a deaminase) or a lead editing polypeptide that is an inactive nuclease or nickase). Mutant variants of RNA-guided nucleases in which the nuclease activity is inactivated or significantly reduced can be referred to as RNA-guided DNA-binding polypeptides (RGDBPs) because the polypeptide is able to bind to but not necessarily cleave the target sequence. RNA-guided nucleases that can only cleave a single strand of a double-stranded nucleic acid molecule are referred to herein as nickases.

The target nucleotide sequence is bound by an RNA-guided DNA-binding polypeptide (e.g., RGN) and hybridized with a guide RNA (e.g., RGN) associated with RBDBP. If the RBDBP has nuclease activity (i.e., is an RGN) (including activity as a nickase), the target sequence can then be cleaved.

The guide RNA may be a single guide RNA or a dual guide RNA system. A single guide RNA includes crRNA and optionally tracrRNA on a single RNA molecule, while a dual guide RNA system includes crRNA and tracrRNA present on two different RNA molecules, which are hybridized to each other through at least a portion of the CRISPR repeat sequence of the crRNA and at least a portion of the tracrRNA that can fully or partially complement the CRISPR repeat sequence of the crRNA. In some embodiments of those embodiments in which the guide RNA is a single guide RNA, the crRNA and optionally the tracrRNA are separated by a linker nucleotide sequence.

Suitable crRNA repeat sequences, tracrRNA and guide RNA sequences of the RGN components of the currently disclosed fusion proteins are disclosed in International Patent Publication Nos. WO 2019/236566, WO 2021/030344, WO 2020/139783, WO 2021/217002, WO 2021/138247, WO 2021/231437, WO 2023/139557, and PCT International Application No. PCT/IB2023/058160 filed on August 12, 2023, each of which is incorporated by reference in its entirety and/or provided in Table 1.

Typically, to avoid the formation of secondary structures within the nucleotides of the linker nucleotide sequence or to avoid the formation of secondary structures including the nucleotides of the linker nucleotide sequence, the linker nucleotide sequence between crRNA and tracrRNA is a linker nucleotide sequence that does not include complementary bases. In some embodiments, the length of the linker nucleotide sequence between crRNA and tracrRNA is at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, or more nucleotides. In some embodiments, the length of the linker nucleotide sequence between crRNA and tracrRNA is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more nucleotides. In some embodiments, the length of the linker nucleotide sequence of a single guide RNA is at least 4 nucleotides. In some embodiments, the length of the linker nucleotide sequence of a single guide RNA is 4 nucleotides.

In certain embodiments, the guide RNA can be introduced into a target cell, organelle, or embryo as an RNA molecule. The guide RNA can be transcribed in vitro or chemically synthesized. In some embodiments, a nucleotide sequence encoding the guide RNA is introduced into a cell, organelle, or embryo. In some embodiments, the nucleotide sequence encoding the guide RNA is operably linked to a promoter (e.g., an RNA polymerase III promoter). The promoter can be a natural promoter or heterologous to the guide RNA encoding the nucleotide sequence. In some embodiments, the promoter is selected from any of the promoters disclosed in International Application No. PCT/US2022/032940 filed on June 10, 2021, which is incorporated herein by reference in its entirety.

In various embodiments, as described herein, the guide RNA can be introduced into a target cell, organelle, or embryo as a ribonucleoprotein complex in which the guide RNA is associated with an RNA-guided nuclease polypeptide.

The guide RNA guides the associated RGBP (e.g., RGN) to a specific target nucleotide sequence of interest via hybridization of the guide RNA with the target nucleotide sequence. The target nucleotide sequence may include DNA, RNA, or a combination of both, and may be single-stranded or double-stranded. The target nucleotide sequence may be genomic DNA (i.e., chromosomal DNA), plastid DNA, or an RNA molecule (e.g., messaging RNA, ribosomal RNA, transfer RNA, microRNA, short interfering RNA). The target nucleotide sequence may be bound (and in some embodiments cleaved) in vitro or in a cell by an RNA-guided DNA-binding polypeptide. The chromosomal sequence targeted by the RGBP (e.g., RGN) may be a nuclear, chromosomal, or mitochondrial chromosomal sequence. In some embodiments, the target nucleotide sequence is unique in the target genome.

In some embodiments, the target nucleotide sequence is adjacent to a pre-spacer adjacent motif (PAM). The PAM is generally within about 1 to about 10 nucleotides from the target nucleotide sequence, including about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 nucleotides from the target nucleotide sequence. In some embodiments, the PAM is within 1 to 10 nucleotides from the target nucleotide sequence, including 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides from the target nucleotide sequence. Unless otherwise stated, the PAM is adjacent to the target nucleotide sequence, or at its 5' or 3' end. In some embodiments, the PAM is 3' of the target sequence. Generally speaking, the PAM is a common sequence of about 2-6 nucleotides, but in some embodiments the length is 1, 2, 3, 4, 5, 6, 7, 8, 9, or more nucleotides.

Suitable PAM sequences for the RGN component of the currently disclosed fusion proteins are disclosed in International Patent Publication Nos. WO 2019/236566, WO 2021/030344, WO 2020/139783, WO 2021/217002, WO 2021/138247, WO 2021/231437, WO 2023/139557, and PCT International Application No. PCT/IB2023/058160 filed on August 12, 2023 (each of which is incorporated by reference in its entirety), and/or are provided in Table 1.

The PAM restricts which sequences a given RGBP (e.g., RGN) can target because its PAM needs to be adjacent to the target nucleotide sequence. Upon recognizing its corresponding PAM sequence, the RGN can cleave the target nucleotide sequence at a specific cleavage site. As used herein, a cleavage site consists of two specific nucleotides within the target nucleotide sequence, and the nucleotide sequence between them is cleaved by the RGN. The cleavage site may include the 1st and 2nd, 2nd and 3rd, 3rd and 4th, 4th and 5th, 5th and 6th, 7th and 8th, or 8th and 9th nucleotides from the PAM in the 5' or 3' direction. Because the RGN can cleave the target nucleotide sequence, resulting in staggered ends, in some embodiments, the cleavage site is defined based on the distance of two nucleotides on the positive (+) strand of the polynucleotide from the PAM and the distance of two nucleotides on the negative (-) strand of the polynucleotide from the PAM.

RGBP and RGN can be used to deliver fusion polypeptides, polynucleotides, or small molecule payloads to specific genomic locations.

In those embodiments in which the fusion protein comprises a meganuclease as a DNA binding component, the target sequence may comprise a pair of inverted 9 base pair "half sites" separated by four base pairs. In the case of a single-chain meganuclease, the N-terminal domain of the protein contacts the first half site, and the C-terminal domain of the protein contacts the second half site. A four base pair 3' overhang is generated by cleavage by the meganuclease. In those embodiments in which the DNA binding polypeptide comprises a compact TALEN, the recognition sequence comprises a first CNNNGN sequence recognized by the I-TevI domain, followed by a non-specific spacer of 4-16 base pairs in length, followed by a second sequence of 16-22 bp in length recognized by the TAL effector domain (this sequence typically has a 5' T base). In those embodiments where the DNA binding polypeptide component of the fusion protein includes a zinc finger, the DNA binding domain typically recognizes an 18 bp recognition sequence comprising a pair of nine base pair "half-sites" separated by 2-10 base pairs, and cleavage by nucleases generates blunt ends or 5' overhangs of variable length (usually four base pairs). III. Deaminases

Some aspects of the invention provide adenine deaminases generated by directed evolution and optimization of the previously disclosed adenine deaminase LPG50148 (shown herein as SEQ ID NO: 5, without its starting methionine), which is disclosed in International Application No. WO 2022/056254, which is incorporated herein by reference in its entirety. These evolved adenine deaminases are shown as SEQ ID NOs: 6, 300-414, 596-598, and 720-723 (again, without its starting methionine).

The term "deaminase" refers to an enzyme that catalyzes a deamination reaction. The deaminase of the present invention is a nucleobase deaminase, and the terms "deaminase" and "nucleobase deaminase" are used interchangeably herein. The deaminase may be a naturally occurring deaminase or an active fragment or variant thereof. The deaminase may be active on a single-stranded nucleic acid such as ssDNA or ssRNA or on a double-stranded nucleic acid such as dsDNA or dsRNA. In some embodiments, the deaminase can only deaminate ssDNA but has no effect on dsDNA.

The deaminases of the present invention can be used to edit DNA or RNA molecules, and can be used as a separate deaminases or as a component of a fusion protein. In some embodiments, the deaminases can be used to edit ssDNA or ssRNA molecules. Deamination of adenine, adenosine or deoxyadenosine produces inosine, which is processed by polymerase to guanine.

To date, there are no known naturally occurring adenine deaminase enzymes that deaminate adenine in DNA. Various approaches have been used to evolve and optimize adenine deaminase enzymes (ADATs) acting on tRNA proteins to be active on DNA molecules in mammalian cells (Gaudelli et al., 2017; Koblan, LW et al., 2018, Nat Biotechnol 36, 843-846; Richter, MF et al., 2020, Nat Biotechnol , doi: 10.1038/s41587-020-0562-8, each of which is incorporated herein by reference in its entirety).

In some embodiments, the currently disclosed adenine deaminase is used in combination with a cytosine deaminase that catalyzes the hydrolysis of cytosine, cytidine or deoxycytidine to uracil, such as those disclosed in International Application Nos. WO 2020/189783 and WO 2022/204093 and U.S. Application Publication No. 2022/0145296, each of which is incorporated herein by reference in its entirety.

The deaminase or its active variants or fragments disclosed herein can be introduced into cells as part of a deaminase-DNA binding polypeptide fusion and/or can be co-expressed with a DNA binding polypeptide-deaminase fusion to increase the efficiency of introducing a desired A＞N (wherein N is C, T or G) mutation (e.g., A＞G mutation) into a target DNA molecule.

The deaminase disclosed herein comprises an amino acid sequence having about 50% to about 100% identity to any one of SEQ ID NOs: 5, 6, 300-414, 596-598, and 720-723. In some embodiments, the deaminase has about 50% to about 100% identity to any one of SEQ ID NOs: 5, 6, 300-414, 596-598, and 720-723, and has at least one of the amino acid residues shown in any one of Tables 2, 4, 6, and 19. In some embodiments, the deaminase has an amino acid sequence that is at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs: 5, 6, 300-414, 596-598, and 720-723, and at least one of the amino acid residues shown in any one of Tables 2, 4, 6, and 19. In some embodiments, the deaminase comprises an amino acid sequence selected from SEQ ID NOs: 303, 319, 366, 375, 406, 596, 597, and 720. Non-limiting examples of such fusion proteins are described in the Examples section herein.

The deaminase may have at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more sequence identity with SEQ ID NO: 5, wherein the deaminase has at least one of the following amino acid residues: a) C at a position corresponding to position 2 of SEQ ID NO: 5; b) F or C at a position corresponding to position 22 of SEQ ID NO: 5; c) Q at a position corresponding to position 23 of SEQ ID NO: 5; d) N at a position corresponding to position 35 of SEQ ID NO: 5; e) L at a position corresponding to position 40 of SEQ ID NO: 5; f) Q at a position corresponding to position 46 of SEQ ID NO: 5; g) A or M at a position corresponding to position 68 of SEQ ID NO: 5; h) H at the position corresponding to position 72 of SEQ ID NO: 5; i) W, A, Q, Y, or D at the position corresponding to position 75 of SEQ ID NO: 5; j) G at the position corresponding to position 76 of SEQ ID NO: 5; k) S at the position corresponding to position 81 of SEQ ID NO: 5; l) M at the position corresponding to position 105 of SEQ ID NO: 5; m) H at the position corresponding to position 108 of SEQ ID NO: 5; n) L at the position corresponding to position 109 of SEQ ID NO: 5; o) I or L at the position corresponding to position 117 of SEQ ID NO: 5; p) F at the position corresponding to position 120 of SEQ ID NO: 5; q) E, T, A, G, or V at the position corresponding to position 121 of SEQ ID NO: 5; r) I or H at the position corresponding to position 122 of SEQ ID NO: 5; s) K at the position corresponding to position 125 of SEQ ID NO: 5; t) A at the position corresponding to position 126 of SEQ ID NO: 5; u) H at the position corresponding to position 135 of SEQ ID NO: 5; v) V at the position corresponding to position 137 of SEQ ID NO: 5; w) Y at the position corresponding to position 138 of SEQ ID NO: 5; x) L at the position corresponding to position 139 of SEQ ID NO: 5; y) K or A at the position corresponding to position 142 of SEQ ID NO: 5; z) A, Q, L, or M at the position corresponding to position 145 of SEQ ID NO: 5; aa) K at the position corresponding to position 148 of SEQ ID NO: 5; bb) Q at the position corresponding to position 151 of SEQ ID NO: 5; cc) NO:5 position corresponding to E or R; dd) SEQ ID NO:5 position corresponding to W; ee) SEQ ID NO:5 position corresponding to R or V; ff) SEQ ID NO:5 position corresponding to F; gg) SEQ ID NO:5 position corresponding to R; hh) SEQ ID NO:5 position corresponding to Q; ii) SEQ ID NO:5 position corresponding to D or W; jj) SEQ ID NO:5 position corresponding to W, H, V, or A; kk) SEQ ID NO:5 position corresponding to R; and ll) SEQ ID NO:5 position corresponding to H.

In some embodiments, the deaminase has: a) N at a position corresponding to position 35 of SEQ ID NO: 5 and W at a position corresponding to position 162 of SEQ ID NO: 5; b) N at a position corresponding to position 35 of SEQ ID NO: 5 and Q at a position corresponding to position 46 of SEQ ID NO: 5; c) S at a position corresponding to position 81 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; d) Q at a position corresponding to position 46 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; e) R at a position corresponding to position 156 of SEQ ID NO: 5 and W at a position corresponding to position 162 of SEQ ID NO: 5; f) A at a position corresponding to position 68 of SEQ ID NO: 5 and S at a position corresponding to position 81 of SEQ ID NO: 5; g) N at the position corresponding to position 35 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; h) N at the position corresponding to position 35 of SEQ ID NO: 5, Q at the position corresponding to position 46 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; i) W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; j) N at the position corresponding to position 35 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; k) N at the position corresponding to position 35 of SEQ ID NO: 5, Q at the position corresponding to position 46 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5 NO:5 position 81 corresponding to S, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; l) SEQ ID NO:5 position 68 corresponding to M, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; m) SEQ ID NO:5 position 46 corresponding to Q, SEQ ID NO:5 position 68 corresponding to M, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; n) SEQ ID NO:5 position 68 corresponding to M, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; NO:5 at a position corresponding to position 81, H at a position corresponding to position 108, R at a position corresponding to position 156, and W at a position corresponding to position 162 of SEQ ID NO:5; o) Q at a position corresponding to position 46, N at a position corresponding to position 35, M at a position corresponding to position 68 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, H at a position corresponding to position 108 of SEQ ID NO:5, W at a position corresponding to position 155 of SEQ ID NO:5, R at a position corresponding to position 156 of SEQ ID NO:5, and W at a position corresponding to position 162 of SEQ ID NO:5; p) S at a position corresponding to position 81 of SEQ ID NO:5, and W at a position corresponding to position 155 of SEQ ID NO:5; q) W at a position corresponding to position 75 of SEQ ID NO: 5, and S at a position corresponding to position 81 of SEQ ID NO: 5; r) S at a position corresponding to position 81 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; s) S at a position corresponding to position 81 of SEQ ID NO: 5, and A at a position corresponding to position 145 of SEQ ID NO: 5; t) W at a position corresponding to position 75 of SEQ ID NO: 5, and W at a position corresponding to position 155 of SEQ ID NO: 5; u) W at a position corresponding to position 155 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; v) A at a position corresponding to position 145 of SEQ ID NO: 5, and W at a position corresponding to position 155 of SEQ ID NO: 5; w) NO:5, W at the position corresponding to position 75, and D at the position corresponding to position 160 of SEQ ID NO:5; x) W at the position corresponding to position 75 of SEQ ID NO:5, and A at the position corresponding to position 145 of SEQ ID NO:5; y) A at the position corresponding to position 145 of SEQ ID NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5; z) W at the position corresponding to position 75 of SEQ ID NO:5, S at the position corresponding to position 81 of SEQ ID NO:5, and W at the position corresponding to position 155 of SEQ ID NO:5; aa) S at the position corresponding to position 81 of SEQ ID NO:5, W at the position corresponding to position 155 of SEQ ID NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5; bb) A at the position corresponding to position 145 of SEQ ID NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5; NO:5 position 81 S, SEQ ID NO:5 position 145 A, and SEQ ID NO:5 position 155 W; cc) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 81 S, and SEQ ID NO:5 position 160 D; dd) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 81 S, and SEQ ID NO:5 position 145 A; ee) SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 145 A, and SEQ ID NO:5 position 160 D; ff) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 81 S, and SEQ ID NO:5 position 145 A; gg) W at the position corresponding to position 75 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; hh) A at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ii) W at the position corresponding to position 75 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; jj) W at the position corresponding to position 75 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. NO:5 position 81 S, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; kk) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 145 A, and SEQ ID NO:5 position 155 W; ll) SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 145 A, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; mm) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 145 A, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; A at a position corresponding to position 145 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; nn) W at a position corresponding to position 75 of SEQ ID NO: 5, A at a position corresponding to position 145 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; oo) W at a position corresponding to position 75 of SEQ ID NO: 5, S at a position corresponding to position 81 of SEQ ID NO: 5, A at a position corresponding to position 145 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; pp) L at a position corresponding to position 40 of SEQ ID NO: 5, and M at a position corresponding to position 105 of SEQ ID NO: 5; qq) L at the position corresponding to position 40 of SEQ ID NO: 5, and V at the position corresponding to position 121 of SEQ ID NO: 5; rr) L at the position corresponding to position 40 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; ss) L at the position corresponding to position 40 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; tt) L at the position corresponding to position 40 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; uu) M at the position corresponding to position 105 of SEQ ID NO: 5, and V at the position corresponding to position 121 of SEQ ID NO: 5; vv) M at the position corresponding to position 105 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; ww) M at the position corresponding to position 105 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; xx) M at the position corresponding to position 105 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; yy) V at the position corresponding to position 121 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; zz) V at the position corresponding to position 121 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; aaa) V at the position corresponding to position 121 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; bbb) M at the position corresponding to position 145 of SEQ ID NO: 5, and NO:5 position corresponding to Q at position 159; ccc) M at position corresponding to position 145 of SEQ ID NO:5, and W at position corresponding to position 160 of SEQ ID NO:5; ddd) Q at position corresponding to position 159 of SEQ ID NO:5, and W at position corresponding to position 160 of SEQ ID NO:5; eee) S at position corresponding to position 81 of SEQ ID NO:5, M at position corresponding to position 145 of SEQ ID NO:5, and W at position corresponding to position 160 of SEQ ID NO:5; fff) S at position corresponding to position 81 of SEQ ID NO:5, V at position corresponding to position 121 of SEQ ID NO:5, and Q at position corresponding to position 159 of SEQ ID NO:5; ggg) A at position corresponding to position 68 of SEQ ID NO:5, and M at position corresponding to position 145 of SEQ ID NO:5, and W at position corresponding to position 160 of SEQ ID NO:5; NO:5 position 81 corresponding to S; hhh) G at the position corresponding to the position 76 of SEQ ID NO:5, and S at the position corresponding to the position 81 of SEQ ID NO:5; iii) S at the position corresponding to the position 81 of SEQ ID NO:5, and L at the position corresponding to the position 117 of SEQ ID NO:5; jjj) A at the position corresponding to the position 68 of SEQ ID NO:5, and G at the position corresponding to the position 76 of SEQ ID NO:5; kkk) A at the position corresponding to the position 68 of SEQ ID NO:5, and L at the position corresponding to the position 117 of SEQ ID NO:5; lll) G at the position corresponding to the position 76 of SEQ ID NO:5, and L at the position corresponding to the position 117 of SEQ ID NO:5; mmm) A at the position corresponding to the position 68 of SEQ ID NO:5, and G at the position corresponding to the position 76 of SEQ ID NO:5; NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; nnn) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ooo) SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ppp) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; qqq) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; rrr) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 109 corresponding to L, SEQ ID NO:5 position 153 corresponding to E, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; sss) SEQ ID NO:5 position 75 corresponding to A, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to A, SEQ ID NO:5 position 145 corresponding to W, SEQ ID NO:5 position 155 corresponding to D, and SEQ ID NO:5 position 160 corresponding to D; NO:5 position corresponding to position 160; ttt) Q at a position corresponding to position 75 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, I at a position corresponding to position 117 of SEQ ID NO:5, Q at a position corresponding to position 145 of SEQ ID NO:5, W at a position corresponding to position 155 of SEQ ID NO:5, and D at a position corresponding to position 160 of SEQ ID NO:5; uuu) Y at a position corresponding to position 75 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, L at a position corresponding to position 117 of SEQ ID NO:5, G at a position corresponding to position 121 of SEQ ID NO:5, L at a position corresponding to position 145 of SEQ ID NO:5, W at a position corresponding to position 155 of SEQ ID NO:5, and D at a position corresponding to position 160 of SEQ ID NO:5; NO:5 position 160 D; vvv) SEQ ID NO:5 position 22 C, SEQ ID NO:5 position 68 A, SEQ ID NO:5 position 75 Y, SEQ ID NO:5 position 76 G, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 108 H, SEQ ID NO:5 position 117 L, SEQ ID NO:5 position 122 H, SEQ ID NO:5 position 138 Y, SEQ ID NO:5 position 139 L, SEQ ID NO:5 position 142 A, SEQ ID NO:5 position 145 A, SEQ ID NO:5 position 146 B, SEQ ID NO:5 position 147 C, SEQ ID NO:5 position 148 D, SEQ ID NO:5 position 150 B, SEQ ID NO:5 position 151 C, SEQ ID NO:5 position 152 A, SEQ ID NO:5 position 153 B, SEQ ID NO:5 position 154 C, SEQ ID NO:5 position 155 C, SEQ ID NO:5 position 156 S, SEQ ID NO:5 position 157 R at the position corresponding to position 153 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, D at the position corresponding to position 160 of SEQ ID NO: 5, and H at the position corresponding to position 162 of SEQ ID NO: 5; or www) S at the position corresponding to position 81 of SEQ ID NO: 5.

In some embodiments, the deaminase comprises an amino acid sequence having: N at a position corresponding to position 35 of SEQ ID NO: 5; S at a position corresponding to position 81 of SEQ ID NO: 5; R at a position corresponding to position 156 of SEQ ID NO: 5; and W at a position corresponding to position 162 of SEQ ID NO: 5. In some embodiments, the deaminase comprises an amino acid sequence having: W at a position corresponding to position 75 of SEQ ID NO: 5; S at a position corresponding to position 81 of SEQ ID NO: 5; W at a position corresponding to position 155 of SEQ ID NO: 5; and D at a position corresponding to position 160 of SEQ ID NO: 5. In some embodiments, the deaminase comprises an amino acid sequence having: S at a position corresponding to position 81 of SEQ ID NO: 5; and L at a position corresponding to position 117 of SEQ ID NO: 5. In some embodiments, the deaminase comprises an amino acid sequence having: A at a position corresponding to position 68 of SEQ ID NO:5; and S at a position corresponding to position 81 of SEQ ID NO:5. In some embodiments, the deaminase comprises an amino acid sequence having: Y at a position corresponding to position 75 of SEQ ID NO:5; S at a position corresponding to position 81 of SEQ ID NO:5; L at a position corresponding to position 117 of SEQ ID NO:5; G at a position corresponding to position 121 of SEQ ID NO:5; L at a position corresponding to position 145 of SEQ ID NO:5; F at a position corresponding to position 155 of SEQ ID NO:5; and D at a position corresponding to position 160 of SEQ ID NO:5. In some embodiments, the deaminase comprises an amino acid sequence having: S at a position corresponding to position 81 of SEQ ID NO: 5; W at a position corresponding to position 155 of SEQ ID NO: 5; and D at a position corresponding to position 160 of SEQ ID NO: 5. In some embodiments, the deaminase comprises an amino acid sequence having: S at a position corresponding to position 81 of SEQ ID NO: 5; L at a position corresponding to position 109 of SEQ ID NO: 5; E at a position corresponding to position 153 of SEQ ID NO: 5; W at a position corresponding to position 155 of SEQ ID NO: 5; and D at a position corresponding to position 160 of SEQ ID NO: 5.

In some embodiments, the deaminase comprises the amino acid sequence of SEQ ID NO: 303. In some embodiments, the deaminase comprises the amino acid sequence of SEQ ID NO: 319. In some embodiments, the deaminase comprises the amino acid sequence of SEQ ID NO: 365. In some embodiments, the deaminase comprises the amino acid sequence of SEQ ID NO: 375. In some embodiments, the deaminase comprises the amino acid sequence of SEQ ID NO: 406. In some embodiments, the deaminase comprises the amino acid sequence of SEQ ID NO: 596. In some embodiments, the deaminase comprises the amino acid sequence of SEQ ID NO: 597. In some embodiments, the deaminase comprises the amino acid sequence of SEQ ID NO: 720.

In some embodiments, the deaminase consists of the amino acid sequence of SEQ ID NO: 303. In some embodiments, the deaminase consists of the amino acid sequence of SEQ ID NO: 319. In some embodiments, the deaminase consists of the amino acid sequence of SEQ ID NO: 365. In some embodiments, the deaminase consists of the amino acid sequence of SEQ ID NO: 375. In some embodiments, the deaminase consists of the amino acid sequence of SEQ ID NO: 406. In some embodiments, the deaminase consists of the amino acid sequence of SEQ ID NO: 596. In some embodiments, the deaminase consists of the amino acid sequence of SEQ ID NO: 597. In some embodiments, the deaminase consists of the amino acid sequence of SEQ ID NO: 720.

The deaminase of the present invention may have improved deaminase activity when compared to the parent LPG50148 deaminase. The improved deaminase activity can be measured by any method known in the art to measure the deamination of a nucleobase alone (e.g., adenine) or when fused to a DNA binding polypeptide (e.g., RGN).

The deaminase disclosed herein may have a nucleobase deamination efficiency that is 1.1 to 10 times, 1.1 to 20 times, 1.1 to 30 times or more higher than the parent LPG50148 deaminase, including but not limited to about 1.1 times, about 1.5 times, about 2 times, about 2.5 times, about 3 times, about 3.5 times, about 4 times, about 4.5 times, about 5 times, about 5.5 times, about 6 times, about 6.5 times, about 7 times, about 8 times, about 9 times, about 10 times, about 11 times, about 12 times, about 13 times, about 14 times, about 15 times, about 16 times, about 17 times, about 18 times, about 19 times, about 20 times, about 21 times, about 22 times, about 23 times, about 24 times, about 25 times, about 26 times, about 27 times, about 28 times, about 29 times, about 30 times, about 31 times, about 32 times, about 33 times, about 34 times, about 35 times, about 36 times, about 37 times, about 38 times, about 39 times, about 40 times, about 41 times, about 42 times, about 43 times, about 44 times, about 45 times, about 46 times, about 47 times, about 48 times, about 49 times, about 50 times, about 51 times, about 52 times, about 53 times, about 54 times, about 55 times, about 56 times, about 57 times, about 58 times, about 59 times, about 60 times, about 61 times, about 62 times, about 63 times, about 64 times, about 65 times, about 66 times, about 67 times, about about 7-fold, about 7.5-fold, about 8-fold, about 8.5-fold, about 9-fold, about 9.5-fold, about 10-fold, about 11-fold, about 12-fold, about 13-fold, about 15-fold, about 16-fold, about 17-fold, about 18-fold, about 19-fold, about 20-fold, about 21-fold, about 22-fold, about 23-fold, about 24-fold, about 25-fold, about 26-fold, about 27-fold, about 28-fold, about 29-fold, and about 30-fold. IV. Heterologous Polypeptides

In some embodiments, the presently disclosed fusion proteins include a heterologous polypeptide inserted into an RGN. A heterologous polypeptide is any polypeptide that is not naturally associated with an RGN protein. In some embodiments, the heterologous polypeptide includes a biologically active protein domain. The heterologous polypeptide may include a detectable marker, a selectable marker, or a purification tag. In some embodiments, the heterologous polypeptide is an alkali-editing polypeptide (e.g., a deaminase) or a lead editing polypeptide. A. Lead Editing Polypeptides

The heterologous polypeptide of the fusion protein disclosed herein can be a lead editing polypeptide, such as a reverse transcriptase.

Prime editing is a versatile and precise genome editing method that uses a nucleic acid-programmable DNA-binding protein that acts in association with a polymerase to write new genetic information directly into a specified DNA site (described in, e.g., US 11,447,770B1; WO2021072328; WO2021226558; WO2020156575; WO2021042047; US11193123; each of which is incorporated herein by reference in its entirety). Prime editing systems use RGNs that are nickases (typically, those in which the HNH domain has been inactivated), and the system is programmed with a prime editing (PE) guide RNA ("PEgRNA"). PEgRNA is a guide RNA that both specifies the target sequence and provides a template for polymerization of the replacement strand containing the edit by means of an extension engineered into the guide RNA (e.g., in an internal portion of the guide RNA, or at the 5' or 3' end). The RGN nickase/lead editing polypeptide fusion is guided by the PEgRNA to the target sequence and nicks the target strand upstream of the sequence to be edited and upstream of the PAM, generating a 3' flap on the target strand. The pegRNA includes a leader binding site (PBS) that is complementary to the 3' flap of the target strand. In some embodiments, the length of the PBS is at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 nucleotides. In certain embodiments, the pegRNA includes a PBS of at least 5 (e.g., at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 28, 19, or 20) nucleotides in length. In some embodiments, the pegRNA may include a PBS of at least 8 nucleotides in length. Hybridization of the PBS to the 3' flap of the target strand allows for polymerization of the replacement strand containing the edit using an extension of PEgRNA as a template. The extension of PEgRNA can be formed from RNA or DNA. In the case of RNA extension, the polymerase of the lead editor can be an RNA-dependent DNA polymerase (e.g., a reverse transcriptase). In the case of DNA extension, the polymerase of the lead editor can be a DNA-dependent DNA polymerase.

The replacement strand containing the desired edit (e.g., a single nucleobase substitution) shares the same sequence as the target strand of the target sequence to be edited (except that it includes the desired edit). Via DNA repair and/or replication mechanisms, the target strand of the target sequence is replaced by the newly synthesized replacement strand containing the desired edit. In some cases, lead editing can be considered a "search-and-replace" genome editing technology because the lead editor not only searches for and locates the desired target sequence to be edited, but also simultaneously encodes the replacement strand (which contains the desired edit that is installed in place of the corresponding target strand of the target sequence). Therefore, in some embodiments, the guide RNA that can be used in the presently disclosed compositions and methods includes an extension that includes an editing template for lead editing. In some embodiments, the lead editing polypeptide that can be fused to the RGN includes a DNA polymerase (e.g., an RNA-dependent DNA polymerase). In some embodiments, the DNA polymerase is a reverse transcriptase. In some embodiments, the RGN is a nickase, such as a nickase in which the HNH domain is inactivated. B. Base Editing Polypeptides

The heterologous polypeptide of the fusion protein disclosed herein can be a base-editing polypeptide, such as a deaminase.

In some embodiments, the deaminase component of the presently disclosed fusion proteins (wherein the deaminase is inserted into the RGN) is any one of SEQ ID NOs: 5, 6, 229-414, 596, 597, and 720-723, including those deaminases disclosed herein (SEQ ID NOs: 300-414, 596-598, and 720-723), or active fragments or variants thereof. The deaminase component can have between 80% and 99% or more sequence identity to any of SEQ ID NOs: 5, 6, 229-414, 596, 597, and 720-723 (which retains deaminase activity), including but not limited to at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more. The fusion protein may include an active fragment of a deaminase as set forth in any one of SEQ ID NOs: 5, 6, 229-414, 596, 597, and 720-723, such as an active fragment that differs from any one of SEQ ID NOs: 5, 6, 229-414, 596, 597, and 720-723 by as few as 1-15 desamine residues, as few as 1-10 (e.g., 6-10), as few as 5, as few as 4, as few as 3, as few as 2, or as few as 1 amino acid residues. In some embodiments, the deaminase inserted into the RGN has about 50% to about 100% identity to any one of SEQ ID NOs: 5, 6, 300-414, 596-598, and 720-723 and has at least one of the amino acid residues set forth in any one of Tables 2, 4, 6, and 19. In some embodiments, the deaminase has an amino acid sequence that is at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs: 5, 6, 300-414, 596-598, and 720-723 and has at least one of the amino acid residues shown in any one of Tables 2, 4, 6, and 19.

In certain embodiments, the active deaminase fragment comprises an N-terminal or C-terminal truncation, which may include a deletion of at least 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 amino acids or more from the N-terminus or C-terminus of the polypeptide set forth in any one of SEQ ID NOs: 5, 6, 229-414, 596, 597, and 720-723. The fusion protein may comprise the deaminase lacking the first and last amino acid residues compared to the parent deaminase from which the deaminase is derived, wherein the deaminase activity is retained. The fusion protein may include a deaminase lacking the first and last amino acid residues of any one of SEQ ID NOs: 5, 6, 229-414, 596, 597, and 720-723, wherein the deaminase activity is retained. In some embodiments, the active deaminase variant includes an internal deletion that may include at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60 amino acids or more of any one of SEQ ID NOs: 5, 6, 229-414, 596, 597, and 720-723. The active fragment of the deaminase may include at least 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050 or more consecutive amino acid residues of the amino acid sequence shown in any one of SEQ ID NOs: 5, 6, 229-414, 596, 597, and 720-723.

In some embodiments, the deaminase component of the presently disclosed fusion protein (wherein the deaminase is inserted into the RGN) is any one of SEQ ID Nos: 303, 319, 365, 375, 406, 597, and 720 or an active variant or fragment thereof.

An "base editor" is a fusion protein comprising an RGN operably linked to a deaminase, such that when bound to a guide RNA, the fusion protein is capable of deamidating a nucleobase of a target nucleic acid sequence (or a proximal target nucleic acid sequence). The RGN of the base editor typically comprises an RGN nickase (typically an RGN nickase with an inactive RuvC domain) or an inactive RGN that does not have nuclease activity. Base editor fusion proteins in which a deaminase has been inserted into an RGN are referred to herein as "inlaid base editors."

The presently disclosed fusion proteins may include an adenine deaminase, such as those disclosed herein (e.g., 5, 6, 248-414, 596, 597, and 720-723). Alkali editors including RGN and adenine deaminase are referred to herein as "A-based editors,""adenine alkali editors," or "ABEs" and may be used for targeted editing of nucleic acid sequences. To date, there are no known naturally occurring adenine deaminase enzymes that deaminate adenine in DNA. A variety of approaches have been used to evolve and optimize tRNA-acting adenine deaminase (ADAT) proteins to be active on DNA molecules in mammalian cells (Gaudelli et al., 2017; Koblan, LW et al., 2018, Nat Biotechnol 36, 843-846; Richter, MF et al., 2020, Nat Biotechnol , doi: 10.1038/s41587-020-0562-8, each of which is incorporated herein by reference in its entirety).

Non-limiting examples of adenine deaminase that can be used in the present invention include, but are not limited to, those disclosed in PCT International Publication No. WO 2022/056254, and SEQ ID NOs: 5, 6, 248-414, 596, 597, and 720-723 or active variants or fragments thereof.

Adenine base editors (ABEs) include RGNs and adenine deaminase. ABEs act by deaminating adenine on a DNA target molecule to inosine (Gaudelli, N. M. et al., 2017). Inosine is recognized by the polymerase as guanine and allows the incorporation of cytosine on the complementary DNA strand opposite the inosine. After one round of replication following deamination, an A:T to G:C base pair change occurs in the genome. In some embodiments, the adenine deaminase or an active variant or fragment thereof of the fusion protein introduces an A>N mutation in a DNA molecule, wherein N is C, G, or T. In further embodiments, they introduce an A>G mutation in a DNA molecule.

In some embodiments, the presently disclosed fusion proteins comprising an RGN having a deaminase inserted therein may include a cytosine deaminase that catalyzes the hydrolysis of cytosine, cytidine, or deoxycytidine to deaminase to uracil. The cytosine deaminase may act on DNA or RNA, and typically acts on single-stranded nucleic acid molecules. In some embodiments, the cytosine deaminase is a deaminase of the apolipoprotein B mRNA editing complex (APOBEC) family. In some embodiments, the cytosine deaminase is an APOBEC1 family deaminase. In some embodiments, the cytosine deaminase is an activation-induced cytosine deaminase (AID). In some embodiments, the cytosine deaminase is an ACF1/ASE deaminase.

Fusion proteins including an RGN and a cytosine deaminase are referred to herein as "C base editors," "cytosine base editors," or "CBEs." CBEs can convert cytosine to uracil, which is then converted to thymine via DNA replication or repair. In some embodiments, a CBE converts cytosine to guanine or cytosine to adenine. Without being bound by any theory or mechanism of action, it is believed that the conversion of cytosine to guanine or adenine by the cytosine base editor is due to the deamination of cytosine to uracil during base excision repair of the uracil residue and the subsequent activity of uracil DNA glycosylase. In some embodiments, the cytosine deaminase or active variant or fragment thereof of the fusion protein introduces a C>N mutation in a DNA molecule, wherein N is A, G, or T. In further embodiments, they introduce a C>G or C>A mutation in a DNA molecule.

Non-limiting examples of cytosine deaminase that can be used in the present invention include, but are not limited to, those disclosed in PCT International Publication Nos. WO 2020/139783, and WO 2022/204093, and SEQ ID NOs: 229-247 or active variants or fragments thereof.

The mutation rate of adenine or cytosine within or adjacent to the target sequence to which the RGN-deaminase fusion protein binds can be measured using any method known in the art, including polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP), or DNA sequencing. V. Fusion Proteins

The present invention provides various types of fusion proteins. Those of ordinary skill in the art will appreciate that whenever a protein is fused to another protein, the N-terminal methionine (Met) of the C-terminal protein can be selectively omitted from the sequence. Therefore, as used herein, reference to a given amino acid sequence fused to another amino acid sequence explicitly includes such sequences with or without the N-terminal Met, regardless of whether such sequences include the N-terminal Met in the sequence listing.

Some aspects of the invention relate to fusion proteins comprising a heterologous polypeptide inserted into an RGN. The heterologous polypeptide can be inserted into the surface of the RGN (i.e., inserted between surface amino acid residues or between amino acid residues within a surface loop).

The heterologous polypeptide can be inserted into the linker domain 2, the wedge (WED) domain, the RuvC domain, the HNH domain, the Rec-2 domain, or the PAM interaction (PI) domain. In some embodiments, the RuvC domain is the RuvCIII domain. The Rec or recognition blade mediates nucleic acid binding through multiple Rec domains (e.g., Rec1-3) by sensing nucleic acids, regulating HNH conformational transitions, and locking the catalytic HNH domain at the splice site. The wedge domain is responsible for recognizing the guide RNA scaffold. Non-limiting examples of domains within RGNs include: RuvC-I from amino acid residues 1-54; BH from amino acid residues 55-83; REC1 from amino acid residues 84-244; REC2 from amino acid residues 245-462; RuvC-II from amino acid residues 463-521; L1 from amino acid residues 522-552; HNH from amino acid residues 553-672; L2 from amino acid residues 673-685; RuvC-III from amino acid residues 686-833; WED from amino acid residues 834-938; and PI from amino acid residues 939-1071; all with reference to APG07433.1 as shown in SEQ ID NO: 1. APG05586 (as shown in SEQ ID NO: 2) has the following domains: RuvC-I from amino acid residues 1-33; BH from amino acid residues 34-71; REC1 from amino acid residues 72-232; REC2 from amino acid residues 233-468; RuvC-II from amino acid residues 469-517; L1 from amino acid residues 518-552; HNH from amino acid residues 553-672; L2 from amino acid residues 673-687; RuvC-III from amino acid residues 688-837; WED from amino acid residues 838-998; and PI from amino acid residues 999-1150. LPG10145 (as SEQ ID NO:4) has the following domains: RuvC-I from amino acid residues 1-42; BH from amino acid residues 43-79; REC1 from amino acid residues 80-236; REC2 from amino acid residues 237-476; RuvC-II from amino acid residues 477-524; L1 from amino acid residues 525-560; HNH from amino acid residues 561-676; L2 from amino acid residues 677-690; RuvC-III from amino acid residues 691-828; WED from amino acid residues 829-976; and PI from amino acid residues 977-1130. APG01604 (SEQ ID NO: 3) has the following domains: RuvC-I from amino acid residues 1-40; BH from amino acid residues 41-74; REC1 from amino acid residues 75-223; REC2 from amino acid residues 224-430; RuvC-II from amino acid residues 431-483; L1 from amino acid residues 484-516; HNH from amino acid residues 517-631; L2 from amino acid residues 632-651; RuvC-III from amino acid residues 652-775; WED from amino acid residues 776-909; and PI from amino acid residues 910-1052.

The PAM interaction domain is the domain that binds to the PAM sequence. The general domain structure of RGN proteins can be determined by comparing the structures of RGN proteins with defined domains.

In those embodiments in which the fusion protein comprises an RGN having at least 90% sequence identity to SEQ ID NO: 1 or 49, a heterologous polypeptide (e.g., a deaminase) can be inserted into the RGN immediately after an amino acid position selected from the group consisting of: i) an amino acid position corresponding to position 30 of SEQ ID NO: 1; ii) an amino acid position corresponding to position 642 of SEQ ID NO: 1; iii) an amino acid position corresponding to position 670 of SEQ ID NO: 1; iv) an amino acid position corresponding to position 737 of SEQ ID NO: 1; v) an amino acid position corresponding to position 772 of SEQ ID NO: 1; vi) an amino acid position corresponding to position 775 of SEQ ID NO: 1; vii) an amino acid position corresponding to position 778 of SEQ ID NO: 1; and viii) an amino acid position corresponding to position 779 of SEQ ID NO: 1; NO: The amino acid position corresponding to position 802 of 1.

In those embodiments in which the fusion protein comprises an RGN having at least 90% sequence identity to SEQ ID NO: 2 or 50, the heterologous polypeptide can be inserted into the RGN immediately after an amino acid position selected from the group consisting of: i) an amino acid position corresponding to position 678 of SEQ ID NO: 2; ii) an amino acid position corresponding to position 736 of SEQ ID NO: 2; iii) an amino acid position corresponding to position 778 of SEQ ID NO: 2; iv) an amino acid position corresponding to position 788 of SEQ ID NO: 2; and v) an amino acid position corresponding to position 922 of SEQ ID NO: 2.

In those embodiments in which the fusion protein comprises an RGN having at least 90% sequence identity to SEQ ID NO:3 or 51, the heterologous polypeptide can be inserted into the RGN immediately after an amino acid position selected from the group consisting of: i) an amino acid position corresponding to position 725 of SEQ ID NO:3; ii) an amino acid position corresponding to position 739 of SEQ ID NO:3; and iii) an amino acid position corresponding to position 744 of SEQ ID NO:3.

In those embodiments in which the fusion protein comprises an RGN having at least 90% sequence identity to SEQ ID NO: 4 or 52, the heterologous polypeptide may be inserted into the RGN immediately after an amino acid position selected from the group consisting of: i) an amino acid position corresponding to position 347 of SEQ ID NO: 4; ii) an amino acid position corresponding to position 524 of SEQ ID NO: 4; iii) an amino acid position corresponding to position 666 of SEQ ID NO: 4; iv) an amino acid position corresponding to position 680 of SEQ ID NO: 4; v) an amino acid position corresponding to position 740 of SEQ ID NO: 4; vi) an amino acid position corresponding to position 785 of SEQ ID NO: 4; vii) an amino acid position corresponding to position 910 of SEQ ID NO: 4; and viii) an amino acid position corresponding to position 911 of SEQ ID NO: 4; NO: The amino acid position corresponding to position 1077 of 4.

In those embodiments in which the fusion protein comprises an RGN having at least 90% sequence identity to SEQ ID NO: 131 or 698, the heterologous polypeptide may be inserted into the RGN immediately after an amino acid position selected from the group consisting of: i) an amino acid position corresponding to position 766 of SEQ ID NO: 131; and ii) an amino acid position corresponding to position 806 of SEQ ID NO: 131.

Fusion proteins of the invention may include base editor fusion proteins, wherein the heterologous polypeptide is a deaminase and the deaminase is inserted into a RGN, such as an RGN nickase or nuclease inactive RGN. In some embodiments, the RGN component of the base editor fusion protein includes an RGN nickase or nuclease inactive RGN, and the RGN nickase or nuclease inactive RGN has about 60% to about 99.5% identity to any one of SEQ ID NOs: 49-52 and 698. In some embodiments, the RGN nickase or nuclease inactive RGN includes an amino acid sequence having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% identity to any one of SEQ ID NOs: 49-52 and 698.

In some embodiments, the base editor fusion protein comprises an RGN nickase or nuclease inactive RGN comprising an amino acid sequence having between 80% and 99% or more sequence identity to any one of SEQ ID NOs: 49-52 and 698, including but not limited to at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more.

The fusion proteins of the invention may include base editor fusion proteins (wherein the heterologous polypeptide is a deaminase and the deaminase is inserted into an RGN, e.g., an RGN nickase or nuclease-inactive RGN), wherein the base editor fusion protein has improved editing activity compared to a parent base editor comprising a deaminase fused to the amino terminus of the RGN. The improved editing activity can be measured by any method known in the art.

Compared to the parent end-to-end fusion protein, the base editor fusion proteins disclosed herein can have an efficiency of 1.1 to 10 times, 1.1 to 20 times, 1.1 to 30 times or more in editing, including but not limited to about 1.1 times, about 1.5 times, about 2 times, about 2.5 times, about 3 times, about 3.5 times, about 4 times, about 4.5 times, about 5 times, about 5.5 times, about 6 times, about 6.5 times, about 7 times, about 8 times, about 9 times, about 10 times, about 11 times, about 12 times, about 13 times, about 14 times, about 15 times, about 16 times, about 17 times, about 18 times, about 19 times, about 20 times, about 21 times, about 22 times, about 23 times, about 24 times, about 25 times, about 26 times, about 27 times, about 28 times, about 29 times, about 30 times, about 31 times, about 32 times, about 33 times, about 34 times, about 35 times, about 36 times, about 37 times, about 38 times, about 39 times, about 40 times, about 41 times, about 42 times, about 43 times, about 44 times, about 45 times, about 46 times, about 47 times, about 48 times, about 49 times, about 50 times, about 51 times, about 52 times, about 53 times, about 54 times, about 55 times, about 56 times, about 57 times, about 58 times, about 59 times, about 60 times, about 61 times, about 62 times, about 63 times, about 64 times, about 65 times, about 66 times, about 67 times, about 68 times, about 6 about 7-fold, about 7.5-fold, about 8-fold, about 8.5-fold, about 9-fold, about 9.5-fold, about 10-fold, about 11-fold, about 12-fold, about 13-fold, about 15-fold, about 16-fold, about 17-fold, about 18-fold, about 19-fold, about 20-fold, about 21-fold, about 22-fold, about 23-fold, about 24-fold, about 25-fold, about 26-fold, about 27-fold, about 28-fold, about 29-fold, and about 30-fold.

Binding of the base editor fusion protein to the target sequence results in modification of nucleotides adjacent to the target sequence. The nucleobase adjacent to the target sequence modified by the deaminase can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 base pairs from the 5' or 3' end of the target sequence. The entire range of nucleotides that can be edited using a base editor fusion protein (e.g., an RGN fused to a deaminase), typically expressed as the distance of nucleotides from a PAM sequence (e.g., nucleotides 8 and 22 upstream, i.e., 5', from a PAM sequence) is referred to herein as the "editing window" for a particular base editor fusion protein. The editing window can be, for example, 1-100 base pairs 5' or 3' of a PAM sequence, including but not limited to 5-50, 5-25, 8-22, 10-20, or 10-21 base pairs 5' or 3' of a PAM sequence.

Non-limiting examples of embedded base editor fusion proteins include: a) LPG50274/LPG50148.2.76 (as shown in SEQ ID NO: 375) or its active variants or fragments inserted after the amino acid position corresponding to position 922 of SEQ ID NO: 2 in nAPG05586 (as shown in SEQ ID NO: 50) or its active variants or fragments, such as the sequence shown in SEQ ID NO: 599; b) LPG50274/LPG50148.2.76 (as shown in SEQ ID NO: 375) or its active variants or fragments inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in nLPG10145 (as shown in SEQ ID NO: 52) or its active variants or fragments, such as the sequence shown in SEQ ID NO: 600; c) LPG50221/LPG50148.2.20 (as shown in SEQ ID NO: 319) or its active variant or fragment inserted after the amino acid position corresponding to position 922 of SEQ ID NO: 2 in nAPG05586 (as shown in SEQ ID NO: 50) or its active variant or fragment, such as the sequence shown in SEQ ID NO: 602; d) LPG50221/LPG50148.2.20 (as shown in SEQ ID NO: 319) or its active variant or fragment inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in nLPG10145 (as shown in SEQ ID NO: 52) or its active variant or fragment, such as the sequence shown in SEQ ID NO: 603; e) LPG50221/LPG50148.2.20 (as shown in SEQ ID NO: 319) or its active variant or fragment inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in nLPG10145 (as shown in SEQ ID NO: 52) or its active variant or fragment, such as the sequence shown in SEQ ID NO: 603; NO: 49) or its active variants or fragments after the amino acid position corresponding to position 772 of SEQ ID NO: 1 LPG50274/LPG50148.2.76 (as shown in SEQ ID NO: 375) or its active variants or fragments, such as the sequence shown in SEQ ID NO: 606; f) LPG50274/LPG50148.2.76 (as shown in SEQ ID NO: 375) or its active variants or fragments, such as the sequence shown in SEQ ID NO: 610, inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in nAPG05586 (as shown in SEQ ID NO: 50) or its active variants or fragments; g) LPG50274/LPG50148.2.76 (as shown in SEQ ID NO: 375) or its active variants or fragments, such as the sequence shown in SEQ ID NO: 610, inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in nAPG07433.1 (as shown in SEQ ID NO: 49) or its active variants or fragments NO:1 after the amino acid position corresponding to position 772 (as shown in SEQ ID NO: 319) or its active variant or fragment, such as the sequence shown in SEQ ID NO: 612; h) LPG50324 (as shown in SEQ ID NO: 597) or its active variant or fragment, such as the sequence shown in SEQ ID NO: 614, inserted into nAPG05586 (as shown in SEQ ID NO: 50) or its active variant or fragment after the amino acid position corresponding to position 922 of SEQ ID NO: 2; i) LPG50221/LPG50148.2.20 (as shown in SEQ ID NO: 319) or its active variant or fragment, inserted into nAPG05586 (as shown in SEQ ID NO: 50) or its active variant or fragment after the amino acid position corresponding to position 922 of SEQ ID NO: 2 NO: 2 after the amino acid position corresponding to position 678, such as the sequence shown in SEQ ID NO: 615; j) LPG50319/LPG50148.2.107 (as shown in SEQ ID NO: 406) or its active variants or fragments inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in nAPG05586 (as shown in SEQ ID NO: 50) or its active variants or fragments, such as the sequence shown in SEQ ID NO: 617; k) LPG50324 (as shown in SEQ ID NO: 597) or its active variants or fragments inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in nAPG05586 (as shown in SEQ ID NO: 50) or its active variants or fragments, such as the sequence shown in SEQ ID NO: 619; l) LPG50319/LPG50148.2.107 (as shown in SEQ ID NO: 406) or its active variants or fragments inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in nAPG05586 (as shown in SEQ ID NO: 50) or its active variants or fragments, such as the sequence shown in SEQ ID NO: 617; NO: 50) or its active variant or fragment after the amino acid position corresponding to position 678 of SEQ ID NO: 2 (as shown in SEQ ID NO: 596) or its active variant or fragment, such as the sequence shown in SEQ ID NO: 620; m) LPG50319/LPG50148.2.107 (as shown in SEQ ID NO: 406) or its active variant or fragment, such as the sequence shown in SEQ ID NO: 621, inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in nLPG10145 (as shown in SEQ ID NO: 52) or its active variant or fragment, such as the sequence shown in SEQ ID NO: 621; n) LPG50324 (as shown in SEQ ID NO: 52) or its active variant or fragment after the amino acid position corresponding to position 910 of SEQ ID NO: 4 ID NO: 597) or its active variant or fragment, such as the sequence shown in SEQ ID NO: 622; o) LPG50319/LPG50148.2.107 (such as SEQ ID NO: 406) or its active variant or fragment inserted after the amino acid position corresponding to position 922 of SEQ ID NO: 2 in nAPG05586 (such as SEQ ID NO: 50) or its active variant or fragment, such as the sequence shown in SEQ ID NO: 623; p) LPG50320 (such as SEQ ID NO: 596) or its active variant or fragment inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in nLPG10145 (such as SEQ ID NO: 52) or its active variant or fragment, such as the sequence shown in SEQ ID NO: 624; q) LPG50320 (as shown in SEQ ID NO: 596) or its active variant or fragment inserted after the amino acid position corresponding to position 922 of SEQ ID NO: 2 in nAPG05586 (as shown in SEQ ID NO: 50) or its active variant or fragment, such as the sequence shown in SEQ ID NO: 626; r) LPG50319/LPG50148.2.107 (as shown in SEQ ID NO: 406) or its active variant or fragment inserted after the amino acid position corresponding to position 772 of SEQ ID NO: 1 in nAPG07433.1 (as shown in SEQ ID NO: 49) or its active variant or fragment, such as the sequence shown in SEQ ID NO: 630; s) LPG50319/LPG50148.2.107 (as shown in SEQ ID NO: 406) or its active variant or fragment inserted after the amino acid position corresponding to position 772 of SEQ ID NO: 1 in nAPG07433.1 (as shown in SEQ ID NO: 49) or its active variant or fragment, such as the sequence shown in SEQ ID NO: 630; LPG50320 (as shown in SEQ ID NO: 596) or its active variant or fragment after the amino acid position corresponding to position 772 of NO: 1, such as the sequence shown in SEQ ID NO: 631; and t) LPG50324 (as shown in SEQ ID NO: 597) or its active variant or fragment inserted into nAPG07433.1 (as shown in SEQ ID NO: 49) or its active variant or fragment after the amino acid position corresponding to position 772 of SEQ ID NO: 1, such as the sequence shown in SEQ ID NO: 632.

Fusion proteins of the invention may include base editor fusion proteins (wherein the heterologous polypeptide is a deaminase and the deaminase is inserted into an RGN (e.g., an RGN nickase or nuclease inactive RGN)), wherein the base editor fusion protein has a shifted editing window when compared to a parent base editor comprising a deaminase fused to the amino terminus of the RGN. The editing window may be shifted to be narrower or wider than that of the parent base editor. The shifted editing window is one that is wider or narrower (e.g., differs by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more nucleotides) when compared to the parental end-to-end fusion protein, and/or the editing window is shifted in the 5' or 3' direction of the target molecule when compared to the parental end-to-end fusion protein, e.g., by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more nucleotides in the 5' or 3' direction.

In some embodiments, the fusion protein includes one or more peptide linkers between the heterologous polypeptide and the RGN. Those of ordinary skill in the art will appreciate that linkers can be optionally added to a sequence whenever a protein is fused to another protein. Thus, as used herein, reference to a given fusion protein explicitly includes such sequences with or optionally without a linker, regardless of whether such sequences are listed as having a linker. The linker between the deaminase and the RGN can determine the editing window of the fusion protein. A variety of linker lengths and flexibilities ranging from very flexible linkers of the (GGGGS) _n and (G) _n forms to more rigid linkers of the (EAAAK) _n and (XP) _n forms can be used to achieve the optimal length and rigidity for the deaminase activity for a particular application. As used herein, the term "peptide linker" refers to a peptide that connects two polypeptides. In some embodiments, the linker connects the RNA-guided nuclease to the deaminase. In some embodiments, the linker connects an inactive RGN or an inactivated RGN to the deaminase. In some embodiments, the linker is 3-100 amino acids in length, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 30-35, 35-40, 40-45, 45-50, 50-60, 60-70, 70-80, 80-90, 90-100, 100-150, or 150-200 amino acids in length. Longer or shorter linkers are also contemplated. In some embodiments, shorter linkers are preferred to reduce the overall size or length of the fusion protein or its coding sequence. Non-limiting examples of peptide linkers between the RGN and the heterologous polypeptide inserted therein include GGS, SGG, and GSSG (as shown in SEQ ID NO: 733). The linker can be located at the N-terminus, C-terminus, or both of the inserted heterologous polypeptide.

In some embodiments, the RGN and the heterologous polypeptide inserted therein are fused directly to each other without a linker sequence in between.

Another aspect of the invention relates to a fusion protein comprising a DNA binding polypeptide operably linked to a deaminase of the invention (e.g., SEQ ID NOs: 6, 300-414, 596-598, and 720-723 or an active fragment or variant thereof). In some embodiments, a DNA binding polypeptide fused to a deaminase of the invention (e.g., a nuclease-inactive RGN or a nickase RGN) can be targeted to a specific location (in some embodiments, a specific genomic locus) of a nucleic acid molecule (i.e., a target nucleic acid molecule) to alter the expression of a desired sequence. In some embodiments, binding of the fusion protein to the target sequence results in deamination of a nucleobase, thereby resulting in conversion from one nucleobase to another nucleobase. In some embodiments, binding of the fusion protein to the target sequence results in deamination of a nucleobase adjacent to the target sequence.

Some aspects of the disclosure provide fusion proteins comprising (i) a DNA binding polypeptide (e.g., a nuclease-inactive or nickase RGN polypeptide); (ii) a deaminase polypeptide; and optionally (iii) a second deaminase. The second deaminase can be the same deaminase as the first deaminase or can be a different deaminase. In some embodiments, the first deaminase and the second deaminase are both adenine deaminases of the present invention.

The present disclosure provides fusion proteins of various configurations. In some embodiments, the fusion protein is an end-to-end fusion, wherein the deaminase polypeptide is fused to the N-terminus of a DNA binding polypeptide (e.g., an RGN polypeptide) or the deaminase polypeptide is fused to the C-terminus of a DNA binding polypeptide (e.g., an RGN polypeptide).

Non-limiting examples of end-to-end base editor fusion proteins include those comprising a deaminase or an active variant or fragment thereof fused to the N-terminus of a nickase or an active variant or fragment thereof of any of the end-to-end fusion proteins used in the examples herein, including but not limited to: a) LPG50221/LPG50148.2.20 (as shown in SEQ ID NO: 319) or an active variant or fragment thereof fused to the N-terminus of nAPG07433.1 (as shown in SEQ ID NO: 49) or an active variant or fragment thereof, such as the sequence shown in SEQ ID NO: 578, 579, or 634; b) LPG50274/LPG50148.2.76 (as shown in SEQ ID NO: 578, 579, or 634) fused to the N-terminus of nAPG07433.1 (as shown in SEQ ID NO: 49) or an active variant or fragment thereof. NO: 375) or its active variants or fragments, such as the sequence shown in SEQ ID NO: 594, 598, or 638; c) LPG50319/LPG50148.2.107 (as shown in SEQ ID NO: 406) or its active variants or fragments, such as the sequence shown in SEQ ID NO: 588 or 616 fused to the N-terminus of nAPG07433.1 (as shown in SEQ ID NO: 49) or its active variants or fragments; d) LPG50320 (as shown in SEQ ID NO: 596) or its active variants or fragments, such as the sequence shown in SEQ ID NO: 593 or 636 fused to the N-terminus of nAPG07433.1 (as shown in SEQ ID NO: 49) or its active variants or fragments; and e) LPG50319/LPG50148.2.107 (as shown in SEQ ID NO: 406) or its active variants or fragments, such as the sequence shown in SEQ ID NO: 588 or 616 fused to the N-terminus of nAPG07433.1 (as shown in SEQ ID NO: 49) or its active variants or fragments. LPG50324 (as shown in SEQ ID NO: 597) or its active variant or fragment fused to the N-terminus of SEQ ID NO: 49) or its active variant or fragment, such as the sequence shown in SEQ ID NO: 637.

In some embodiments, an end-to-end deaminase and a DNA binding polypeptide (e.g., an RNA-guided DNA binding polypeptide) are fused to each other via a linker. As used herein, the term "linker" refers to a chemical group or molecule that connects two molecules or parts, such as a binding domain and a cleavage domain of a nuclease. In some embodiments, a linker connects an RNA-guided nuclease to a deaminase. In some embodiments, a linker connects an inactive or inactivated RGN to a deaminase. In other embodiments, a linker connects two deaminases. In some embodiments, a linker connects an RNA-guided nuclease to a USP. In some embodiments, a linker connects a deaminase to a USP. In certain embodiments, a linker connects an RNA-guided nuclease-deaminase fusion to a USP. Typically, a linker is located between or flanking two groups, molecules, or other moieties and is attached to each group, molecule, or other moiety via a covalent bond, thereby connecting the two. In some embodiments, the linker is an amino acid or multiple amino acids (e.g., a peptide or protein). In some embodiments, the linker is an organic molecule, group, polymer, or chemical moiety. In some embodiments, the length of the linker is 3-100 amino acids, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 30-35, 35-40, 40-45, 45-50, 50-60, 60-70, 70-80, 80-90, 90-100, 100-150, or 150-200 amino acids in length. Longer or shorter linkers are also contemplated. In some embodiments, shorter linkers are preferably used to reduce the overall size or length of the fusion protein or its coding sequence.

In some embodiments, the linker between the deaminase and the DNA binding polypeptide in the end-to-end fusion comprises any one of SEQ ID NOs: 704, 705, and 707-712. Additional suitable linker motifs and linker configurations will be apparent to one of ordinary skill in the art. In some embodiments, suitable linker motifs and configurations include those described in Chen et al., 2013 ( Adv Drug Deliv Rev. 65(10): 1357-69, the entire contents of which are incorporated herein by reference). Additional suitable linker sequences will be apparent to one of ordinary skill in the art. In some embodiments, the linker sequence comprises an amino acid sequence as set forth in SEQ ID NO: 233 or 234.

In some embodiments, the general architecture of exemplary fusion proteins provided herein includes the following structures: [NH ₂ ]-[deaminase]-[DBP]-[COOH]; [NH ₂ ]-[DBP]-[deaminase]-[COOH]; [NH ₂ ]-[DBP]-[deaminase]-[deaminase]-[COOH]; [NH ₂ ]-[deaminase]-[DBP]-[deaminase]-[COOH]; or [NH ₂ ]-[deaminase]-[deaminase]-[DBP]-[COOH], wherein DBP is a DNA binding polypeptide, NH ₂ is the N-terminus of the fusion protein, and COOH is the C-terminus of the fusion protein. In some embodiments, the fusion protein includes two or more deaminase polypeptides.

In certain embodiments, the general architecture of exemplary fusion proteins provided herein includes the following structures: [NH ₂ ]-[deaminase]-[RGN]-[COOH]; [NH ₂ ]-[RGN]-[deaminase]-[COOH]; [NH ₂ ]-[RGN]-[deaminase]-[deaminase]-[COOH]; [NH ₂ ]-[deaminase]-[RGN]-[deaminase]-[COOH]; or [NH ₂ ]-[deaminase]-[deaminase]-[RGN]-[COOH], wherein NH ₂ is the N-terminus of the fusion protein and COOH is the C-terminus of the fusion protein. In some embodiments, the fusion protein includes two or more deaminase polypeptides.

In some embodiments, the fusion protein comprises the following structure: [NH ₂ ]-[deaminase]-[nuclease-inactive RGN]-[COOH]; [NH ₂ ]-[deaminase]-[deaminase]-[nuclease-inactive RGN]-[COOH]; [NH ₂ ]-[nuclease-inactive RGN]-[deaminase]-[COOH]; [NH ₂ ]-[deaminase]-[nuclease-inactive RGN]-[deaminase]-[COOH]; or [NH ₂ ]-[nuclease-inactive RGN]-[deaminase]-[deaminase]-[COOH]. It should be understood that "nuclease-inactive RGN" means any RGN, including any CRISPR-Cas protein that has been mutated to be nuclease-inactive. In some embodiments, the fusion protein comprises two or more deaminase polypeptides.

In some embodiments, the fusion protein comprises the following structures: [NH ₂ ]-[deaminase]-[RGN nickase]-[COOH]; [NH ₂ ]-[deaminase]-[deaminase]-[RGN nickase]-[COOH]; [NH ₂ ]-[RGN nickase]-[deaminase]-[COOH]; [NH ₂ ]-[deaminase]-[RGN nickase]-[deaminase]-[COOH]; or [NH ₂ ]-[RGN nickase]-[deaminase]-[deaminase]-[COOH]. It should be understood that "RGN nickase" represents any RGN, including any CRISPR-Cas protein that has been mutated to an active nickase.

In some embodiments, the fusion protein provided herein includes the full-length sequence of deaminase. In some embodiments, however, the fusion protein provided herein does not include the full-length sequence of deaminase but only includes its fragment.

In some embodiments, the fusion proteins of the invention include a DNA binding polypeptide (eg, RGN) and a deaminase, wherein the deaminase has an amino acid sequence that is about 50% to about 100% identical to any one of SEQ ID NOs: 6, 300-414, 596-598, and 720-723.

In some embodiments, the fusion protein of the invention comprises a DNA binding polypeptide (e.g., RGN) and a deaminase, wherein the deaminase has an amino acid sequence having about 50% to about 100% identity to any one of SEQ ID NOs: 6, 300-414, 596-598, and 720-723 and has at least one of the amino acid residues shown in any one of Tables 2, 4, 6, and 19. In some embodiments, the fusion proteins of the invention include a DNA binding polypeptide (e.g., RGN) and a deaminase, wherein the deaminase has an amino acid sequence that is at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs: 6, 300-414, 596-598, and 720-723 and has at least one of the amino acid residues shown in any one of Tables 2, 4, 6, and 19. Examples of such fusion proteins are described in the Examples section herein.

In some embodiments, the fusion protein includes a deaminase polypeptide. In some embodiments, the fusion protein includes at least two deaminase polypeptides operably linked directly or via a peptide linker. In some embodiments, the fusion protein includes a deaminase polypeptide and a second deaminase polypeptide is co-expressed with the fusion protein.

In some embodiments, the "-" used in the above general framework indicates the presence of an optional linker sequence. In some embodiments, the fusion protein provided herein does not include a linker sequence. In some embodiments, there is at least one of the optional linker sequences.

Other exemplary features that may be present on the presently disclosed deaminases or fusion proteins are localization sequences, such as nuclear localization sequences, cytoplasmic localization sequences, export sequences (such as nuclear export sequences), or other localization sequences, and sequence tags that can be used for solubilization, purification, or detection of fusion proteins. Suitable localization signal sequences and sequences for protein tags provided herein include, but are not limited to, biotin carboxylase carrier protein (BCCP) tags, myc-tags, calcitonin-tags, FLAG-tags (e.g., 3XFLAG-tags), hemagglutinin (HA)-tags, polyhistidine tags (also known as histidine tags or His tags), maltose binding protein (MBP)-tags, nus-tags, glutathione-S-transferase (GST)-tags, green fluorescent protein (GFP)-tags, thioredoxin-tags, S-tags, Softags (e.g., Softag 1, Softag 3), streptags, biotin ligase tags, FlAsH tags, V5 tags, and SBP-tags. Additional suitable sequences will be apparent to those of ordinary skill in the art.

The compositions and methods disclosed herein can utilize a deaminase or fusion protein comprising at least one nuclear localization signal (NLS) to enhance the transport of the deaminase or fusion protein to the cell nucleus. Nuclear localization signals are known in the art and generally include a stretch of basic amino acids (see, e.g., Lange et al., J. Biol. Chem . (2007) 282:5101-5105). In some embodiments, the deaminase or fusion protein includes 2, 3, 4, 5, 6 or more nuclear localization signals. The nuclear localization signal can be a heterologous NLS. Non-limiting examples of nuclear localization signals that can be used for the presently disclosed RGNs are SV40 large T-antigen, nucleoplasmin, the nuclear localization signal of c-Myc (see, e.g., Ray et al. (2015) Bioconjug Chem 26(6): 1004-7), POLD1 DNA polymerase delta 1, active adenosine deaminase acting on RNA (ADAR2), interactors with RNA polymerase II 1 (Iwr1) (Czeko E. et al., Mol Cell 2011, which is incorporated by reference in its entirety), and OpT (U.S. Publication No. 2020/0109382, which is incorporated by reference in its entirety). In embodiments, the RGN comprises an NLS sequence as set forth in any one of SEQ ID NOs: 430, 431, and 713-718. The deaminase or fusion protein may include one or more NLS sequences at its N-terminus, C-terminus, or both N-terminus and C-terminus. For example, the deaminase or fusion protein may include two NLS sequences at the N-terminal region and four NLS sequences at the C-terminal region. In some embodiments, the deaminase or fusion protein includes an SV40 NLS at the N-terminus (e.g., a sequence as shown in SEQ ID NO: 430) and a nucleoplasmin NLS at its C-terminus (e.g., a sequence as shown in SEQ ID NO: 431). In some embodiments, the deaminase or fusion protein includes a c-Myc promoter at its N-terminus and its C-terminus (e.g., a sequence as shown in SEQ ID NO: 718).

When the NLS is attached to the N-terminus, C-terminus, or both of the deaminase or fusion protein, an NLS linker protein may be present to separate the deaminase or fusion protein from the NLS. Such an NLS linker protein may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more amino acids in length. In some embodiments, the NLS linker protein is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, or at least 8 amino acids in length. In some embodiments, the NLS linker protein between the NLS and the deaminase or fusion protein has a sequence as shown in SEQ ID NO: 706, 719, or 728. In some embodiments, the deaminase or fusion protein includes a c-Myc promoter (e.g., a sequence as shown in SEQ ID NO: 718) at its N-terminus (which is separated from the deaminase or fusion protein by an NLS linker protein having a sequence as shown in SEQ ID NO: 728), and a c-Myc promoter (e.g., a sequence as shown in SEQ ID NO: 718) at its C-terminus (which is separated from the deaminase or fusion protein by an NLS linker protein having a sequence as shown in SEQ ID NO: 728).

In some embodiments, the compositions and methods disclosed herein utilize a deaminase or fusion protein comprising at least one cell penetrating domain that promotes cellular uptake of the deaminase or fusion protein. Cell penetrating domains are known in the art and typically include a stretch of positively charged amino acid residues (i.e., a polycationic cell penetrating domain), alternating polar and non-polar amino acid residues (i.e., amphoteric cell penetrating domains), or hydrophobic amino acid residues (i.e., a hydrophobic cell penetrating domain) (see, e.g., Milletti F. (2012) Drug Discov Today 17: 850-860). A non-limiting example of a cell penetrating domain is the transactivating transcription activator protein (TAT) from human immunodeficiency virus 1.

The nuclear localization signal and/or cell penetrating domain can be located at the N-terminus, C-terminus and/or internal position of the deaminase or fusion protein. VI. Nucleotides encoding deaminase, fusion protein and / or gRNA

The disclosure provides polynucleotides encoding the presently disclosed deaminases, fusion proteins, or gRNAs. In some embodiments, the polynucleotide encodes a fusion protein comprising a deaminases and a DNA binding polypeptide, such as a meganuclease, a zinc finger fusion protein, or a TALEN. The disclosure also provides polynucleotides encoding a fusion protein comprising a deaminases and an RNA-guided DNA binding polypeptide (RGDBP). Such RNA-guided DNA binding polypeptides can be RGNs or RGN variants. Protein variants can be nuclease-inactive or nickases. RGNs can be CRISPR-Cas proteins or active variants or fragments thereof. Examples of CRISPR-Cas nucleases are well known in the art, and similar corresponding mutations can produce mutant variants that are also nickase- or nuclease-inactive.

Embodiments of the present invention provide polynucleotides encoding fusion proteins comprising an RGBP (e.g., RGN) described herein and a deaminase. In some embodiments, a second polynucleotide encodes a guide RNA required for the RGBP to target a nucleotide sequence of interest. In some embodiments, the guide RNA and the fusion protein are encoded by the same polynucleotide.

In some embodiments, the guide RNA and the fusion protein are encoded by the same polynucleotide. In other embodiments, the guide RNA and the fusion protein are encoded by two separate polynucleotides.

The use of the term "polynucleotide" is not intended to limit the present disclosure to polynucleotides including DNA, although such DNA polynucleotides are contemplated. One of ordinary skill in the art will recognize that polynucleotides can include ribonucleotides (RNA) (e.g., mRNA) and combinations of ribonucleotides and deoxyribonucleotides. Such deoxyribonucleotides and ribonucleotides include naturally occurring molecules as well as synthetic analogs. The polynucleotides disclosed herein also encompass sequences in all forms, including but not limited to single-stranded forms, double-stranded forms, stem-and-ring structures, cyclic forms (e.g., including circular RNA), etc.

One embodiment of the invention is a nucleic acid molecule comprising a sequence encoding a deaminase having about 50% to about 100% identity to any one of SEQ ID NOs: 5, 6, 300-414, 596-598, and 720-723. One embodiment of the invention is a nucleic acid molecule comprising a sequence encoding a deaminase having about 50% to about 100% identity to any one of SEQ ID NOs: 5, 6, 300-414, 596-598, and 720-723 and having at least one of the amino acid residues shown in any one of Tables 2, 4, 6, and 19. One embodiment of the invention is a nucleic acid molecule encoding a sequence of a deaminase having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identity to any one of SEQ ID NOs: 5, 6, 300-414, 596-598, and 720-723 and at least one of the amino acid residues shown in any one of Tables 2, 4, 6, and 19, wherein the nucleic acid molecule encodes a deaminase having deaminase activity. The nucleic acid molecule may also include a heterologous promoter or terminator. The nucleic acid molecule may encode a fusion protein in which the encoded deaminase is operably linked to a DNA binding polypeptide and, optionally, a second deaminase. In some embodiments, the nucleic acid molecule encodes a fusion protein in which the encoded deaminase is operably linked to an RGN and, optionally, a second deaminase.

In some embodiments, nucleic acid molecules comprising polynucleotides encoding the deaminase or fusion protein of the present invention are codon optimized for expression in an organism of interest. A "codon optimized" coding sequence is a polynucleotide coding sequence whose codon usage frequency is designed to mimic the optimal codon usage frequency or transcription conditions of a specific host cell. The translated amino acid sequence is not changed because the change of one or more codons at the nucleic acid level enhances expression in a specific host cell or organism. Nucleic acid molecules can be codon optimized in whole or in part. Codon tables and other references providing optimal information for a wide range of organisms are available in the art (see, for example, Campbell and Gowri (1990) Plant Physiol. 92: 1-11, regarding optimal codon usage in plants). Methods are available in the art for synthesizing plant-optimized genes. See, for example, U.S. Patent Nos. 5,380,831, and 5,436,391, and Murray et al. (1989) Nucleic Acids Res. 17:477-498, incorporated herein by reference.

In some embodiments, polynucleotides encoding the deaminases, fusion proteins and/or gRNAs described herein are provided in expression cassettes for in vitro expression or expression in cells, organelles, embryos or organisms of interest. The cassette may include 5' and 3' regulatory sequences that are operably linked to polynucleotides encoding the deaminases, fusion proteins and/or gRNAs that allow the polynucleotides to be expressed as provided herein. The cassette may additionally contain at least one additional gene or genetic element to be co-transformed into an organism. If an additional gene or element is included, the composition is operably linked. The term "operably linked" is intended to mean a functional connection between two or more elements. For example, an operably linked promoter to a coding region of interest (e.g., a region encoding a deaminase, RGN, and/or gRNA) is a functional link that allows expression of the coding region of interest. Operably linked elements may be contiguous or non-contiguous. When used to refer to the connection of two protein coding regions, by being operably linked means that the coding regions are in the same reading frame. In some embodiments, additional (one or more) genes or (one or more) elements are provided on multiple expression cassettes. For example, a nucleotide sequence encoding a deaminase or fusion protein disclosed herein may be present on one expression cassette, while a nucleotide sequence encoding a gRNA may be on a separate expression cassette. Another example may have a nucleotide sequence encoding the presently disclosed deaminase alone on a first expression cassette, a second expression cassette encoding a fusion protein comprising the deaminase, and a nucleotide sequence encoding a gRNA on a third expression cassette. Such expression cassettes are provided with a plurality of restriction sites and/or recombination sites for enabling insertion of the polynucleotide under transcriptional regulation of the regulatory region. Expression cassettes comprising selectable marker genes may also be present.

The expression cassette may include a transcriptional, transcriptional (and in some embodiments, translational) start region (i.e., promoter) in the 5'-3' transcriptional direction, a deaminase encoding polynucleotide of the present invention, a fusion protein encoding polynucleotide of the present invention, and a transcriptional (and in some embodiments, translational) termination region (i.e., termination region) that functions in the organism of interest. Promoters useful in the present invention are capable of directing or driving expression of the coding sequence in a host cell. Regulatory regions (e.g., promoters, transcriptional regulatory regions, and translational termination regions) may be endogenous or heterologous to the host cell or to each other. As used herein, "heterologous" with respect to a sequence is a sequence that originates from a foreign species, or, if from the same species, is substantially modified from its native form in a composition and/or genomic locus by deliberate human intervention. As used herein, a chimeric gene comprises a coding sequence operably linked to a transcription initiation region that is heterologous to the coding sequence.

Convenient termination regions can be obtained from the Ti plasmid of A. tumefaciens , for example, the octopine synthase and nopaline synthase termination regions. See also Guerineau et al. (1991) Mol. Gen. Genet. 262:141-144; Proudfoot (1991) Cell 64:671-674; Sanfacon et al. (1991) Genes Dev. 5:141-149; Mogen et al. (1990) Plant Cell 2:1261-1272; Munroe et al. (1990) Gene 91:151-158; Ballas et al. (1989) Nucleic Acids Res. 17:7891-7903; and Joshi et al. (1987) Nucleic Acids Res. 15:9627-9639.

Additional regulatory signals include, but are not limited to, transcription initiation start site operators, activators, enhancers, other regulatory elements, ribosomal binding sites, initiation codons, termination signals, and the like. See, e.g., U.S. Patent Nos. 5,039,523 and 4,853,331; EPO 0480762A2; Sambrook et al. (1992) Molecular Cloning: A Laboratory Manual, ed. Maniatis et al. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York), hereinafter "Sambrook 11"; Davis et al., eds. (1980) Advanced Bacterial Genetics (Cold Spring Harbor Laboratory Press), Cold Spring Harbor, New York, and references cited therein.

In preparing the expression cassette, the various DNA fragments may be manipulated to provide the DNA sequence in the proper orientation and, where appropriate, in the proper reading frame. To this end, adapters or linkers may be employed to join the DNA fragments, or other manipulations may be involved to provide for appropriate restriction sites, removal of excess DNA, removal of restriction sites, and the like. For this purpose, in vitro mutagenesis, primer repair, restriction, annealing, re-substitution (e.g., transition and transversion) may be involved.

Many promoters can be used in the practice of the present invention. The promoter can be selected based on the desired outcome. The nucleic acid can be combined with a constitutive, inducible, growth stage specific, cell type specific, tissue preferred, tissue specific or other promoter for expression in the organism of interest. See, e.g., the promoters shown in WO 99/43838 and in U.S. Patent Nos. 8,575,425; 7,790,846; 8,147,856; 8,586832; 7,772,369; 7,534,939; 6,072,050; 5,659,026; 5,608,149; 5,608,144; 5,604,121; 5,569,597; 5,466,785; 5,399,680; 5,268,463; 5,608,142; and 6,177,611; which are incorporated herein by reference.

For expression in plants, constitutive promoters also include the CaMV 35S promoter (Odell et al. (1985) Nature 313:810-812); rice actin (McElroy et al. (1990) Plant Cell 2:163-171); ubiquitin (Christensen et al. (1989) Plant Mol. Biol. 12:619-632 and Christensen et al. (1992) Plant Mol. Biol. 18:675-689); pEMU (Last et al. (1991) Theor. Appl. Genet. 81:581-588); and MAS (Velten et al. (1984) EMBO J. 3:2723-2730).

Examples of inducible promoters are the Adh1 promoter which is inducible by hypoxia or cold stress, the Hsp70 promoter which is inducible by heat stress, the PPDK promoter which is inducible by light, and the Pepcarboxylase promoter. Also useful are chemically induced promoters, for example, the safener-induced In2-2 promoter (U.S. Patent No. 5,364,780), the auxin-induced Axig1 promoter which is nutrient-specific but also active in healing tissues (PCT US01/22169), steroid-responsive promoters (see, for example, Schena et al. (1991) Proc. Natl. Acad. Sci . USA 88:10421-10425 and McNellis et al. (1998) Plant J. 14(2):247-257), and tetracycline-induced and tetracycline-repressible promoters (see, e.g., Gatz et al. (1991) Mol. Gen. Genet . 227:229-237, and U.S. Pat. Nos. 5,814,618 and 5,789,156), which are incorporated herein by reference.

In some embodiments, tissue-specific or tissue-preferred promoters can be used to target the expression of expression constructs within specific tissues. In some embodiments, tissue-specific or tissue-preferred promoters are active in plant tissues. Examples of developmentally controlled promoters in plants include promoters that preferentially initiate transcription in certain tissues such as leaves, roots, fruits, seeds, or flowers. A "tissue-specific" promoter is a promoter that initiates transcription only in certain tissues. Unlike constitutive expression of a gene, tissue-specific expression is the result of several levels of gene regulatory interactions. Therefore, promoters from homologous or closely related plant species may be preferably used to achieve efficient and reliable expression of transgenic genes in specific tissues. In some embodiments, expression includes tissue-optimal promoters. A "tissue-optimal" promoter is a promoter that preferably, but not necessarily exclusively or only in certain tissues, initiates transcription.

In some embodiments, the nucleic acid molecule encoding the deaminase or fusion protein described herein includes a cell type specific promoter. A "cell type specific" promoter is a promoter that drives expression primarily in certain cell types in one or more organs. For example, some examples of plant cells (where a cell type specific promoter that functions in plants may be primarily active) include BETL cells, roots, vascular cells in leaves, stalk cells, and stem cells. The nucleic acid molecule may also include a cell type preferred promoter. A "cell type preferred" promoter is a promoter that primarily drives expression mostly, but not necessarily entirely, or only in certain cell types in one or more organs. For example, some examples of plant cells in which preferred promoters that function in plants may be preferably active include BETL cells, roots, vascular cells in leaves, stalk cells, and stem cells.

In some embodiments, the nucleic acid sequence encoding the deaminase, fusion protein and/or gRNA is, for example, operably linked to a promoter sequence recognized by a bacteriophage RNA polymerase for in vitro mRNA synthesis. In such embodiments, the RNA transcribed in vitro can be purified for use in the methods described herein. For example, the promoter sequence can be a T7, T3, or SP6 promoter sequence or a variant of a T7, T3, or SP6 promoter sequence. In such embodiments, the expressed protein and/or RNA can be purified for use in the genome modification methods described herein.

In certain embodiments, the polynucleotide encoding the deaminase, fusion protein and/or gRNA is linked to a polyadenylation signal (e.g., SV40 polyA signal and other signals that function in plants) and/or at least one transcriptional termination sequence. In some embodiments, as described elsewhere herein, the sequence encoding the deaminase or fusion protein is linked to a sequence encoding at least one nuclear localization signal, at least one cell penetrating domain and/or at least one signal peptide capable of transporting the protein to a specific subcellular location.

In some embodiments, the polynucleotide encoding the deaminase, fusion protein and/or gRNA is present in one or more vectors. "Vector" refers to a polynucleotide composition used to transfer, deliver or introduce nucleic acid into a host cell. Suitable vectors include plasmid vectors, phagemids, cosmids, artificial/minichromosomes, transposons, and viral vectors (e.g., lentiviral vectors, adeno-associated viral vectors, bacilli). In some embodiments, the vector includes additional expression control sequences (e.g., enhancer sequences, Kozak sequences, polyadenylation sequences, transcription termination sequences), selectable marker sequences (e.g., antibiotic resistance genes), origins of replication, and the like. Additional information can be found in "Current Protocols in Molecular Biology" Ausubel et al., John Wiley & Sons, New York, 2003; or in "Molecular Cloning: A Laboratory Manual" Sambrook & Russell, Cold Spring Harbor Press, Cold Spring Harbor, N.Y., 3rd edition, 2001.

In some embodiments, the vector includes a selectable marker gene for selection of transformed cells. Selectable marker genes are used for selection of transformed cells or tissues. Marker genes include genes encoding antibiotic resistance, such as genes encoding neomycin phosphotransferase II (NEO) and hygromycin phosphotransferase (HPT); and genes that confer resistance to herbicidal compounds such as glufosinate ammonium, bromoxynil, imidazolinone, and 2,4-dichlorophenoxyacetate (2,4-D).

In some embodiments, the expression cassette or vector comprising a sequence encoding a fusion protein further comprises a sequence encoding a gRNA. In some embodiments, the sequence (s) encoding the gRNA is operably linked to at least one transcription control sequence for expression of the gRNA in an organism or host cell of interest. For example, the polynucleotide encoding the gRNA is operably linked to a promoter sequence recognized by RNA polymerase III (Pol III). Examples of suitable Pol III promoters include, but are not limited to, mammalian U6, U3, H1, and 7SL RNA promoters, rice U6 and U3 promoters, and promoters disclosed in PCT International Application No. PCT/US2022/032940 filed on June 10, 2022, which is incorporated herein by reference in its entirety.

As noted, expression constructs comprising nucleotide sequences encoding deaminases, fusion proteins, and/or gRNAs can be used to transform an organism of interest. Methods for transformation involve introducing a nucleotide construct into an organism of interest. By "introducing" it is intended that the nucleotide construct is introduced into a host cell in such a way that the construct enters the interior of the host cell. The methods of the present invention do not require a specific method for introducing a nucleotide construct into a host organism by simply allowing the nucleotide construct to enter the interior of at least one cell of the host organism. In some embodiments, an mRNA encoding a deaminases or a fusion protein is introduced into a host cell. In some embodiments where the fusion protein comprises an RGN, an mRNA encoding a fusion protein is introduced into a cell, and a gRNA is introduced into a cell. The host cell can be a eukaryotic cell or a prokaryotic cell. In some embodiments, the eukaryotic host cell is a plant cell, a mammalian cell, or an insect cell. Methods for introducing nucleotide constructs into plants and other host cells are known in the art, including but not limited to stable transformation methods, transient transformation methods, and virus-mediated methods.

These methods can produce transformed organisms, such as plants, including whole plants, plant organs (e.g., leaves, stems, roots, etc.), seeds, plant cells, propagules, embryos, and their progeny. Plant cells may be differentiated or non-differentiated (e.g., healing tissue, suspension culture cells, protoplasts, leaf cells, root cells, epidermal cells, pollen).

A "transgenic organism" or "transformed organism" or "stably transformed" organism or cell or tissue refers to an organism into which a polynucleotide encoding a deaminase or fusion protein of the invention has been incorporated or integrated. It should be recognized that other exogenous or endogenous nucleic acid sequences or DNA fragments may also be incorporated into the host cell. Agrobacterium- and biolistic-mediated transformation remain the two main methods used for transformation of plant cells. However, transformation of host cells can be performed by infection, transfection, microinjection, electroporation, microprojection, gene gun or particle bombardment, electroporation, silica/carbon fiber, ultrasound-mediated, PEG-mediated, calcium phosphate co-precipitation, polycation DMSO technique, DEAE dextran procedure, and virus-mediated, liposome-mediated and the like. Virus-mediated introduction of polynucleotides encoding deaminases, fusion proteins, and/or gRNAs includes retrovirus-, lentivirus-, adenovirus-, and adeno-associated virus-mediated introduction and expression, as well as the use of cauliflower mosaic virus (e.g., cauliflower mosaic virus), geminivirus (e.g., bean golden yellow mosaic virus or maize streak virus), and RNA plant viruses (e.g., tobacco mosaic virus).

Transformation protocols and protocols for introducing polypeptide or polynucleotide sequences into plants can vary depending on the type of host cell targeted for transformation (e.g., monocot or dicot cell). Methods for transformation are known in the art and include those described in U.S. Patent Nos.: 8,575,425; 7,692,068; 8,802,934; 7,541,517; each of which is incorporated herein by reference. See also Rakoczy-Trojanowska, M. (2002) Cell Mol Biol Lett. 7:849-858; Jones et al. (2005) Plant Methods 1:5; Rivera et al. (2012) Physics of Life Reviews 9:308-345; Bartlett et al. (2008) Plant Methods 4:1-12; Bates, GW (1999) Methods in Molecular Biology 111:359-366; Binns and Thomashow (1988) Annual Reviews in Microbiology 42:575-606; Christou, P. (1992) The Plant Journal 2:275-281; Christou, P. (1995) Euphytica 85:13-27; Tzfira et al. (2004) TRENDS in Genetics 20:375-383; Yao et al. (2006) Journal of Experimental Botany 57:3737-3746; Zupan and Zambryski (1995) Plant Physiology 107:1041-1047; Jones et al. (2005) Plant Methods 1:5.

Transformation can result in stable or transient introduction of a nucleic acid into a cell. "Stable transformation" is intended to mean that the nucleotide construct introduced into a host cell is integrated into the genome of the host cell and can be inherited by its progeny. "Transient transformation" is intended to mean that a polynucleotide is introduced into a host cell without integrating into the genome of the host cell.

Methods for chloroplast transformation are known in the art. See, e.g., Svab et al. (1990) Proc. Natl. Acad. Sci. USA 87:8526-8530; Svab and Maliga (1993) Proc. Natl. Acad. Sci. USA 90:913-917; Svab and Maliga (1993) EMBO J. 12:601-606. The method relies on particle gun delivery of DNA containing a selectable marker and targeting the DNA to the plastid genome via homologous recombination. In addition, chloroplast transformation can be accomplished by transcriptional activation of silent plastid-borne transgenes through the organized expression of nuclear-encoded and plastid-directed RNA polymerases. This system has been reported in McBride et al. (1994) Proc. Natl. Acad. Sci. USA 91:7301-7305.

The cells that have been transformed can be grown into transgenic organisms, such as plants, in a conventional manner. See, for example, McCormick et al. (1986) Plant Cell Reports 5: 81-84. These plants can then be grown and pollinated with the same transformed strain or a different strain, and the resulting hybrids with the deaminase or fusion protein polynucleotide identified. Two or more generations can be grown to ensure stable maintenance and inheritance of the deaminase or fusion protein polynucleotide, and then seeds are harvested to ensure the presence of the deaminase or fusion protein polynucleotide. In this way, the present invention provides transformed seeds (also referred to as "transgenic seeds") having a nucleotide construct of the present invention (e.g., an expression cassette of the present invention) stably incorporated into its genome.

In some embodiments, transformed cells can be introduced into an organism. These cells can be derived from an organism in which the cells were transformed in vitro.

The sequences provided herein can be used for transformation of any plant species, including but not limited to monocots and dicots. Examples of plants of interest include but are not limited to maize (corn), sorghum, wheat, sunflower, tomato, crucifers, pepper, potato, cotton, rice, soybean, sugar beet, sugar cane, tobacco, barley, and rapeseed, Brassica sp., alfalfa, rye, millet, safflower, peanut, sweet potato, cassava, coffee, coconut, pineapple, citrus, cocoa, tea, banana, avocado, fig, guava, mango, olive, papaya, cashew, macadamia, almond, oat, vegetables, ornamental plants and conifers.

Vegetables include, but are not limited to, tomatoes, lettuce, green beans, beans, peas, and members of the genus Curcumis such as cucumber, cantaloupe, and musk melon. Ornamental plants include, but are not limited to, azaleas, hydrangeas, hibiscus, roses, tulips, daffodils, dwarf yews, carnations, poinsettias, and chrysanthemums. Preferably, the plants of the present invention are crops (e.g., corn, sorghum, wheat, sunflowers, tomatoes, crucifers, peppers, potatoes, cotton, rice, soybeans, sugar beets, sugar cane, tobacco, barley, rapeseed, etc.).

The term "plant" as used herein includes plant cells, plant protoplasts, plant cell tissue cultures from which plants can be regenerated, plant wound tissue, plant pieces, and intact plant cells in plants or parts of plants such as embryos, pollen, ovules, seeds, leaves, flowers, branches, fruits, kernels, ears, cobs, shells, stems, roots, root tips, anthers, and the like. Grains are intended to express mature seeds produced by commercial growers for purposes other than planting or propagating species. Progeny, variants, and mutants of regenerated plants are also included in the scope of the present invention, provided that these parts include the introduced polynucleotides. Further provided are processed plant products or by-products that maintain the sequences disclosed herein, for example, including soybean meal.

In some embodiments, polynucleotides encoding deaminases, fusion proteins and/or gRNAs are used to transform any eukaryotic species, including but not limited to animals (e.g., mammals, insects, fish, birds, and reptiles), fungi, amoebas, algae, and yeast. In some embodiments, polynucleotides encoding deaminases, fusion proteins and/or gRNAs are used to transform any prokaryotic species, including but not limited to archaea and bacteria (e.g., Bacillus spp. , Klebsiella spp. , Streptomyces spp. , Rhizobium spp ., Escherichia spp. , Pseudomonas spp. , Salmonella spp., Shigella spp ., Vibrio spp. , Yersinia spp ., Mycoplasma spp. , Agrobacterium spp. Agrobacterium ), Lactobacillus spp .

In some embodiments, conventional viral and non-viral gene transfer methods are used to introduce nucleic acids into mammalian cells or target tissues. Such methods can be used to administer nucleic acids encoding the deaminases or fusion proteins of the invention and optionally gRNA to cells in culture or in a host organism. Non-viral vector delivery systems include DNA plasmids, RNA (e.g., transcripts of the vectors described herein), naked nucleic acids, and nucleic acids complexed with delivery vehicles such as liposomes. Viral vector delivery systems include DNA and RNA viruses that have episomal or integrated genomes after delivery to cells. Non-limiting examples include vectors using cauliflower mosaic virus (e.g., cauliflower mosaic virus), geminivirus (e.g., leguminous golden mosaic virus or maize stripe virus), and RNA plant virus (e.g., tobacco mosaic virus). For a review of gene therapy procedures, see Anderson, Science 256: 808-813 (1992); Nabel & Feigner, TIBTECH 11: 211-217 (1993); Mitani & Caskey, TIBTECH 11: 162-166 (1993); Dillon, TIBTECH 11: 167-175 (1993); Miller, Nature 357: 455-460 (1992); Van Brunt, Biotechnology 6(10): 1149-1154 (1988); Vigne, Restorative Neurology and Neuroscience 8: 35-36 (1995); Kremer & Perricaudet, British Medical Bulletin 51(1): 31-44 (1995); Haddada et al., in Current Topics in Microbiology and Immunology, Doerfler and Bohm (eds.) (1995); and Yu et al., Gene Therapy 1:13-26 (1994).

Non-viral delivery methods for nucleic acids include liposome transfection, Agrobacterium-mediated transformation, nuclear transfection, microinjection, gene guns, virosomes, liposomes, immunoliposomes, polycation or lipid: nucleic acid conjugates, naked DNA, artificial virus particles, and reagents to enhance uptake of DNA. For example, liposome transfection is described in U.S. Patent Nos. 5,049,386, 4,946,787, and 4,897,355, and liposome transfection reagents are commercially available (e.g., Transfectam™ and Lipofectin™). Cationic and neutral lipids suitable for efficient receptor-recognition lipofection of polynucleotides include those of Feigner, WO 91/17424; WO 91/16024. Delivery can be to cells (e.g., in vitro or ex vivo administration) or to target tissues (e.g., in vivo administration). The preparation of lipid:nucleic acid complexes, such as immunolipid complexes, including targeted liposomes, is well known to those skilled in the art (see, e.g., Crystal, Science 270:404-410 (1995); Blaese et al., Cancer Gene Ther. 2:291-297 (1995); Behr et al., Bioconjugate Chem. 5:382-389 (1994); Remy et al., Bioconjugate Chem. 5:647-654 (1994); Gao et al., Gene Therapy 2:710-722 (1995); Ahmad et al., Cancer Res. 52:4817-4820). (1992); U.S. Patent Nos. 4,186,183; 4,217,344; 4,235,871; 4,261,975; 4,485,054; 4,501,728; 4,774,085; 4,837,028; and 4,946,787).

The use of RNA or DNA virus-based systems to deliver nucleic acids utilizes highly evolved processes to target viruses to specific cells in the body and transport the viral payload to the cell nucleus. Viral vectors can be administered directly to patients (in vivo), or viral vectors can be used to treat cells in vitro, and the modified cells can be optionally administered to patients (ex vivo). Traditional viral-based systems can include retroviral, lentiviral, adenoviral, adeno-associated, and herpes simplex virus vectors for gene transfer. With retroviral, lentiviral, and adeno-associated virus gene transfer methods, integration in the host genome is possible, often resulting in long-term expression of the inserted transgene. In addition, high transduction efficiencies have been observed in many different cell types and target tissues.

The tropism of a retrovirus can be altered by incorporating foreign envelope proteins, thereby expanding the potential target population of target cells. Lentiviral vectors are retroviral vectors that are able to transduce or infect non-dividing cells and generally produce high viral titers. Therefore, the choice of a retroviral gene transfer system will depend on the target tissue. Retroviral vectors are composed of cis-acting long terminal repeat sequences that have the packaging capacity for up to 6-10 kb of foreign sequences. The minimal cis-acting LTRs are sufficient for replication and packaging of the vector, which is then used to integrate the desired gene into the target cells to provide permanent transgene expression. Widely used retroviral vectors include those based on mouse leukemia virus (MuLV), gibbon ape leukemia virus (GaLV), simian immunodeficiency virus (SIV), human immunodeficiency virus (HIV), and combinations thereof (see, e.g., Buchscher et al., J. Virol. 66:2731-2739 (1992); Johann et al., J. Virol. 66:1635-1640 (1992); Sommnerfelt et al., Virol. 176:58-59 (1990); Wilson et al., J. Virol. 63:2374-2378 (1989); Miller et al., J. Virol. 65:2220-2224 (1991); PCT/US94/05700).

In applications where transient expression is preferred, adenovirus-based systems can be used. Adenovirus-based vectors are capable of very high transduction efficiencies in many cell types and do not require cell division. High titers and high expression levels have been achieved using such vectors. The vectors can be produced in large quantities in a relatively simple system. Adeno-associated virus ("AAV") vectors can also be used to transduce cells with target nucleic acids, for example, in the in vitro production of nucleic acids and peptides, and in in vivo and ex vivo gene therapy procedures (see, e.g., West et al., Virology 160:38-47 (1987); U.S. Pat. No. 4,797,368; WO 93/24641; Katin, Human Gene Therapy 5:793-801 (1994); Muzyczka, J. Clin. Invest. 94:1351 (1994). The construction of recombinant AAV vectors is described in many publications, including U.S. Pat. No. 5,173,414; Tratschin et al., Mol. Cell. Biol. 5:3251-3260 (1985); Tratschin et al., Mol. Cell. Biol. 4:2072-2081 (1984); Hermonat & Muzyczka, PNAS 81:6466-6470 (1984); and Samulski et al., J. Virol. 63:03822-3828 (1989). Packaging cells are often used to form viral particles that can infect host cells. Such cells include 293 cells for packaging adenoviruses and ψJ2 cells or PA317 cells for packaging retroviruses.

Viral vectors used in gene therapy are typically produced by generating a cell strain that packages a nucleic acid vector into a viral particle. The vector typically contains the minimal viral sequences required for packaging and subsequent integration into the host, with other viral sequences replaced by an expression cassette for the polynucleotide(s) to be expressed. The missing viral functions are typically provided in trans by the packaging cell strain. For example, AAV vectors used in gene therapy typically have only the ITR sequences from the AAV genome required for packaging and integration into the host genome. The viral DNA is packaged in a cell strain that contains a helper plasmid that encodes the other AAV genes (i.e., rep and cap) but lacks the ITR sequences.

Adenovirus can also be used as a helper to infect cell lines. Helper viruses promote replication of AAV vectors and expression of AAV genes from helper plasmids. Due to the lack of ITR sequences, the helper plasmids are not packaged in large quantities. Adenovirus contamination can be reduced by, for example, heat treatment, to which adenovirus is more sensitive than AAV. Other methods for delivering nucleic acids to cells are known to those of ordinary skill in the art. See, for example, US20030087817, which is incorporated herein by reference.

Ideally, the coding sequence of the fusion protein of the present invention and the corresponding guide RNA for fusion protein targeting can all be packaged in a single AAV vector. Generally speaking, the size limit of the accepted AAV vector is 4.7 kb, but larger sizes can be considered, but the cost is reduced packaging efficiency. In order to ensure that the expression box of both the fusion protein and its corresponding guide RNA can be loaded into the AAV vector, an active deletion variant of the RGN can be used. In addition to shortening the amino acid sequence and thus shortening the coding sequence of the RGN and/or deaminase of the fusion protein, the peptide linker connecting the RGN and the deaminase can also be shortened or removed. Finally, the genetic elements of the promoter, enhancer and/or terminator can also be engineered through deletion analysis to determine the minimum size required for each one that will work. The present invention also teaches methods for using the fusion proteins for targeted base editing via in vivo AAV vector delivery.

In some embodiments, host cells are transiently or non-transiently transfected with one or more vectors described herein. In some embodiments, cells are transfected when they naturally exist in an individual. In some embodiments, transfected cells are taken from an individual.

In some embodiments, the transfected cells are eukaryotic cells. In some embodiments, the eukaryotic cells are animal cells (e.g., mammals, insects, fish, birds, and reptiles). In some embodiments, the transfected cells are human cells. In some embodiments, the transfected cells are hematopoietic cells, for example, immune cells (i.e., cells of the innate or adaptive immune system), including but not limited to: B cells, T cells, natural killer (NK) cells, high-potential stem cells, induced high-potential stem cells, chimeric antigen receptor T (CAR-T) cells, monocytes, macrophages, and dendritic cells. The transfected cells can be allogeneic cells (e.g., allogeneic T cells) or autologous cells (e.g., autologous T cells).

In some embodiments, the cell is obtained from a cell (e.g., a cell strain) taken from an individual. In some embodiments, the cell or cell strain is prokaryotic. In some embodiments, the cell or cell strain is eukaryotic. In other embodiments, the cell or cell strain is obtained from an insect, bird, plant, or fungal species. In some embodiments, the cell or cell strain can be a mammal, for example, such as a human, monkey, mouse, cow, pig, goat, hamster, rat, cat, or dog. A variety of cell strains for tissue culture are known in the art. Examples of cell lines include, but are not limited to, C8161, CCRF-CEM, MOLT, mIMCD-3, NHDF, HeLaS3, Huhl, Huh4, Huh7, HUVEC, HASMC, HEKn, HEKa, MiaPaCell, Panel, PC-3, TF1, CTLL-2, CIR, Rat6, CVI, RPTE, A10, T24, 182, A375, ARH-77, Calul, SW480, SW620, SKOV3, SK-UT, CaCo2, P388D1, SEM-K2, WEHI-231, HB56, TIB55, lurkat, 145.01 , LRMB, Bcl-1, BC-3, IC21, DLD2, Raw264.7, NRK, NRK-52E, MRC5, MEF, Hep G2, HeLa B, HeLa T4. COS, COS-1, COS-6, COS-M6A, BS-C-1 monkey kidney epithelial cells, BALB/3T3 mouse embryonic fibroblasts, 3T3 Swiss, 3T3-L1, 132-d5 human fetal fibroblasts; 10.1 mouse fibroblasts, 293-T, 3T3, 721, 9L, A2780, A2780ADR, A2780cis, A172, A20, A253, A431, A-549, ALC, B16, B35, BCP-I cells, BEAS-2B, bEnd.3, BHK-21, BR 293, BxPC3, C3H-10Tl/2, C6/36, Cal-27, CHO, CHO-7, CHO-IR, CHO-Kl, CHO-K2, CHO-T, CHO Dhfr-/-, COR-L23, COR-L23/CPR, COR-L235010, CORL23/ R23, COS-7, COV-434, CML Tl, CMT, CT26 , D17, DH82, DU145, DuCaP, EL4, EM2, EM3, EMT6/AR1, EMT6/AR10.0, FM3, H1299, H69, HB54, HB55, HCA2, HEK-293, HeLa, Hepalclc7, HL-60, HMEC, HT-29, lurkat, lY cells, K562 cells, Ku812, KCL22, KGl, KYOl, LNCap, Ma-Mel 1-48, MC-38, MCF-7, MCF-l0A, MDA-MB-231, MDA-MB-468, MDA-MB-435, MDCKII, MDCKII, MOR/0.2R, MONO-MAC 6, MTD-lA, MyEnd, NCI-H 69/CPR, NCI-H69/LX10, NCI-H69/LX20, NCI-H69/LX4, NIH-3T3, NALM-1, NW-145, OPCN/OPCT cell lines, Peer, PNT-lA/ PNT 2, RenCa, RIN-5F, RMA/RMAS, Saos-2 cells, Sf-9, SkBr3, T2, T-47D, T84, THP1 cell strains, U373, U87, U937, VcaP, Vero cells, WM39, WT-49, X63, YAC-1, YAR, and transgenic varieties thereof. Cell strains can be obtained from a variety of sources known to those of ordinary skill in the art (see, for example, American Type Culture Collection (ATCC) (Manassas, Va.)).

In some embodiments, cells transfected with one or more vectors described herein are used to establish new cell lines comprising one or more vector-derived sequences. In some embodiments, cells transiently transfected with a fusion protein and optionally a gRNA of the invention, or with a ribonucleoprotein complex of the invention and modified by the activity of the fusion protein or ribonucleoprotein complex are used to establish new cell lines comprising cells containing the modification but lacking any other exogenous sequences. In some embodiments, cells transiently or non-transiently transfected with one or more vectors described herein, or cell lines derived from such cells, are used to evaluate one or more test compounds.

In some embodiments, one or more vectors described herein are used to produce non-human transgenic animals or transgenic plants. In some embodiments, the transgenic animal is an insect. In other embodiments, the insect is a pest, such as a mosquito or a wall bug. In some embodiments, the insect is a plant pest, such as a corn rootworm or a fall armyworm. In some embodiments, the transgenic animal is a bird, such as a chicken, a turkey, a goose, or a duck. In some embodiments, the transgenic animal is a mammal, such as a human, a mouse, a rat, a hamster, a monkey, ape, a rabbit, a pig, a cow, a horse, a goat, a sheep, a cat, or a dog. VII. Variants and fragments of polypeptides and polynucleotides

The present disclosure provides deaminases active on DNA molecules and fusion proteins comprising deaminases, and fusion proteins comprising RGN and a heterologous polypeptide (e.g., deaminases). RGN may include any of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699, active variants or fragments thereof, and polynucleotides encoding the same. Deaminases may include any of SEQ ID NOs: 6, 229-414, 596, 597, and 720-723, active variants or fragments thereof, and polynucleotides encoding the same.

Although the activity of the variant or fragment may be altered compared to the polynucleotide or polypeptide of interest, the variant and fragment should retain the functionality of the polynucleotide or polypeptide of interest. For example, the variant or fragment may have increased activity, decreased activity, a different activity profile, or any other change in activity when compared to the polynucleotide or polypeptide of interest.

Fragments and variants of the deaminase of the present invention having adenine deaminase activity will retain this activity if they are part of a fusion protein further comprising a DNA binding polypeptide or fragment thereof.

Fragments and variants of the fusion proteins of the present invention that have base editing activity (e.g., fusion protein fragments and variants that include fragments or variants of deaminase, or fusion protein fragments and variants that include fragments or variants of a DNA binding polypeptide (e.g., RGN)) will retain that activity.

The term "fragment" refers to a portion of a polynucleotide or polypeptide sequence of the present invention. A "fragment" or "biologically active portion" includes a polynucleotide that includes a sufficient number of consecutive nucleotides to retain biological activity. A "fragment" or "biologically active portion" includes a polypeptide that includes a sufficient number of consecutive amino acid residues to retain biological activity. Fragments of the deaminases or RGNs disclosed herein include those that are shorter than the full-length sequence due to the use of alternative downstream start sites. In some embodiments, a biologically active portion of an RGN or deaminase is a polypeptide comprising, e.g., 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, or more consecutive amino acid residues of any one of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699, or a variant thereof. In some embodiments, a biologically active portion of RGN or deaminase is a polypeptide comprising, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, or more consecutive amino acid residues of any one of SEQ ID NOs: 5, 6, 229-414, 596, 597, and 720-723, or a variant thereof. Such biologically active portions can be prepared by recombinant techniques and assessed for activity.

In general, "variants" are intended to mean substantially similar sequences. For polynucleotides, variants include deletions and/or additions of one or more nucleotides at one or more internal sites within a natural polynucleotide and/or substitutions of one or more nucleotides at one or more sites in a natural polynucleotide. As used herein, "natural" or "wild-type" polynucleotides or polypeptides include naturally occurring nucleotide sequences or amino acid sequences, respectively. For polynucleotides, conservative variants include those sequences that encode the natural amino acid sequence of the gene of interest due to the degeneracy of the genetic code. For example, naturally occurring allelic variants that can be identified (e.g., using polymerase chain reaction (PCR) and hybridization techniques) using well-known molecular biology techniques are summarized below. Variant polynucleotides also include synthetically derived polynucleotides, such as those generated by using site-directed mutagenesis but which still encode a polypeptide or polynucleotide of interest. Variants of a particular polynucleotide disclosed herein will have about 40% to about 99% or more sequence identity to that particular polynucleotide as determined by sequence alignment programs and parameters described elsewhere herein. Generally, variants of a particular polynucleotide disclosed herein will have at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or more sequence identity to that particular polynucleotide as determined by sequence alignment programs and parameters described elsewhere herein.

Variants of a particular polynucleotide disclosed herein (i.e., a reference polynucleotide) can also be evaluated by comparing the percentage of sequence identity between a polypeptide encoded by a variant polynucleotide and a polypeptide encoded by a reference polynucleotide. The percentage of sequence identity between any two polypeptides can be calculated using sequence alignment programs and parameters described elsewhere herein. When any given polynucleotide pair disclosed herein is evaluated by comparing the percentage of sequence identity shared by the two polypeptides encoded by them, the percentage of sequence identity between the two encoded polypeptides is about 40% to about 99% or more sequence identity, and in some embodiments at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or more sequence identity.

In some embodiments, the polynucleotides disclosed herein encode a deaminase comprising an amino acid sequence having at least about 40% to about 99% or more identity with the amino acid sequence of any one of SEQ ID NOs: 5, 6, 300-414, 596-598, and 720-723, wherein the deaminase comprises at least one of the amino acid residues shown in any one of Tables 2, 4, 6, and 19. In some embodiments, the polynucleotides disclosed herein encode a deaminase comprising an amino acid sequence having at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more identity to the amino acid sequence of any one of SEQ ID NOs: 5, 6, 300-414, 596-598, and 720-723, wherein the deaminase comprises at least one of the amino acid residues set forth in any one of Tables 2, 4, 6, and 19.

Biologically active variants of adenine deaminase of the present invention may differ by as few as 1-15 amino acid residues, as few as 1-10 (e.g., 6-10), as few as 5, as few as 4, as few as 3, as few as 2, or as few as 1 amino acid residue. In specific embodiments, the polypeptide includes an N-terminal or C-terminal truncation, which may include a deletion of at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 amino acids or more from the N-terminus or C-terminus of the polypeptide. In some embodiments, the polypeptide comprises an internal deletion which can include a deletion of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60 amino acids or more.

It will be appreciated that the RGNs and deaminases provided herein may be modified to generate variant proteins and polynucleotides. Designed changes may be introduced through the use of site-directed mutagenesis techniques. In some embodiments, native, unknown or unidentified polynucleotides and/or polypeptides that are structurally and/or functionally related to the sequences disclosed herein may also be considered within the scope of the invention. Conservative amino acid substitutions may be made in non-conserved regions that do not alter the function of the polypeptide as an adenine deaminase.

Variant polynucleotides and proteins also encompass sequences and proteins resulting from mutagenic and recombinogenic procedures such as DNA shuffling. Using such procedures, one or more different RGNs or deaminases are manipulated to generate new deaminases with desired properties. In this manner, a library of recombinant polynucleotides is generated from a population of related sequence polynucleotides comprising sequence regions that have substantial sequence identity and can be homologously recombined in vitro or in vivo. For example, using this approach, sequence motifs encoding a domain of interest can be shuffled between the sequences provided herein and other subsequently identified genes to obtain new genes encoding proteins with improved properties of interest (e.g., in the case of enzymes, increased K _m ). Such strategies for DNA shuffling are known in the art. See, e.g., Stemmer (1994) Proc. Natl. Acad. Sci. USA 91:10747-10751; Stemmer (1994) Nature 370:389-391; Crameri et al. (1997) Nature Biotech . 15:436-438; Moore et al. (1997) J. Mol. Biol . 272:336-347; Zhang et al. (1997) Proc. Natl. Acad. Sci. USA 94:4504-4509; Crameri et al. (1998) Nature 391:288-291; and U.S. Patent Nos. 5,605,793 and 5,837,458. "Shuffled" nucleic acids are nucleic acids produced by a shuffle procedure, e.g., any of the shuffle procedures described herein. Shuffled nucleic acids are produced by, for example, artificially and optionally recursively (physically or virtually) recombining two or more nucleic acids (or strings). In general, one or more screening steps are used in the shuffling process to identify nucleic acids of interest; this screening step can be performed before or after any recombination step. In some (but not all) shuffling embodiments, it is desirable to perform multiple rounds of recombination before selection to increase the diversity of the pool to be screened. Optionally, the entire process of recombination and selection is repeated recursively. Depending on the context, shuffling can refer to the entire process of recombination and selection, or alternatively, it can refer to only the recombination portion of the entire process.

As used herein, "sequence identity" or "identity" in the context of two polynucleotide or polypeptide sequences refers to residues in two sequences that are identical when aligned for maximum correspondence over a specified comparison window. It should be recognized that different residue positions typically differ by conservative amino acid substitutions, in which amino acid residues are substituted for other amino acid residues with similar chemical properties (e.g., charge or hydrophobicity) and thus do not change the functional properties of the molecule. Protein sequences that differ by such conservative substitutions are said to have "sequence similarity" or "similarity." Means for measuring sequence similarity are well known to those of ordinary skill in the art. Typically, this involves counting conservative substitutions as partial mismatches rather than complete mismatches. Thus, for example, while the score for identical amino acids is 1, and the score for non-conservative substitutions is zero, the score for conservative substitutions is a score between 0 and 1. Scores for conservative substitutions are calculated, for example, as implemented in the program PC/GENE (Intelligenetics, Mountain View, California).

As used herein, "sequence identity percentage" refers to a value determined by comparing two optimally aligned sequences over a comparison window, wherein the portion of the polynucleotide sequence in the comparison window may include additions or deletions (i.e., gaps) compared to a reference sequence (excluding additions or deletions) for the optimal alignment of the two sequences. The percentage is calculated by determining the number of positions where the same nucleic acid base or amino acid residue appears in the two sequences to obtain the number of matching positions, dividing the number of matching positions by the total number of positions in the comparison window, and multiplying the result by 100 to obtain the sequence identity percentage.

Unless otherwise indicated, the sequence identity/similarity values provided herein refer to the values obtained using GAP version 10 using the following parameters: % identity and similarity for nucleotide sequences using GAP weight 50 and length weight 3 and the nwsgapdna.cmp scoring matrix; % identity and similarity for amino acid sequences using GAP weight 8 and length weight 2 and the BLOSUM62 scoring matrix; or any equivalent programs. "Equivalent program" means any sequence comparison program that, for any two sequences involved, produces an alignment with consistent nucleotide or amino acid residue matches and consistent sequence identity percentages when compared to the corresponding alignment produced by GAP version 10.

Two sequences are "optimally aligned" when they are aligned for similarity scoring using a defined amino acid substitution matrix (e.g., BLOSUM62), gap existence penalty, and gap extension penalty to achieve the highest score possible for that pair of sequences. Amino acid substitution matrices and their use in quantifying the similarity between two sequences are well known in the art and are described, for example, in Dayhoff et al. (1978) "A model of evolutionary change in proteins";"Atlas of Protein Sequence and Structure", Vol. 5, Supplement 3 (Edited by MO Dayhoff), pp. 345-352; Natl. Biomed. Res. Found., Washington, DC; and Henikoff et al. (1992) Proc. Natl. Acad. Sci. USA 89: 10915-10919. The BLOSUM62 matrix is often used as the default scoring substitution matrix in sequence alignment workflows. Gap presence penalty is used for the introduction of a single amino acid gap in one of the aligned sequences, while gap extension penalty is used for each additional empty amino acid position inserted into an already opened gap. Alignment is defined by the amino acid position of each sequence at the start and end of the alignment, and optionally by inserting one or more spacers in one or both sequences to achieve the highest possible score. Although optimal alignment and scoring can be done manually, the process can be facilitated by using a computer-implemented alignment algorithm (e.g., Altschul et al. (1997) Nucleic Acids Res . 25: 3389-3402, described in spaced BLAST 2.0, and available to the public on the website of the National Center for Biotechnology Information (www.ncbi.nlm.nih.gov). Optimal alignments including multiple alignments can be prepared using, for example, PSI-BLAST, available via www.ncbi.nlm.nih.gov and described in Altschul et al. (1997) Nucleic Acids Res . 25:3389-3402.

With respect to an amino acid sequence that is optimally aligned to a reference sequence, an amino acid residue "corresponds to" the position in the reference sequence to which the residue is paired in the alignment. The "position" is indicated by a number that identifies each amino acid in the reference sequence in sequence based on its position relative to the N-terminus. Because of deletions, insertions, truncations, fusions, etc. that must be considered when determining the optimal alignment, the number of amino acid residues in the test sequence, which is typically determined by simply counting from the N-terminus, will not necessarily be the same as the number of their corresponding positions in the reference sequence. For example, in the case of a deletion in the aligned test sequence, there will be no amino acid that corresponds to the position of the deletion site in the reference sequence. In the case of an insertion in the aligned reference sequence, the insertion will not correspond to any amino acid position in the reference sequence. In the case of truncations or fusions, there may be stretches of amino acids in the reference sequence or the aligned sequence that do not correspond to any amino acids in the corresponding sequence. VIII. Antibodies

Antibodies directed against deaminases, fusion proteins, or ribonucleoproteins comprising deaminases of the invention (including deaminases having an amino acid sequence as shown in any one of SEQ ID NOs: 6, 300-414, 596-598, and 720-723, or active variants or fragments thereof) are also contemplated. Methods for generating antibodies are well known in the art (see, e.g., Harlow and Lane (1988) Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY; and U.S. Patent No. 6,265). These antibodies can be used in kits for the detection and separation of ribonucleoproteins, deaminases, or fusion proteins described herein. Thus, the present disclosure provides kits comprising antibodies that specifically bind to polypeptides or ribonucleoproteins described herein, including, for example, polypeptides comprising a sequence having at least 85% identity to any one of SEQ ID NOs: 5, 6, 300-414, 596-598, and 720-723, wherein the deaminase comprises at least one of the amino acid residues shown in any one of Tables 2, 4, 6, and 19. IX. Systems for Binding and / or Modifying Target Sequences of Interest and Ribonucleoprotein Complexes and Methods of Making Them

The present disclosure provides a system for targeting a nucleic acid sequence and modifying the target nucleic acid sequence. In some embodiments, the system targets a heterologous polypeptide to a nucleic acid sequence and can modify the target nucleic acid sequence. In those embodiments in which the heterologous polypeptide comprises an alkali-editing polypeptide (e.g., a deaminase) or a lead editing polypeptide, the alkali-editing polypeptide (e.g., a deaminase) or a lead editing polypeptide is fused to an RGN (e.g., an RGN nickase or nuclease-inactive RGN) responsible for modifying the targeted nucleic acid sequence. The guide RNA hybridizes with the target sequence of interest and also forms a complex with the RGN component of the fusion protein, thereby guiding the fusion protein to bind to the target sequence.

In some embodiments, an RNA-guided DNA binding polypeptide, such as an RGN (e.g., an RGN nickase or nuclease-inactive RGN), and the gRNA is responsible for targeting the ribonucleoprotein complex to a nucleic acid sequence of interest and a deaminase polypeptide fused to the RDBBP is responsible for modifying the targeted nucleic acid sequence. In those embodiments in which the deaminase is an adenine deaminase, the base editor modifies A>N. In some embodiments, the adenine deaminase converts A>G. The guide RNA hybridizes with the target sequence of interest and also forms a complex with the RNA-guided DNA binding polypeptide, thereby directing the RNA-guided DNA binding polypeptide to bind to the target sequence. The RNA-guided DNA binding polypeptide is part of a fusion protein that also includes a deaminase, such as the deaminase described herein. In some embodiments, the RNA-guided DNA binding polypeptide is an RGN, such as Cas9. Other examples of RNA-guided DNA-binding polypeptides include RGNs, such as those described in International Patent Application Publication Nos. WO 2019/236566 and WO 2020/139783, each of which is incorporated by reference in its entirety. In some embodiments, the RNA-guided DNA-binding polypeptide is a type II CRISPR-Cas polypeptide or an active variant or fragment thereof. In some embodiments, the RNA-guided DNA-binding polypeptide is a type V CRISPR-Cas polypeptide or an active variant or fragment thereof. In some embodiments, the RNA-guided DNA-binding polypeptide is a type VI CRISPR-Cas polypeptide. In some embodiments, the DNA-binding polypeptide of the fusion protein does not require RNA guidance, for example, a zinc finger nuclease, a TALEN, or a meganuclease polypeptide. In some embodiments, the nuclease activity of the DNA-binding polypeptide has been partially or completely inactivated. In other embodiments, the RNA-guided DNA-binding polypeptide comprises the amino acid sequence of RGN (for example, APG07433.1 (SEQ ID NO: 1)), or an active variant or fragment thereof (for example, nickase nAPG07433.1 (SEQ ID NO: 49)).

In some embodiments, the system provided herein for binding and modifying a target sequence of interest is a ribonucleoprotein complex, which is at least one RNA molecule bound to at least one protein (i.e., a fusion protein). The ribonucleoprotein complex provided herein includes at least one guide RNA as an RNA composition and a fusion protein as a protein composition, the fusion protein including an RNA-guided DNA-binding polypeptide (e.g., RGN) and a heterologous polypeptide (e.g., deamidase) inserted therein. In some embodiments, the ribonucleoprotein complex is purified from a cell or organism that has been transformed with a polynucleotide encoding the fusion protein and the guide RNA and cultured under conditions that allow the expression of the fusion protein and the guide RNA.

Methods for making deaminase, fusion protein, or fusion protein ribonucleoprotein complex are provided. Such methods include: culturing cells comprising a nucleotide sequence encoding a deaminase, fusion protein, and, in some embodiments, a nucleotide sequence encoding a guide RNA, under conditions where the deaminase or fusion protein (and, in some embodiments, a guide RNA) is expressed. The deaminase, fusion protein, or fusion ribonucleoprotein can then be purified from a lysate of the cultured cells.

Methods for purifying deaminase, fusion protein or fusion ribonucleoprotein complex from a lysate of a biological sample are known in the art (e.g., particle size screening and/or affinity chromatography, 2D-PAGE, HPLC, reverse phase chromatography, immunoprecipitation). In a specific method, the deaminase or fusion protein is recombinantly produced and includes a purification tag that facilitates its purification, including but not limited to: glutathione-S-transferase (GST), chitin binding protein (CBP), maltose binding protein, thioredoxin (TRX), poly (NANP), tandem affinity purification (TAP) tag, myc, AcV5, AU1, AU5, E, ECS, E2, FLAG, HA, nus, Softag 1, Softag 3, Strep, SBP, Glu-Glu, HSV, KT3, S, S1, T7, V5, VSV-G, 6xHis, biotin carboxyl carrier protein (BCCP) and calcitonin. Generally, the tagged deaminase, fusion protein or fusion ribonucleoprotein complex is purified using immunoprecipitation or other similar methods known in the art.

An "isolated" or "purified" polypeptide, or biologically active portion thereof, is substantially or essentially free from components that normally associate with or interact with the polypeptide as found in the environment in which it naturally occurs. Thus, an isolated or purified polypeptide is substantially free of other cellular material or culture medium when produced by recombinant techniques, or substantially free of chemical precursors or other chemicals when chemically synthesized. Proteins that are substantially free of cellular material include preparations of protein having less than 30%, less than 20%, less than 10%, less than 5%, or less than 1% (by dry weight) of contaminating protein. When the protein of the invention or biologically active portion thereof is produced recombinantly, the optimal culture medium exhibits less than 30%, less than 20%, less than 10%, less than 5% or less than 1% (by dry weight) of chemical precursors or non-protein chemicals of concern.

Specific methods provided herein for binding and/or cleaving target sequences of interest involve the use of in vitro assembled ribonucleoprotein complexes. In vitro assembly of ribonucleoprotein complexes can be performed using methods known in the art, wherein a fusion protein comprising RGBP (e.g., RGN) is contacted with a guide RNA under conditions that allow the RGBP (e.g., RGN) fusion protein to bind to the guide RNA. "Contacting," as used herein, refers to bringing together the components of a desired reaction under conditions suitable for the desired reaction. The RGBP (e.g., RGN) fusion protein can be purified from a biological sample, cell lysate or culture medium, produced by in vitro translation, or chemically synthesized. The guide RNA can be purified from a biological sample, cell lysate or culture medium, translated in vitro, or chemically synthesized. The RDBBP (e.g., RGN) fusion protein and the guide RNA can be contacted in a solution (e.g., a buffered saline solution) to allow for in vitro assembly of the ribonucleoprotein complex. X. Methods for locating a heterologous polypeptide to a target DNA molecule or modifying a target DNA molecule

The present disclosure provides methods for localizing a heterologous polypeptide (e.g., a deaminase) to a target nucleic acid molecule of interest (e.g., a target DNA molecule) or modifying a target nucleic acid molecule. The method comprises delivering a fusion protein disclosed herein or a polynucleotide encoding the fusion protein to a target sequence or a cell, an organelle, or an embryo comprising the target sequence. In certain embodiments, the method comprises delivering a system comprising at least one guide RNA or a polynucleotide encoding the at least one guide RNA and at least one fusion protein disclosed herein to a target sequence or a cell, an organelle, or an embryo comprising the target sequence.

In some embodiments, the methods include contacting a DNA molecule with (a) a fusion protein; and (b) a gRNA that targets the fusion protein of (a) to a target nucleotide sequence of the DNA molecule; wherein the DNA molecule is contacted with the fusion protein and the gRNA in an effective amount and under conditions suitable for binding of the RGBDP (e.g., RGN) composition to the target sequence.

The target DNA molecule may include a sequence associated with a disease or condition, and wherein the editing of at least one base within the causal mutation may result in a sequence that is not associated with the disease or condition. In some embodiments, the disease or condition affects animals. In other embodiments, the disease or condition affects mammals, e.g., humans, cows, horses, dogs, cats, goats, sheep, pigs, monkeys, rats, mice, or hamsters. In some embodiments, the target DNA sequence resides in an allelic gene of a crop plant, wherein a specific allelic gene for a trait of interest results in a plant of lower agronomic value. The editing of at least one base within this region results in an allelic gene that improves the trait of the plant and increases the agronomic value of the plant.

After delivering the polynucleotide encoding the guide RNA and/or fusion protein, the cell or embryo can then be cultured under conditions in which the guide RNA and/or fusion protein is expressed. In various embodiments, the method includes contacting the target sequence with a ribonucleoprotein complex comprising a gRNA and a fusion protein. In certain embodiments, the method includes introducing the ribonucleoprotein complex of the present invention into a cell, organelle, or embryo comprising the target sequence. The ribonucleoprotein complex of the present invention can be a ribonucleoprotein complex that has been purified from a biological sample, recombinantly produced and subsequently purified, or assembled in vitro as described herein. In those embodiments in which the ribonucleoprotein complex that is contacted with the target sequence or cell, organelle or embryo has been assembled in vitro, the method can further comprise the in vitro assembly of the complex prior to contacting with the target sequence, cell, organelle or embryo.

Any method known in the art, including but not limited to electroporation, can be used to introduce the purified or in vitro assembled ribonucleoprotein complex of the present invention into cells, organelles or embryos. In some embodiments, the fusion protein (or a polynucleotide encoding the fusion protein) and a polynucleotide encoding or comprising a guide RNA are introduced into cells, organelles or embryos using any method known in the art (e.g., electroporation).

When delivered to or contacted with the target sequence or a cell, organelle or embryo comprising the target sequence, the guide RNA directs the fusion protein to bind to the target sequence in a sequence-specific manner. In those cases where the fusion protein comprises a base editing polypeptide (e.g., a deaminase) or a lead editing polypeptide, the target sequence can then be modified.

In some embodiments where the fusion protein is an abase editor (i.e., an abase editing polypeptide including, for example, a deaminase), binding of the fusion protein to the target sequence results in modification of nucleotides adjacent to the target sequence. The nucleotides adjacent to the target sequence that are modified by the deaminase can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 base pairs from the 5' or 3' end of the target sequence. The full range of nucleotides that can be edited using an abase editor fusion protein (e.g., an RGN fused to a deaminase), typically expressed as the distance of the nucleotide from the PAM sequence (e.g., nucleotides at positions 8 and 22 upstream (i.e., 5') of the PAM sequence) is referred to herein as the "editing window" of a particular abase editor fusion protein. The editing window can be, for example, 1-100 base pairs 5' or 3' of the PAM sequence, including but not limited to 5-50, 5-25, 8-22, 10-20, or 10-21 base pairs 5' or 3' of the PAM sequence. Fusion proteins comprising an adenine deaminase (e.g., those disclosed herein) and an RNA-guided DNA binding polypeptide (e.g., RGN) can introduce a targeted A>N mutation into a targeted DNA molecule. In some embodiments, the fusion protein introduces a targeted A>G mutation into a targeted DNA molecule.

Methods for measuring binding of fusion proteins to target sequences are known in the art and include chromatin immunoprecipitation assays, gel mobility shift assays, DNA pull-down assays, reporter assays, microplate capture and detection assays. Similarly, methods for measuring cleavage or modification of target sequences are known in the art and include in vitro or in vivo cleavage assays, where cleavage is confirmed using PCR, sequencing, or gel electrophoresis (with or without a suitable label (e.g., radioisotope, fluorescent substance) attached to the target sequence to facilitate detection of degradation products). In some embodiments, a nick-triggered exponential expansion reaction (NTEXPAR) assay is used (see, e.g., Zhang et al. (2016) Chem. Sci. 7: 4951-4957). In vivo shearing can be assessed using the Surveyor assay (Guschin et al. (2010) Methods Mol Biol 649:247-256).

Methods for measuring the base editing activity of base editor fusion proteins or lead editor fusion proteins are known in the art and include those described herein and any form of sequence analysis of the target nucleic acid molecule after contact with the base editor or lead editor (e.g., PCR, sequencing, or gel electrophoresis with or without attachment of a suitable tag). When compared to a similar base editor fusion protein including the parent LPG50148 deaminase, the base editor fusion protein including the deaminase disclosed herein can exhibit improved editing activity (i.e., improved editing efficiency or reduced RNA editing), a larger editing window, or both. Deaminases including the present invention (e.g., SEQ ID NO: 5, 6, 300-414, 596-598, and 720-723, or an active variant or fragment thereof (including at least one of the amino acid residues shown in any one of Tables 2, 4, 6, and 19)) can have a base editing efficiency that is 1.1 to 10 times, 1.1 to 20 times, 1.1 to 30 times, or higher than that of a second base editor fusion protein that includes a parent LPG50148 deaminase and the same DNA binding polypeptide (e.g., RGN) as the first base editor fusion protein, Including but not limited to about 1.1 times, about 1.5 times, about 2 times, about 2.5 times, about 3 times, about 3.5 times, about 4 times, about 4.5 times, about 5 times, about 5.5 times, about 6 times, about 6.5 times, about 7 times, about 7.5 times, about 8 times, about 8.5 times, about 9 times, about 9.5 times, about 10 times, about 11 times, about 12 times, about 13 times, about 15 times, about 16 times, about 17 times, about 18 times, about 19 times, about 20 times, about 21 times, about 22 times, about 23 times, about 24 times, about 25 times, about 26 times, about 27 times, about 28 times, about 29 times, and about 30 times. A base editor fusion protein comprising the deaminase of the present invention can exhibit reduced RNA editing when compared to a similar base editor fusion protein comprising the parent LPG50148 deaminase. A first base editor fusion protein comprising a deaminase of the present invention can exhibit an RNA editing rate of about 1% to about 99%, including but not limited to about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, and about 99%, of a second base editor fusion protein comprising a parent LPG50148 deaminase and the same DNA binding polypeptide (e.g., RGN) as the first base editor fusion protein.

The deaminase of the present invention (e.g., SEQ ID NO: 5, 6, 300-414, 596-598, and 720-723, or an active variant or fragment thereof (including at least one of the amino acid residues shown in any one of Tables 2, 4, 6, and 19)) can have an editing window that is at least one nucleotide longer than one or both sides of the editing window of a second base editor fusion protein that includes a parent LPG50148 deaminase and a DNA binding protein (e.g., RGN) that is the same as the first base editor fusion protein, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more nucleotides longer than one or both sides of the editing window of the parent base editor.

In some embodiments, the method involves the use of a fusion protein in which an RDBBP (e.g., RGN) is complexed with more than one guide RNA. The more than one guide RNA can target different regions of a single gene or can target multiple genes. This multiple targeting enables the deaminase or lead editing polypeptide of the fusion protein to modify nucleic acids, thereby introducing multiple mutations in a target nucleic acid molecule of interest (e.g., a genome).

In some embodiments where the method involves the use of an RNA-guided nuclease (RGN), such as a nickase RGN (i.e., a nickase RGN that is only capable of cleaving a single strand of a double-stranded polynucleotide (e.g., nAPG07433.1 (SEQ ID NO: 49)), the method can include introducing two different RGNs or RGN variants that target the same or overlapping target sequences and cleave different strands of the polynucleotide. For example, an RGN nickase that only cleaves the plus (+) strand of a double-stranded polynucleotide can be introduced along with a second RGN nickase that only cleaves the minus (-) strand of a double-stranded polynucleotide. In some embodiments, two different fusion proteins are provided, wherein each fusion protein comprises a different RGN having a different PAM recognition sequence, allowing a greater diversity of nucleotide sequences to be targeted for mutation.

Those of ordinary skill in the art will appreciate that any of the currently disclosed methods can be used to target a single target sequence or multiple target sequences. Thus, methods include the use of fusion proteins comprising a single RDBBP (e.g., RGN) combined with multiple different guide RNAs, which can target multiple different sequences within a single gene and/or multiple genes. Methods in which multiple different guide RNAs are introduced in combination with multiple different RGN fusion proteins are also encompassed herein. These guide RNAs and guide RNA/fusion protein systems can target multiple different sequences within a single gene and/or multiple genes.

In some embodiments, fusion proteins comprising RNA-guided DNA binding polypeptides (e.g., RGNs) and heterologous polypeptides (e.g., deaminases) can be used to generate mutations in targeted genes or targeted regions of genes of interest. In some embodiments, the fusion proteins of the present invention can be used for saturation induction of targeted genes or regions of targeted genes of interest, followed by high-throughput forward genetic screening to identify novel mutations and/or phenotypes. In some embodiments, the fusion proteins described herein can be used to generate mutations in targeted genomic locations, which may or may not include coding DNA sequences. Cell line libraries generated by the above-described targeted induction can also be used to study gene function or gene expression. XI. Target polynucleotides

In one aspect, the present invention provides a method for modifying a target polynucleotide in a eukaryotic cell, which can be in vivo, in vitro or in vitro. In some embodiments, the method comprises sampling a cell or a cell population from a human or non-human animal or plant (including microalgae) and modifying the cell or cells. The culture can occur at any stage in vitro. The cell or cells can even be reintroduced into a human, non-human animal or plant (including microalgae).

Using natural variation, plant breeders combine most useful genes for desired qualities such as yield, quality, uniformity, cold tolerance, and resistance to pests. These desired qualities also include growth, day length preference, temperature requirements, start date of flower or reproductive development, fatty acid content, insect resistance, disease resistance, nematode resistance, fungal resistance, herbicide resistance, tolerance to various environmental factors (including drought, heat, humidity, cold, wind, and unfavorable soil conditions including high salinity). The sources of these useful genes include local or exotic varieties, heirloom varieties, wild plant close sources, and induced mutations such as treatment of plant materials with inducing agents. Using the present invention, plant breeders are provided with new tools for inducing mutations. Accordingly, one skilled in the art can employ the present invention to induce the increase of useful genes with greater precision than previous inducers, and thereby accelerate and improve plant breeding programs.

The target polynucleotide of the fusion protein of the present invention can be any polynucleotide that is endogenous or exogenous to a eukaryotic cell. For example, the target polynucleotide can be a polynucleotide present in the nucleus of a eukaryotic cell. In some embodiments, the target polynucleotide is a sequence encoding a gene product (e.g., a protein) or a non-coding sequence (e.g., a regulatory polynucleotide or junk DNA). In some embodiments, the target sequence of the fusion protein of the present invention is associated with a PAM (pre-spacer adjacent motif); that is, a short sequence recognized by an RNA-guided DNA-binding polypeptide (e.g., RGN). The exact sequence and length requirements of the PAM vary depending on the RNA-guided DNA-binding polypeptide used, but the PAM is typically a 2-5 base pair sequence adjacent to the pre-spacer sequence (i.e., the target sequence).

The target polynucleotides of the fusion proteins of the present invention may include many disease-associated genes and polynucleotides, as well as genes and polynucleotides associated with signaling biochemical pathways. Examples of target polynucleotides include sequences associated with signaling biochemical pathways, for example, genes or polynucleotides associated with signaling biochemical pathways. Examples of target polynucleotides include disease-associated genes or polynucleotides. "Disease-associated" genes or polynucleotides refer to any gene or polynucleotide that produces transcripts or translational products at abnormal levels or in abnormal forms in cells obtained from diseased tissues compared to non-disease-controlled tissues or cells. It can be a gene that becomes expressed at an abnormally high level; it can be a gene that becomes expressed at an abnormally low level, wherein the altered expression is associated with the occurrence and/or progression of the disease. A disease-associated gene also refers to a gene that is a direct cause of the disease or has a mutation or genetic variation that is in linkage imbalance (e.g., a causal mutation) with a gene that causes the disease. The transcript or translation product may be known or unknown, and may further be at normal or abnormal levels.

Non-limiting examples of disease-associated genes that can be targeted using the presently disclosed methods and compositions can be found on the World Wide Web at the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins University (Baltimore, Maryland) and the National Center for Biotechnology Information at the National Library of Medicine (Bethesda, Md.).

In some embodiments, the methods include contacting a DNA molecule comprising a target DNA sequence with a fusion protein of the present invention, wherein the DNA molecule is contacted with the fusion protein in an effective amount and under conditions suitable for modification of the target DNA molecule. In certain embodiments, the methods include contacting a DNA molecule comprising a target DNA sequence with (a) an RGN fusion protein of the present invention; and (b) a gRNA that targets the fusion protein of (a) to the target nucleotide sequence of the DNA strand; wherein the DNA molecule is contacted with the fusion protein and gRNA in an effective amount and under conditions suitable for deamination of at least one nucleobase. In some embodiments, the target DNA sequence includes a sequence associated with a disease or condition, and wherein deamination of the nucleobase results in a sequence that is not associated with the disease or condition. In some embodiments, the target DNA sequence is present in an allelic gene of a crop plant, wherein a particular allelic gene for a trait of interest results in a plant of lower agronomic value. Deamination of the nucleobase results in an allelic gene that improves the trait and increases the agronomic value of the plant.

In some embodiments, the target DNA sequence includes a point mutation associated with a disease or condition, and wherein the deamination of the mutant base results in a sequence not associated with the disease or condition. In some embodiments, deamination corrects a point mutation in a sequence associated with a disease or condition.

In some embodiments, the sequence associated with a disease or condition encodes a protein, and deamination or lead editing introduces a stop codon into the sequence associated with the disease or condition, resulting in truncation of the encoded protein. In some embodiments, the contacting is performed in vivo in an individual susceptible to, suffering from, or diagnosed with a disease or condition. In some embodiments, the disease or condition is a disease associated with a point mutation or a monobasic mutation in the genome. In some embodiments, the disease is a genetic disease, cancer, a metabolic disease, or a lytic storage disorder. XII. Pharmaceutical compositions and treatment methods

Provided herein are methods for treating a disease in an individual in need thereof. The method comprises administering to an individual in need thereof a fusion protein disclosed herein or a polynucleotide encoding the fusion protein, a gRNA or a polynucleotide encoding the gRNA, a fusion protein system disclosed herein, or a cell modified by or comprising any of these compositions.

In some embodiments, treatment comprises in vivo gene editing by administering a presently disclosed fusion protein, gRNA, or presently disclosed fusion protein system, or polynucleotide(s) encoding the fusion protein, gRNA, or presently disclosed fusion protein system to an individual in need thereof. In some embodiments, treatment comprises ex vivo gene editing in which cells are ex vivo genetically modified with a presently disclosed fusion protein, gRNA, or presently disclosed fusion protein system, or polynucleotide(s) encoding the fusion protein, gRNA, or presently disclosed fusion protein system, and then administering the modified cells to an individual. In some embodiments, the genetically modified cells are derived from an individual to which the modified cells are then administered, and the transplanted cells are referred to herein as autologous. In some embodiments, the genetically modified cells are derived from a different individual (i.e., donor) of the same species as the individual to whom the modified cells are administered (i.e., recipient), and the transplanted cells are referred to herein as allogeneic. In some examples described herein, the cells can be expanded in culture prior to administration to an individual in need of treatment.

In some embodiments, the disease to be treated with the presently disclosed compositions is a disease treatable by immunotherapy (e.g., using chimeric antigen receptor (CAR) T cells). Such diseases include, but are not limited to, cancer.

In some embodiments, modification of the target sequence (e.g., deamination) results in correction of a genetic defect or correction of a point mutation that causes loss of function of a gene product. In some embodiments, the genetic defect is associated with a disease or condition (e.g., a lytic storage disease or a metabolic disease (e.g., type I diabetes)). Thus, in some embodiments, the disease to be treated with the presently disclosed compositions is associated with a mutated sequence (i.e., the sequence is causal for the disease or condition or is causal for a symptom associated with the disease or condition) to treat the disease or condition, or to reduce a symptom associated with the disease or condition.

In some embodiments, the disease to be treated with the presently disclosed compositions is associated with a causal mutation. As used herein, a "causal mutation" refers to a specific nucleotide, multiple nucleotides, or nucleotide sequence in the genome that contributes to the severity or occurrence of a disease or condition in an individual. Correction of the causal mutation results in improvement of at least one symptom caused by the disease or condition. In some embodiments, correction of the causal mutation results in improvement of at least one symptom caused by the disease or condition. In some embodiments, the causal mutation is adjacent to a PAM site recognized by an RDBBP (e.g., RGN) of a fusion protein disclosed herein. The causal mutation can be corrected with a fusion protein. Non-limiting examples of disease-associated genes and mutations are available from the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, Md.) and the National Center for Biotechnology Information, National Library of Medicine (Bethesda, Md.), available on the World Wide Web.

In some embodiments, the methods provided herein are used to introduce deactivation point mutations into genes or alleles encoding gene products associated with diseases or conditions. For example, in some embodiments, methods are provided herein that use fusion proteins to introduce deactivation point mutations into oncogenes (e.g., in the treatment of proliferative diseases). In some embodiments, deactivation mutations can produce premature stop codons in the coding sequence, which leads to the expression of truncated gene products (e.g., truncated proteins lacking the function of full-length proteins). In some embodiments, the purpose of the methods provided herein is to restore the function of dysfunctional genes via genome editing. Fusion proteins provided herein can be effective for human therapies based on gene editing in vitro, such as by correcting disease-associated mutations in human cell culture. Those skilled in the art will appreciate that the fusion proteins provided herein (e.g., fusion proteins comprising an RNA-guided DNA binding polypeptide and an adenine deaminase polypeptide) can be used to correct any single-point A>G mutation. Deamination of the mutant A to G results in correction of the mutation.

As used herein, "treat" or "treating," or "alleviating," or "improving," may be used interchangeably. These terms refer to an approach for obtaining beneficial or desired results, including, but not limited to, therapeutic benefit and/or preventive benefit. By therapeutic benefit is meant any treatment-related improvement in, or effect on, one or more diseases, disorders, or symptoms being treated. For preventive benefit, the composition may be administered to an individual at risk for developing a particular disease, disorder, or symptom, or to an individual reporting one or more physiological symptoms of a disease, even though the disease, disorder, or symptom may not yet present signs.

The term "effective amount" or "therapeutically effective amount" refers to an amount of a drug sufficient to achieve beneficial or desired results. The therapeutically effective amount may vary depending on one or more of the following: the individual and disease condition being treated, the weight and age of the individual, the severity of the disease condition, the mode of administration, and the like, which can be easily determined by one of ordinary skill in the art. The specific dose may vary depending on one or more of the following: the specific drug selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, and the delivery system in which it is carried.

The term "administering" refers to placing an active ingredient in an individual by a method or route that causes the introduced active ingredient to be at least partially localized at a desired site (e.g., a site of injury or repair) so that (one or more) desired effects are produced. In those embodiments in which cells are administered, the cells may be administered by any suitable route that results in delivery to a desired location in an individual, wherein at least a portion of the transplanted cells or components of the cells remain viable. The survival period of cells after administration to an individual may be as short as a few hours (e.g., twenty-four hours), to a few days, to as long as several years, or even the life span of the patient, i.e., long-term implantation. For example, in some aspects described herein, an effective amount of photoreceptor cells or retinal progenitor cells is administered via a systemic route of administration (e.g., an intraperitoneal or intravenous route).

In some embodiments, administration includes administration by viral delivery. In some embodiments, administration includes administration by electroporation. In some embodiments, administration includes administration by nanoparticle delivery. In some embodiments, administration includes administration by liposome delivery. In some embodiments, administration includes administration by lipid nanoparticle (LNP) delivery. In some embodiments, LNP or its lipid composition is described in WO2022173531, WO2022150485, or U.S. Provisional Application No. 63/492,537 filed on March 28, 2023, the contents of each of which are incorporated herein by reference in their entirety. Any effective route of administration can be used to administer an effective amount of the pharmaceutical composition described herein. In some embodiments, administration comprises administration by a method selected from the group consisting of intravenously, subcutaneously, intramuscularly, orally, rectally, by aerosol, parenterally, ocularly, pulmonary, transdermally, vaginally, aurally, nasally, and by external administration, or any combination thereof. In some embodiments, for delivery of cells, administration by injection or perfusion is used.

As used herein, the term "subject" refers to any individual for whom diagnosis, treatment, or therapy is desired. In some embodiments, the subject is an animal. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. The human can be an adult, a teenager, a child, or an infant.

The efficacy of a treatment can be determined by a skilled clinician. However, a treatment is considered "effective treatment" if any or all of the signs or symptoms of the disease or condition are altered in a beneficial manner (e.g., reduced by at least 10%), or other clinically accepted symptoms or markers of the disease are ameliorated or improved. Efficacy can also be measured by the individual not experiencing worsening as assessed by hospitalization, or not requiring medical intervention (e.g., the progression of the disease is stopped or at least slowed). Methods for measuring these indicators are known to those of ordinary skill in the art. Treatment includes: (1) inhibiting the disease, e.g., arresting or slowing the progression of symptoms; or (2) slowing the disease, e.g., causing regression of symptoms; and (3) preventing or reducing the likelihood of symptom development.

Provided is a pharmaceutical composition comprising the presently disclosed fusion protein or a polynucleotide encoding the fusion protein, the presently disclosed system, or a cell comprising any of the fusion protein, the polynucleotide encoding the fusion protein, or the system, and a pharmaceutically acceptable carrier.

As used herein, "pharmaceutically acceptable carrier" refers to a material that does not cause significant irritation to an organism and does not eliminate the activity and properties of the active ingredient (e.g., deaminase or fusion protein or nucleic acid molecule encoding deaminase or fusion protein). The carrier must have a sufficiently high purity and sufficiently low toxicity to make it suitable for administration to the individual being treated. The carrier may be inert, or it may have a pharmaceutical benefit. In some embodiments, a pharmaceutically acceptable carrier includes one or more compatible solid or liquid fillers, diluents, or encapsulating materials suitable for administration to humans or other vertebrates. In some embodiments, the pharmaceutical composition includes a non-naturally occurring pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier is not found to be essentially together with the active ingredient and is therefore heterologous.

The pharmaceutical compositions used in the presently disclosed methods can be formulated with suitable carriers, excipients and other agents that provide suitable transfer, delivery, tolerance and the like. Many suitable formulations are known to those of ordinary skill in the art. See, for example, Remington, The Science and Practice of Pharmacy (21st edition, 2005). Non-limiting examples include: sterile diluents, such as water for injection, aqueous saline, non-volatile oils, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methyl paraben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates or phosphates; and agents for osmotic pressure regulation, such as sodium chloride or glucose. Specific carriers for intravenous administration are physiological saline or phosphate-buffered saline (PBS). Pharmaceutical compositions for oral or parenteral use can be prepared in dosage units suitable for supplying a certain dose of the active ingredient. Such unit dosage forms include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc. These compositions may also contain adjuvants including preservatives, wetting agents, emulsifiers, and dispersants. Protection against the action of microorganisms can be ensured by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, and the like). It is also desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of injectable drug forms can be caused by the use of agents that delay absorption (e.g., aluminum monostearate and gelatin).

In some embodiments in which cells comprising or containing the presently disclosed fusion proteins, systems, or polynucleotides encoding the fusion proteins, systems are administered to an individual, the cells are administered as a suspension with a pharmaceutically acceptable carrier. One of ordinary skill in the art will recognize that a pharmaceutically acceptable carrier to be used in a cell composition will not include an amount of buffer, compound, cryopreservative, preservative, or other agent that substantially interferes with the viability of the cells to be delivered to the individual. The formulations comprising cells may include, for example, osmotic pressure buffers that allow the maintenance of cell membrane integrity, and optionally nutrients that maintain cell viability or enhance implantation upon administration. Such formulations and suspensions are known to those of ordinary skill in the art, and/or can be adapted for use with the cells disclosed herein using routine experimentation.

The cell composition may also be emulsified or presented as a liposomal composition, provided that the emulsification procedure does not adversely affect cell viability. The cells and any other active ingredients may be mixed with a pharmaceutically acceptable and compatible formulation of the active ingredient and in an amount suitable for use in the treatment methods described herein.

The additives included in the cell composition may include pharmaceutically acceptable salts of the composition therein. Pharmaceutically acceptable salts include acid addition salts formed, for example, with inorganic acids such as hydrochloric acid or phosphoric acid, or with organic acids such as acetic acid, tartaric acid, mandelic acid and the like (formed with free amino groups of the polypeptide). Salts formed with free carboxyl groups may also be derived, for example, from inorganic bases such as sodium, potassium, ammonium, calcium or iron hydroxides, and organic bases such as isopropylamine, trimethylamine, 2-ethylaminoethanol, histidine, procaine and the like. XIII. Cells containing polynucleotide gene modifications

Provided herein are cells and organisms comprising a target nucleic acid molecule of interest (optionally with a gRNA as described herein) that has been modified using a process mediated by a fusion protein.

In some embodiments, the fusion protein comprises a deaminase polypeptide, or an active variant or fragment thereof, the deaminase polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 5, 6, 300-414, 596-598, and 720-723, the active variant or fragment comprising at least one of the amino acid residues shown in any one of Tables 2, 4, 6, and 19. In some embodiments, the fusion protein comprises a deaminase comprising an amino acid sequence having about 50% to about 99% identity or more to any one of: 5, 6, 300-414, 596-598, and 720-723. In some embodiments, the fusion protein comprises a deaminase comprising an amino acid sequence having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to any one of: 5, 6, 300-414, 596-598, and 720-723. In some embodiments, the fusion protein comprises a deaminase and a DNA binding polypeptide (e.g., an RNA-guided DNA binding polypeptide). In other embodiments, the fusion protein comprises a deaminase and an RGN or a variant thereof, such as APG07433.1 (SEQ ID NO: 1) or its nickase variant nAPG07433.1 (SEQ ID NO: 49). In some embodiments, the fusion protein comprises a deaminase and Cas9 or a variant thereof, such as dCas9 or a nickase Cas9. In some embodiments, the fusion protein comprises a nuclease-inactive or nickase variant of a type II CRISPR-Cas polypeptide. In some embodiments, the fusion protein comprises a nuclease-inactive or nickase variant of a type V CRISPR-Cas polypeptide. In some embodiments, the fusion protein comprises a nuclease-inactive or nickase variant of a type VI CRISPR-Cas polypeptide.

The modified cell can be a eukaryotic cell (e.g., a mammal, plant, insect, bird cell) or a prokaryotic cell. Also provided are organelles and embryos comprising at least one nucleotide sequence modified by a method utilizing a fusion protein as described herein. Genetically modified cells, organisms, organelles, and embryos can be heterologous or homologous to the modified nucleotide sequence. Mutations introduced by fusion proteins can result in altered expression (up or down), inactivated or altered protein products, or expression of integrated sequences. In those cases where the mutation results in inactivation of a gene or expression of a non-functional protein product, the genetically modified cell, organism, organelle, or embryo is referred to as a "knockout." The knockout phenotype can be the result of a deletion mutation (i.e., a deletion of at least one nucleotide), an insertion mutation (i.e., an insertion of at least one nucleotide), or a nonsense mutation (i.e., a substitution of at least one nucleotide such that a stop codon is introduced).

In some embodiments, the mutation introduced by the fusion protein results in the generation of a variant protein product. The variant protein product exhibited may have at least one amino acid substitution and/or at least one amino acid addition or deletion. Compared to the wild-type protein, the variant protein product may exhibit modified characteristics or activities, including but not limited to altered enzyme activity or substrate specificity.

In some embodiments, the mutation introduced by the fusion protein results in an altered protein expression pattern. As a non-limiting example, a mutation in a regulatory region that controls protein product expression can result in overexpression or downregulation or an altered tissue or temporal expression pattern of the protein product.

Cells that have been modified can be grown into organisms, such as plants, in a conventional manner. See, e.g., McCormick et al. (1986) Plant Cell Reports 5:81-84. These plants can then be grown and pollinated with the same modified strain or different strains, and the resulting hybrids have the genetic modification. The present invention provides genetically modified seeds. Progeny, variants, and mutants of the regenerated plants are also included within the scope of the present invention, provided that these parts include the genetic modification. Further provided are processed plant products or by-products that retain the genetic modification, including, for example, soybean meal.

The methods provided herein can be used for modification of any plant species, including but not limited to monocots and dicots. Examples of plants of interest include but are not limited to: maize (corn), sorghum, wheat, sunflower, tomato, crucifers, pepper, potato, cotton, rice, soybean, sugar beet, sugar cane, tobacco, barley, and rapeseed, sedge species, alfalfa, rye, millet, safflower, peanut, sweet potato, cassava, coffee, coconut, pineapple, citrus, cocoa, tea, banana, avocado, fig, guava, mango, olive, papaya, cashew, macadamia, almond, oat, vegetables, ornamental plants and conifers.

Vegetables include, but are not limited to, tomatoes, lettuce, green beans, beans, peas, and members of the genus Cucurbita such as cucumbers, netted melons, and cantaloupe. Ornamental plants include, but are not limited to, azaleas, hydrangeas, hibiscus, roses, tulips, daffodils, dwarf yews, carnations, poinsettias, and chrysanthemums. Preferably, the plants of the present invention are agricultural crops (e.g., corn, sorghum, wheat, sunflowers, tomatoes, cruciferous plants, peppers, potatoes, cotton, rice, soybeans, sugar beets, sugar cane, tobacco, barley, rapeseed, etc.).

The methods provided herein can also be used to genetically modify any prokaryotic species, including but not limited to: Archaea and bacteria (e.g., Bacillus, Klebsiella, Streptomyces, Rhizobium, Escherichia, Pseudomonas, Salmonella, Shigella, Vibrio, Yersinia, Mycoplasma, Agrobacterium, Lactobacillus).

The methods provided herein can be used to genetically modify any eukaryotic species or cells from eukaryotic species, including but not limited to: animals (e.g., mammals, insects, fish, birds, and reptiles), fungi, amoebas, algae, and yeast. In some embodiments, the cells modified by the methods disclosed herein include cells of hematopoietic origin, such as immune cells (i.e., cells of the innate or adaptive immune system), including but not limited to B cells, T cells, natural killer (NK) cells, high-potential stem cells, induced high-potential stem cells, chimeric antigen receptor T (CAR-T) cells, monocytes, macrophages, and dendritic cells.

The modified cells can be introduced into an organism. In the case of autologous cell transplantation, these cells can be derived from the same organism (e.g., a human) in which the cells were modified ex vivo. In some embodiments, in the case of allogeneic cell transplantation, the cells are derived from another organism (e.g., another human) within the same species. XIV. Kits

Some aspects of this disclosure provide kits comprising a deamidase or fusion protein of the invention. In certain embodiments, the disclosure provides kits comprising a fusion protein and a guide RNA. In addition, in some embodiments, the kits include suitable reagents, buffers, and/or instructions for using the fusion protein, such as in vitro or in vivo DNA or RNA editing. In some embodiments, the kits include instructions for the design and use of suitable gRNAs for targeted editing of nucleotide sequences.

The articles "a" and "an" are used herein to refer to one or to more than one (ie, at least one) of the grammatical object of the article. As an example, "a polypeptide" means one or more polypeptides.

All publications and patent applications mentioned in the specification indicate the level of ordinary knowledge in the field to which the present disclosure belongs. All publications and patent applications are incorporated herein by reference, as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be apparent that certain changes and modifications may be practiced within the scope of the appended claims.

Non-limiting implementation methods include: 1. A fusion protein comprising an RNA-guided nuclease (RGN) and at least one heterologous polypeptide inserted therein, wherein the RGN comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699. 2. The fusion protein of embodiment 1, wherein the RGN comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699. 3. The fusion protein of embodiment 1, wherein the RGN comprises an amino acid sequence of any one of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699. 4. The fusion protein of embodiment 1, wherein the RGN comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 1-4 and 57-139. 5. The fusion protein of embodiment 1, wherein the RGN comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 1-4 and 57-139. 6. The fusion protein of embodiment 1, wherein the RGN comprises an amino acid sequence of any one of SEQ ID NOs: 1-4 and 57-139. 7. A fusion protein of any one of embodiments 1-6, wherein the heterologous polypeptide is inserted into the linker domain 2, wedge domain, RuvC domain, HNH domain, Rec-2 domain or PAM interaction domain of the RGN. 8. The fusion protein of embodiment 7, wherein the RuvC domain is the RuvCIII domain. 9. A fusion protein of any one of embodiments 1-8, wherein: a) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 1 and the at least one heterologous polypeptide is inserted into the RGN immediately after an amino acid position selected from the group consisting of: i) an amino acid position corresponding to position 30 of SEQ ID NO: 1; ii) an amino acid position corresponding to position 642 of SEQ ID NO: 1; iii) an amino acid position corresponding to position 670 of SEQ ID NO: 1; iv) an amino acid position corresponding to position 737 of SEQ ID NO: 1; v) an amino acid position corresponding to position 772 of SEQ ID NO: 1; vi) an amino acid position corresponding to position 775 of SEQ ID NO: 1; vii) an amino acid position corresponding to position 778 of SEQ ID NO: 1; and viii) an amino acid position corresponding to position 802 of SEQ ID NO: 1; b) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 2 and the at least one heterologous polypeptide is inserted into the RGN immediately after an amino acid position selected from the group consisting of: i) an amino acid position corresponding to position 678 of SEQ ID NO: 2; ii) an amino acid position corresponding to position 736 of SEQ ID NO: 2; iii) an amino acid position corresponding to position 778 of SEQ ID NO: 2; iv) an amino acid position corresponding to position 788 of SEQ ID NO: 2; and v) an amino acid position corresponding to position 922 of SEQ ID NO: 2; c) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 2 and the at least one heterologous polypeptide is inserted into the RGN immediately after an amino acid position selected from the group consisting of: i) an amino acid position corresponding to position 678 of SEQ ID NO: 2; ii) an amino acid position corresponding to position 736 of SEQ ID NO: 2; iii) an amino acid position corresponding to position 778 of SEQ ID NO: 2; iv) an amino acid position corresponding to position 788 of SEQ ID NO: 2; and v) an amino acid position corresponding to position 922 of SEQ ID NO: 2; NO:3 has an amino acid sequence with at least 90% sequence identity and the at least one heterologous polypeptide is inserted into the RGN immediately after an amino acid position selected from the group consisting of: i) an amino acid position corresponding to position 725 of SEQ ID NO:3; ii) an amino acid position corresponding to position 739 of SEQ ID NO:3; and iii) an amino acid position corresponding to position 744 of SEQ ID NO:3; d) the RGN includes an amino acid sequence with at least 90% sequence identity to SEQ ID NO:4 and the at least one heterologous polypeptide is inserted into the RGN immediately after an amino acid position selected from the group consisting of: i) an amino acid position corresponding to position 347 of SEQ ID NO:4; ii) an amino acid position corresponding to position 524 of SEQ ID NO:4; iii) an amino acid position corresponding to position 744 of SEQ ID NO:3 NO:4; iv) an amino acid position corresponding to position 666 of SEQ ID NO:4; v) an amino acid position corresponding to position 680 of SEQ ID NO:4; v) an amino acid position corresponding to position 740 of SEQ ID NO:4; vi) an amino acid position corresponding to position 785 of SEQ ID NO:4; vii) an amino acid position corresponding to position 910 of SEQ ID NO:4; and viii) an amino acid position corresponding to position 1077 of SEQ ID NO:4; or e) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:131 and the at least one heterologous polypeptide is inserted into the RGN immediately after an amino acid position selected from the group consisting of: i) an amino acid position corresponding to position 766 of SEQ ID NO:131; and ii) an amino acid position corresponding to position 806 of SEQ ID NO:131. 10. The fusion protein of any one of embodiments 1-9, wherein the heterologous polypeptide comprises a base editing polypeptide or a lead editing polypeptide. 11. The fusion protein of embodiment 10, wherein the lead editing polypeptide comprises a DNA polymerase. 12. The fusion protein of embodiment 10, wherein the lead editing polypeptide is a reverse transcriptase. 13. The fusion protein of embodiment 10, wherein the base editing polypeptide comprises a deaminase. 14. The fusion protein of embodiment 13, wherein the deaminase is cytosine deaminase or adenine deaminase. 15. The fusion protein of embodiment 13 or 14, wherein the fusion protein is an alkaline editor fusion protein, and wherein the alkaline editor fusion protein has improved editing activity compared to the parent alkaline editor comprising the deaminase fused to the amino terminus of the RGN. 16. The fusion protein of embodiments 13-15, wherein the at least one heterologous polypeptide is inserted into the RGN immediately after an amino acid position selected from the group consisting of: a) an amino acid position corresponding to position 642 of SEQ ID NO: 1; b) an amino acid position corresponding to position 670 of SEQ ID NO: 1; c) an amino acid position corresponding to position 737 of SEQ ID NO: 1; d) an amino acid position corresponding to position 772 of SEQ ID NO: 1; e) an amino acid position corresponding to position 775 of SEQ ID NO: 1; and f) an amino acid position corresponding to position 778 of SEQ ID NO: 1; and Wherein the fusion protein is an alkaline editor fusion protein, and wherein the alkaline editor fusion protein has a shifted editing window compared to a parent alkaline editor comprising the deaminase fused to the amino terminus of the RGN. 17. A fusion protein of any one of embodiments 13-16, wherein the deaminase lacks the first amino acid residue and the last amino acid residue compared to the parent deaminase from which the deaminase is derived. 18. The fusion protein of any one of embodiments 13-17, wherein the deaminase comprises adenine deaminase and the fusion protein is an adenosine base editor (ABE) fusion protein. 19. The fusion protein of embodiment 18, wherein the adenine deaminase comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 5, 6, 248-414, 596, 597, and 720-723. 20. The fusion protein of embodiment 18, wherein the adenine deaminase comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 5, 6, 248-414, 596, 597, and 720-723. 21. The fusion protein of embodiment 18, wherein the adenine deaminase comprises an amino acid sequence of any one of SEQ ID NOs: 5, 6, 248-414, 596, 597, and 720-723. 22. The fusion protein of embodiment 18, wherein the adenine deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 5 or 6. 23. The fusion protein of embodiment 18, wherein the adenine deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 5 or 6. 24. The fusion protein of embodiment 18, wherein the adenine deaminase comprises an amino acid sequence of SEQ ID NO: 5 or 6. 25. The fusion protein of embodiment 18, wherein the ABE fusion protein comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 8-10, 13-21, 27-31, 36-38, 40-41, 43-48, 647, and 650. 26. The fusion protein of embodiment 18, wherein the ABE fusion protein comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 8-10, 13-21, 27-31, 36-38, 40-41, 43-48, 647, and 650. 27. The fusion protein of embodiment 18, wherein the ABE fusion protein comprises an amino acid sequence shown in any one of SEQ ID NOs: 8-10, 13-21, 27-31, 36-38, 40-41, 43-48, 647, and 650. 28. The fusion protein of embodiment 18, wherein the ABE fusion protein comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 8-10 and 14-16, and wherein the ABE fusion protein has an editing window that is shifted compared to the parent ABE base editor, the parent ABE base editor comprising the adenine deaminase fused to the amino terminus of the RGN. 29. The fusion protein of embodiment 18, wherein the ABE fusion protein has an amino acid sequence with at least 95% sequence identity to any one of SEQ ID NOs: 8-10 and 14-16, and wherein the ABE fusion protein has an editing window that is shifted compared to the parent ABE base editor, the parent ABE base editor comprising the adenine deaminase fused to the amino terminus of the RGN. 30. The fusion protein of embodiment 18, wherein the ABE fusion protein comprises the amino acid sequence shown in any one of SEQ ID NOs: 8-10 and 14-16. 31. The fusion protein of any one of embodiments 1-30, wherein the RGN is an RGN that is not activated by nickase or nuclease. 32. The fusion protein of embodiment 31, wherein the RGN nickase comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 49-56, 698 and 699 and retains nickase activity. 33. The fusion protein of embodiment 31, wherein the RGN nickase comprises the amino acid sequence of any one of SEQ ID NOs: 49-56, 698 and 699. 34. The fusion protein of any one of embodiments 1-33, wherein the RGN and the heterologous polypeptide are directly fused to each other without a linker sequence in between. 35. A fusion protein according to any one of embodiments 1-34, wherein the fusion protein further comprises at least one nuclear localization signal (NLS). 36. A ribonucleoprotein (RNP) complex, comprising a fusion protein of any one of embodiments 1-35 and 232-243 and a guide RNA bound to the fusion protein. 37. A nucleic acid molecule comprising a polynucleotide encoding a fusion protein, wherein the fusion protein comprises an RNA-guided nuclease (RGN) and at least one heterologous polypeptide inserted therein, wherein the RGN comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699. 38. The nucleic acid molecule of embodiment 37, wherein the RGN comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699. 39. The nucleic acid molecule of embodiment 37, wherein the RGN comprises an amino acid sequence of any one of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699. 40. The nucleic acid molecule of embodiment 37, wherein the RGN comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 1-4, 57-139. 41. The nucleic acid molecule of embodiment 37, wherein the RGN comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 1-4, 57-139. 42. The nucleic acid molecule of embodiment 37, wherein the RGN comprises an amino acid sequence of any one of SEQ ID NOs: 1-4, 57-139. 43. A nucleic acid molecule of any one of embodiments 1-6, wherein the heterologous polypeptide is inserted into the linker domain 2, wedge domain, RuvC domain, HNH domain, Rec-2 domain or PAM interaction domain of the RGN. 44. The nucleic acid molecule of embodiment 7, wherein the RuvC domain is a RuvCIII domain. 45. A nucleic acid molecule according to any one of embodiments 37-44, wherein: a) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 1 and the at least one heterologous polypeptide is inserted into the RGN immediately after an amino acid position selected from the group consisting of: i) an amino acid position corresponding to position 30 of SEQ ID NO: 1; ii) an amino acid position corresponding to position 642 of SEQ ID NO: 1; iii) an amino acid position corresponding to position 670 of SEQ ID NO: 1; iv) an amino acid position corresponding to position 737 of SEQ ID NO: 1; v) an amino acid position corresponding to position 772 of SEQ ID NO: 1; vi) an amino acid position corresponding to position 775 of SEQ ID NO: 1; vii) an amino acid position corresponding to position 778 of SEQ ID NO: 1; and viii) an amino acid position corresponding to position 779 of SEQ ID NO: 1; NO:1; b) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:2 and the at least one heterologous polypeptide is inserted in the RGN immediately after the amino acid position selected from the group consisting of: i) an amino acid position corresponding to position 678 of SEQ ID NO:2; ii) an amino acid position corresponding to position 736 of SEQ ID NO:2; iii) an amino acid position corresponding to position 778 of SEQ ID NO:2; iv) an amino acid position corresponding to position 788 of SEQ ID NO:2; and v) an amino acid position corresponding to position 922 of SEQ ID NO:2; c) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:2 and the at least one heterologous polypeptide is inserted in the RGN immediately after the amino acid position selected from the group consisting of: i) an amino acid position corresponding to position 678 of SEQ ID NO:2; ii) an amino acid position corresponding to position 736 of SEQ ID NO:2; iii) an amino acid position corresponding to position 778 of SEQ ID NO:2; iv) an amino acid position corresponding to position 788 of SEQ ID NO:2; and v) an amino acid position corresponding to position 922 of SEQ ID NO:2; NO:3 has an amino acid sequence with at least 90% sequence identity and the at least one heterologous polypeptide is inserted into the RGN immediately after an amino acid position selected from the group consisting of: i) an amino acid position corresponding to position 725 of SEQ ID NO:3; ii) an amino acid position corresponding to position 739 of SEQ ID NO:3; and iii) an amino acid position corresponding to position 744 of SEQ ID NO:3; d) the RGN includes an amino acid sequence with at least 90% sequence identity to SEQ ID NO:4 and the at least one heterologous polypeptide is inserted into the RGN immediately after an amino acid position selected from the group consisting of: i) an amino acid position corresponding to position 347 of SEQ ID NO:4; ii) an amino acid position corresponding to position 524 of SEQ ID NO:4; iii) an amino acid position corresponding to position 744 of SEQ ID NO:3. NO:4; iv) an amino acid position corresponding to position 666 of SEQ ID NO:4; v) an amino acid position corresponding to position 680 of SEQ ID NO:4; v) an amino acid position corresponding to position 740 of SEQ ID NO:4; vi) an amino acid position corresponding to position 785 of SEQ ID NO:4; vii) an amino acid position corresponding to position 910 of SEQ ID NO:4; and viii) an amino acid position corresponding to position 1077 of SEQ ID NO:4; or e) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:131 and the at least one heterologous polypeptide is inserted into the RGN immediately after an amino acid position selected from the group consisting of: i) an amino acid position corresponding to position 766 of SEQ ID NO:131; and ii) an amino acid position corresponding to position 806 of SEQ ID NO:131. 46. The nucleic acid molecule of embodiment 45, wherein the heterologous polypeptide comprises a base editing polypeptide or a lead editing polypeptide. 47. The nucleic acid molecule of embodiment 46, wherein the lead editing polypeptide comprises a DNA polymerase. 48. The nucleic acid molecule of embodiment 46, wherein the lead editing polypeptide comprises a reverse transcriptase. 49. A nucleic acid molecule according to any one of the embodiments of embodiment 46, wherein the base editing polypeptide comprises a deaminase. 50. The nucleic acid molecule of embodiment 49, wherein the deaminase is cytosine deaminase or adenine deaminase. 51. The nucleic acid molecule of embodiment 49 or 50, wherein the fusion protein is an alkaline editor fusion protein, and wherein the alkaline editor fusion protein has improved editing activity compared to the parent alkaline editor comprising the deaminase fused to the amino terminus of the RGN. 52. A nucleic acid molecule of any one of embodiments 49-51, wherein the at least one heterologous polypeptide is inserted into the RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 1 immediately after an amino acid position selected from the group consisting of: a) an amino acid position corresponding to position 671 of SEQ ID NO: 1; b)      an amino acid position corresponding to position 670 of SEQ ID NO: 1; c) an amino acid position corresponding to position 737 of SEQ ID NO: 1; d)      an amino acid position corresponding to position 772 of SEQ ID NO: 1; e) an amino acid position corresponding to position 775 of SEQ ID NO: 1; and f) an amino acid position corresponding to position 778 of SEQ ID NO: 1; and Wherein the fusion protein is an alkaline editor fusion protein, and wherein the alkaline editor fusion protein has a shifted editing window compared to a parent alkaline editor comprising the deaminase fused to the amino terminus of the RGN. 53. A nucleic acid molecule according to any one of embodiments 49-52, wherein the deaminase lacks the first amino acid residue and the last amino acid residue compared to the parent deaminase from which the deaminase is derived. 54. A nucleic acid molecule according to any one of embodiments 49-53, wherein the deaminase comprises adenine deaminase and is an adenosine base editor (ABE) fusion protein. 55. The nucleic acid molecule of embodiment 54, wherein the adenine deaminase comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 5, 6, 248-414, 596, 597, and 720-723. 56. The nucleic acid molecule of embodiment 54, wherein the adenine deaminase comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 5, 6, 248-414, 596, 597, and 720-723. 57. The nucleic acid molecule of embodiment 54, wherein the adenine deaminase comprises an amino acid sequence of any one of SEQ ID NOs: 5, 6, 248-414, 596, 597, and 720-723. 58. The nucleic acid molecule of embodiment 54, wherein the adenine deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 5 or 6. 59. The nucleic acid molecule of embodiment 54, wherein the adenine deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 5 or 6. 60. The nucleic acid molecule of embodiment 54, wherein the adenine deaminase comprises an amino acid sequence of SEQ ID NO: 5 or 6. 61. The nucleic acid molecule of embodiment 54, wherein the fusion protein comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 8-10, 13-21, 27-31, 36-38, 40-41, 43-48, 647, and 650. 62. The nucleic acid molecule of embodiment 54, wherein the ABE fusion protein comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 8-10, 13-21, 27-31, 36-38, 40-41, 43-48, 647, and 650. 63. The nucleic acid molecule of embodiment 54, wherein the ABE fusion protein comprises an amino acid sequence shown in any one of SEQ ID NOs: 8-10, 13-21, 27-31, 36-38, 40-41, 43-48, 647, and 650. 64. The nucleic acid molecule of embodiment 54, wherein the ABE fusion protein comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 8-10 and 14-16, and wherein the ABE fusion protein has an editing window that is shifted compared to the parent ABE base editor, the parent ABE base editor comprising the adenine deaminase fused to the amino terminus of the RGN. 65. The nucleic acid molecule of embodiment 54, wherein the ABE fusion protein comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 8-10 and 14-16, and wherein the ABE fusion protein has an editing window that is shifted compared to the parent ABE base editor, the parent ABE base editor comprising the adenine deaminase fused to the amino terminus of the RGN. 66. The nucleic acid molecule of embodiment 54, wherein the ABE fusion protein comprises the amino acid sequence shown in any one of SEQ ID NOs: 8-10 and 14-16. 67. The nucleic acid molecule of any one of embodiments 37-66, wherein the RGN is a nickase or nuclease inactive RGN. 68. The nucleic acid molecule of embodiment 67, wherein the RGN nickase comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 49-56, 698 and 699 and retains nickase activity. 69. The nucleic acid molecule of embodiment 67, wherein the RGN nickase comprises an amino acid sequence of any one of SEQ ID NOs: 49-56, 698 and 699. 70. The nucleic acid molecule of any one of embodiments 37-69, wherein the RGN and the heterologous polypeptide are directly fused to each other without a linker sequence in between. 71. A nucleic acid molecule according to any one of embodiments 37-70, wherein the fusion protein further comprises at least one nuclear localization signal (NLS). 72. A nucleic acid molecule according to any one of embodiments 37-71, wherein the nucleic acid molecule is codon-optimized for expression in eukaryotic cells. 73. A nucleic acid molecule according to any one of embodiments 37-71, wherein the nucleic acid molecule is codon-optimized for expression in prokaryotic cells. 74. A vector comprising a nucleic acid molecule of any one of embodiments 37-73 and 244-255. 75. The vector of embodiment 74 further comprises at least one nucleotide sequence encoding a guide RNA capable of hybridizing with a non-target sequence of the target sequence of the RGN. 76. The vector of embodiment 74, wherein the guide RNA is a single guide RNA (sgRNA). 77. The vector of embodiment 74, wherein the guide RNA is a dual guide RNA. 78. A cell comprising a fusion protein of any one of embodiments 1-35 and 232-243 or an RNP complex of embodiment 36. 79. A cell comprising a fusion protein of any one of embodiments 1-35 and 232-243, wherein the cell further comprises a guide RNA. 80. A cell comprising a nucleic acid molecule of any one of embodiments 37-73 and 244-255. 81. A cell comprising a vector of any one of embodiments 74-77. 82. A cell according to any one of embodiments 78-81, wherein the cell is a prokaryotic cell. 83. A cell according to any one of embodiments 78-81, wherein the cell is a eukaryotic cell. 84. The cell of embodiment 83, wherein the eukaryotic cell is a mammalian cell. 85. The cell of embodiment 84, wherein the mammalian cell is a human cell. 86. The cell of embodiment 85, wherein the human cell is an immune cell. 87. The cell of embodiment 86, wherein the immune cell is a stem cell. 88. The cells of implementation method 87, wherein the stem cells are induced high-potential stem cells. 89. The cell of embodiment 83, wherein the eukaryotic cell is an insect cell or a bird cell. 90. The cell of embodiment 83, wherein the eukaryotic cell is a fungal cell. 91. The cell of embodiment 83, wherein the eukaryotic cell is a plant cell. 92. A plant comprising the cell of embodiment 91. 93. A seed comprising a cell of implementation method 91. 94. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a fusion protein of any one of embodiments 1-35 and 232-243, an RNP complex of embodiment 36, a nucleic acid molecule of any one of embodiments 37-73 and 244-255, a vector 74-77 of any one of embodiments 74-77, or a cell of any one of embodiments 84-88. 95. A method for preparing a fusion protein, comprising culturing cells of any of embodiments 78-91 under conditions in which the fusion protein is expressed. 96. A method for preparing a fusion protein, comprising introducing a nucleic acid molecule of any one of embodiments 37-73 and 237-243 or a vector of any one of embodiments 74-77 into a cell, and culturing the cell under conditions in which the fusion protein is expressed. 97. The method of embodiment 95 or 96 further includes purifying the fusion protein. 98. A method for preparing an RGN fusion ribonucleoprotein complex, comprising introducing a nucleic acid molecule of any one of embodiments 37-73 and 237-243 and a nucleic acid molecule comprising an expression cassette encoding a guide RNA, or a vector of any one of embodiments 74-77 into a cell, and culturing the cell under conditions in which the fusion protein and gRNA are expressed and form an RGN fusion ribonucleoprotein complex. 99. The method of embodiment 98 further includes purifying the RGN fusion ribonucleoprotein complex. 100. A system for localizing a heterologous polypeptide to a target DNA molecule comprising a target DNA sequence, the system comprising: a) a fusion protein, or a nucleotide sequence encoding the fusion protein, wherein the fusion protein comprises an RNA-guided nuclease (RGN) and at least one heterologous polypeptide inserted therein; wherein the RGN comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699; and b) one or more guide RNAs capable of hybridizing with a non-target strand of the target DNA sequence or one or more nucleotide sequences encoding the one or more guide RNAs; and wherein the one or more guide RNAs are capable of forming a complex with the fusion protein to guide the fusion protein to bind to the target DNA sequence. 101. The system of embodiment 100, wherein the RGN comprises an amino acid sequence having at least 95% sequence identity with any of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699. 102. The system of embodiment 100, wherein the RGN comprises an amino acid sequence of any one of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699. 103. The system of embodiment 100, wherein the RGN comprises an amino acid sequence having at least 90% sequence identity with any of SEQ ID NOs: 1-4 and 57-139. 104. The system of embodiment 100, wherein the RGN comprises an amino acid sequence having at least 95% sequence identity with any of SEQ ID NOs: 1-4 and 57-139. 105. The system of embodiment 100, wherein the RGN comprises an amino acid sequence of any one of SEQ ID NOs: 1-4 and 57-139. 106. The system of any one of embodiments 100-105, wherein the heterologous polypeptide is inserted into the linker domain 2, wedge domain, RuvC domain, HNH domain, Rec-2 domain, or PAM interaction domain of the RGN. 107. The system of embodiment 106, wherein the RuvC domain is a RuvCIII domain. 108. The system of any of embodiments 100-107, wherein: i) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 1 and the at least one heterologous polypeptide is inserted into the RGN immediately after an amino acid position selected from the group consisting of: A. The amino acid position corresponding to position 30 of SEQ ID NO: 1; B. The amino acid position corresponding to position 642 of SEQ ID NO: 1; C. The amino acid position corresponding to position 671 of SEQ ID NO: 1; D. The amino acid position corresponding to position 737 of SEQ ID NO: 1; E. The amino acid position corresponding to position 772 of SEQ ID NO: 1; F. The amino acid position corresponding to position 775 of SEQ ID NO: 1; G. The amino acid position corresponding to position 778 of SEQ ID NO: 1; and H. The amino acid position corresponding to position 802 of SEQ ID NO: 1; ii) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 2 and the at least one heterologous polypeptide is inserted into the RGN immediately after an amino acid position selected from the group consisting of: A. The amino acid position corresponding to position 678 of SEQ ID NO: 2; B. The amino acid position corresponding to position 736 of SEQ ID NO: 2; C. The amino acid position corresponding to position 778 of SEQ ID NO: 2; D. The amino acid position corresponding to position 788 of SEQ ID NO: 2; and E. The amino acid position corresponding to position 992 of SEQ ID NO:2; iii) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:3 and the at least one heterologous polypeptide is inserted into the RGN immediately after an amino acid position selected from the group consisting of: A. The amino acid position corresponding to position 725 of SEQ ID NO: 3; B. The amino acid position corresponding to position 739 of SEQ ID NO: 3; and C. An amino acid position corresponding to position 744 of SEQ ID NO:3; iv) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:4 and the at least one heterologous polypeptide is inserted into the RGN immediately after an amino acid position selected from the group consisting of: A. The amino acid position corresponding to position 347 of SEQ ID NO: 4; B. The amino acid position corresponding to position 524 of SEQ ID NO: 4; C. The amino acid position corresponding to position 666 of SEQ ID NO: 4; D. The amino acid position corresponding to position 680 of SEQ ID NO: 4; E. The amino acid position corresponding to position 740 of SEQ ID NO: 4; F. The amino acid position corresponding to position 785 of SEQ ID NO: 4; G. The amino acid position corresponding to position 910 of SEQ ID NO: 4; and H. The amino acid position corresponding to position 1077 of SEQ ID NO:4; or v) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:131 and the at least one heterologous polypeptide is inserted into the RGN immediately after an amino acid position selected from the group consisting of: A. The amino acid position corresponding to position 766 of SEQ ID NO: 131; and B. The amino acid position corresponding to position 806 of SEQ ID NO: 131. 109. The system of any one of embodiments 100-108, wherein the heterologous polypeptide comprises a base editing polypeptide or a lead editing polypeptide. 110. The system of embodiment 109, wherein the lead editing polypeptide comprises a DNA polymerase. 111. The system of embodiment 109, wherein the lead editing polypeptide comprises a reverse transcriptase. 112. The system of embodiment 109, wherein the base editing polypeptide comprises a deaminase. 113. The system of embodiment 112, wherein the deaminase is a cytosine deaminase or an adenine deaminase. 114. The system of embodiment 112 or 113, wherein the fusion protein is an alkaline editor fusion protein, and wherein the alkaline editor fusion protein has improved editing activity compared to a parent alkaline editor comprising the deaminase fused to the amino terminus of the RGN. 115. The system of any of embodiments 112-114, wherein the at least one heterologous polypeptide is inserted into the RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 1 immediately after an amino acid position selected from the group consisting of: a) an amino acid position corresponding to position 642 of SEQ ID NO: 1; b) an amino acid position corresponding to position 670 of SEQ ID NO: 1; c) an amino acid position corresponding to position 737 of SEQ ID NO: 1; d) an amino acid position corresponding to position 772 of SEQ ID NO: 1; e) an amino acid position corresponding to position 775 of SEQ ID NO: 1; and f) an amino acid position corresponding to position 778 of SEQ ID NO: 1; and Wherein the fusion protein is an alkaline editor fusion protein, and wherein the alkaline editor fusion protein has a shifted editing window compared to a parent alkaline editor comprising the deaminase fused to the amino terminus of the RGN. 116. The system of any of embodiments 112-115, wherein the deaminase lacks the first amino acid residue and the last amino acid residue compared to the parent deaminase from which the deaminase is derived. 117. The system of any one of embodiments 112-116, wherein the deaminase comprises adenine deaminase and the fusion protein is an adenosine base editor (ABE) fusion protein. 118. The system of embodiment 117, wherein the adenine deaminase comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 5, 6, 248-414, 596, 597, and 720-723. 119. The system of embodiment 117, wherein the adenine deaminase comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 5, 6, 248-414, 596, 597, and 720-723. 120. The system of embodiment 117, wherein the adenine deaminase comprises an amino acid sequence of any one of SEQ ID NOs: 5, 6, 248-414, 596, 597, and 720-723. 121. The system of embodiment 117, wherein the adenine deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 5 or 6. 122. The system of embodiment 117, wherein the adenine deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 5 or 6. 123. The system of embodiment 117, wherein the adenine deaminase comprises an amino acid sequence of SEQ ID NO: 5 or 6. 124. The system of embodiment 117, wherein the ABE fusion protein comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 8-10, 13-21, 27-31, 36-38, 40-41, 43-48, 647, and 650. 125. The system of embodiment 117, wherein the ABE fusion protein comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 8-10, 13-21, 27-31, 36-38, 40-41, 43-48, 647, and 650. 126. The system of embodiment 117, wherein the ABE fusion protein comprises an amino acid sequence shown in any one of SEQ ID NOs: 8-10, 13-21, 27-31, 36-38, 40-41, 43-48, 647, and 650. 127. The system of embodiment 117, wherein the ABE fusion protein comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 8-10 and 14-16, and wherein the ABE fusion protein has an editing window that is shifted compared to a parent ABE base editor, the parent ABE base editor comprising the adenine deaminase fused to the amino terminus of the RGN. 128. The system of embodiment 117, wherein the ABE fusion protein comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 8-10 and 14-16, and wherein the ABE fusion protein has an editing window that is shifted compared to a parent ABE base editor, the parent ABE base editor comprising the adenine deaminase fused to the amino terminus of the RGN. 129. The system of embodiment 117, wherein the ABE fusion protein comprises an amino acid sequence shown in any one of SEQ ID NOs: 8-10 and 14-16. 130. The system of any of embodiments 100-129, wherein the RGN is a nickase or nuclease inactive RGN. 131. The system of embodiment 130, wherein the RGN nickase comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 49-56, 698, and 699 and retains nickase activity. 132. The system of embodiment 130, wherein the RGN nickase comprises the amino acid sequence of any one of SEQ ID NOs: 49-56, 698, and 699. 133. The system of any of embodiments 100-132, wherein the RGN and the heterologous polypeptide are directly fused to each other without a linker sequence in between. 134. The system of any of embodiments 100-133, wherein the fusion protein further comprises at least one nuclear localization signal (NLS). 135. The system of any of embodiments 100-134, wherein the nucleotide sequence encoding the fusion protein is codon-optimized for expression in eukaryotic cells. 136. The system of any one of embodiments 100-135, wherein at least one of the nucleotide sequence encoding one or more guide RNAs and the nucleotide sequence encoding the fusion protein is operably linked to a promoter heterologous to the nucleotide sequence. 137. The system of any of embodiments 100-136, wherein the target DNA sequence is a eukaryotic target DNA sequence. 138. The system of any of embodiments 100-137, wherein the target DNA sequence is positioned adjacent to a protospacer adjacent motif (PAM) recognized by an RGN. 139. A system of any one of embodiments 100-138, wherein the nucleotide sequence encoding one or more guide RNAs and the nucleotide sequence encoding the fusion protein are located on a vector. 140. A cell comprising a system of any one of embodiments 100-139 and 256-267. 141. The cell of embodiment 140, wherein the cell is a eukaryotic cell. 142. The cell of embodiment 141, wherein the eukaryotic cell is a mammalian cell. 143. The cell of embodiment 142, wherein the mammalian cell is a human cell. 144. The cell of embodiment 143, wherein the human cell is an immune cell. 145. The cell of embodiment 144, wherein the immune cell is a stem cell. 146. The cells of embodiment 145, wherein the stem cells are induced high-potential stem cells. 147. The cell of embodiment 141, wherein the eukaryotic cell is an insect cell. 148. The cell of embodiment 141, wherein the eukaryotic cell is a plant cell. 149. A plant comprising cells of implementation method 148. 150. A seed comprising a cell of implementation method 148. 151. The cell of embodiment 140, wherein the cell is a prokaryotic cell. 152. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a system of any one of embodiments 100-139 and 256-267 or a cell of any one of embodiments 142-146. 153. A method for localizing a heterologous polypeptide to a target DNA molecule comprising a target DNA sequence, the method comprising delivering the system of any one of embodiments 100-139 and 256-267 to the target DNA molecule or a cell comprising the target DNA molecule. 154. A method for modifying a target DNA molecule comprising a target DNA sequence, the method comprising delivering a system of any of embodiments 100-139 and 256-267 to the target DNA molecule or a cell comprising the target DNA molecule. 155. The method of embodiment 154, wherein the deaminase comprises adenine deaminase and wherein the modified target DNA molecule comprises an A＞N mutation of at least one nucleotide in the target DNA molecule, wherein N is C, G, or T. 156. The method of embodiment 155, wherein the modified target DNA molecule includes an A＞G mutation of at least one nucleotide in the target DNA molecule. 157. A method for localizing a heterologous polypeptide to a target DNA molecule comprising a target DNA sequence, comprising: a) assembling a ribonucleotide complex in vitro under conditions suitable for forming the ribonucleotide complex by combining: i) one or more guide RNAs capable of hybridizing with a non-target strand of the target DNA sequence; and ii) a fusion protein comprising an RNA-guided nuclease (RGN) and at least one heterologous polypeptide inserted therein, wherein the RGN comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699; and b) contacting the target DNA molecule or a cell comprising the target DNA molecule with the in vitro assembled ribonucleotide complex; One or more guide RNAs hybridize with the non-target strands of the target DNA sequence, thereby guiding the fusion protein to bind to the target DNA sequence. 158. The method of embodiment 157, wherein the RGN comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699. 159. The method of embodiment 157, wherein the RGN comprises an amino acid sequence having the amino acid sequence of any one of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699. 160. The method of embodiment 157, wherein the RGN comprises at least 90% sequence identity with any of SEQ ID NOs: 1-4 and 57-139. 161. The method of embodiment 157, wherein the RGN comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 1-4 and 57-139. 162. The method of embodiment 157, wherein the RGN comprises an amino acid sequence of any one of SEQ ID NOs: 1-4 and 57-139. 163. The method of any one of embodiments 157-162, wherein the heterologous polypeptide is inserted into the linker domain 2, wedge domain, RuvC domain, HNH domain, Rec-2 domain, or PAM interaction domain of the RGN. 164. The method of embodiment 163, wherein the RuvC domain is a RuvCIII domain. 165. The method of any of embodiments 157-164, wherein: a) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 1 and the at least one heterologous polypeptide is inserted into the RGN immediately after an amino acid position selected from the group consisting of: I) an amino acid position corresponding to position 30 of SEQ ID NO: 1; II) an amino acid position corresponding to position 642 of SEQ ID NO: 1; III) an amino acid position corresponding to position 670 of SEQ ID NO: 1; IV) an amino acid position corresponding to position 737 of SEQ ID NO: 1; V) an amino acid position corresponding to position 772 of SEQ ID NO: 1; VI) an amino acid position corresponding to position 775 of SEQ ID NO: 1; VII) an amino acid position corresponding to position 778 of SEQ ID NO: 1; and VIII) an amino acid position corresponding to position 779 of SEQ ID NO: 1; NO:1; b) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:2 and the at least one heterologous polypeptide is inserted into the RGN immediately after an amino acid position selected from the group consisting of: I) an amino acid position corresponding to position 678 of SEQ ID NO:2; II) an amino acid position corresponding to position 736 of SEQ ID NO:2; III) an amino acid position corresponding to position 778 of SEQ ID NO:2; IV) an amino acid position corresponding to position 788 of SEQ ID NO:2; and V) an amino acid position corresponding to position 922 of SEQ ID NO:2; c) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:2 and the at least one heterologous polypeptide is inserted into the RGN immediately after an amino acid position selected from the group consisting of: I) an amino acid position corresponding to position 678 of SEQ ID NO:2; II) an amino acid position corresponding to position 736 of SEQ ID NO:2; III) an amino acid position corresponding to position 778 of SEQ ID NO:2; IV) an amino acid position corresponding to position 788 of SEQ ID NO:2; and V) an amino acid position corresponding to position 922 of SEQ ID NO:2; NO:3 has an amino acid sequence with at least 90% sequence identity and the at least one heterologous polypeptide is inserted into the RGN immediately after an amino acid position selected from the group consisting of: I) an amino acid position corresponding to position 725 of SEQ ID NO:3; II) an amino acid position corresponding to position 739 of SEQ ID NO:3; III) an amino acid position corresponding to position 744 of SEQ ID NO:3; d) the RGN includes an amino acid sequence with at least 90% sequence identity to SEQ ID NO:4 and the at least one heterologous polypeptide is inserted into the RGN immediately after an amino acid position selected from the group consisting of: I) an amino acid position corresponding to position 347 of SEQ ID NO:4; II) an amino acid position corresponding to position 524 of SEQ ID NO:4; III) an amino acid position corresponding to position 666 of SEQ ID NO:4; IV) an amino acid position corresponding to position 680 of SEQ ID NO: 4; V) an amino acid position corresponding to position 740 of SEQ ID NO: 4; VI) an amino acid position corresponding to position 785 of SEQ ID NO: 4; VII) an amino acid position corresponding to position 910 of SEQ ID NO: 4; and VIII) an amino acid position corresponding to position 1077 of SEQ ID NO: 4; or e) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 131 and the at least one heterologous polypeptide is inserted into the RGN immediately after an amino acid position selected from the group consisting of: I) an amino acid position corresponding to position 766 of SEQ ID NO: 131; and II) an amino acid position corresponding to position 806 of SEQ ID NO: 131. 166. The method of any of embodiments 157-165, wherein the heterologous polypeptide comprises a base editing polypeptide or a lead editing polypeptide and wherein the method further comprises modifying the target DNA molecule to produce a modified target DNA molecule. 167. The method of embodiment 166, wherein the target DNA molecule includes a causal mutation for a disease or condition and wherein the modification of the target DNA molecule corrects the causal mutation. 168. The method of implementation method 167, wherein the correction of causal mutations includes correcting meaningless mutations. 169. The method of any of embodiments 166-168, wherein the lead editing polypeptide comprises a DNA polymerase. 170. The method of any of embodiments 166-168, wherein the lead editing polypeptide comprises a reverse transcriptase. 171. The method of any of embodiments 166-168, wherein the base editing polypeptide comprises a deaminase. 172. The method of embodiment 171, wherein the deaminase is cytosine deaminase or adenine deaminase. 173. The method of embodiment 171 or 172, wherein the fusion protein is an alkaline editor fusion protein, and wherein the alkaline editor fusion protein has improved editing activity compared to a parent alkaline editor comprising the deaminase fused to the amino terminus of the RGN. 174. The method of any of embodiments 171-173, wherein the at least one heterologous polypeptide is inserted into the RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 1 immediately after an amino acid position selected from the group consisting of: a) an amino acid position corresponding to position 642 of SEQ ID NO: 1; b) an amino acid position corresponding to position 670 of SEQ ID NO: 1; c) an amino acid position corresponding to position 737 of SEQ ID NO: 1; d) an amino acid position corresponding to position 772 of SEQ ID NO: 1; e) an amino acid position corresponding to position 775 of SEQ ID NO: 1; and f) an amino acid position corresponding to position 778 of SEQ ID NO: 1; and Wherein the fusion protein is an alkaline editor fusion protein, and wherein the alkaline editor fusion protein has a shifted editing window compared to a parent alkaline editor comprising the deaminase fused to the amino terminus of the RGN. 175. The method of any of embodiments 171-174, wherein the deaminase lacks the first amino acid residue and the last amino acid residue compared to the parent deaminase from which the deaminase is derived. 176. The method of any one of embodiments 171-175, wherein the deaminase comprises adenine deaminase and the fusion protein is an adenosine base editor (ABE) fusion protein. 177. The method of embodiment 176, wherein the adenine deaminase comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 5, 6, 248-414, 596, 597, and 720-723. 178. The method of embodiment 176, wherein the adenine deaminase comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 5, 6, 248-414, 596, 597, and 720-723. 179. The method of embodiment 176, wherein the adenine deaminase comprises an amino acid sequence of any one of SEQ ID NOs: 5, 6, 248-414, 596, 597, and 720-723. 180. The method of embodiment 176, wherein the adenine deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 5 or 6. 181. The method of embodiment 176, wherein the adenine deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 5 or 6. 182. The method of embodiment 176, wherein the adenine deaminase comprises an amino acid sequence of SEQ ID NO: 5 or 6. 183. The method of embodiment 176, wherein the ABE fusion protein comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 8-10, 13-21, 27-31, 36-38, 40-41, 43-48, 647, and 650. 184. The method of embodiment 176, wherein the ABE fusion protein comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 8-10, 13-21, 27-31, 36-38, 40-41, 43-48, 647, and 650. 185. The method of embodiment 176, wherein the ABE fusion protein comprises an amino acid sequence shown in any one of SEQ ID NOs: 8-10, 13-21, 27-31, 36-38, 40-41, 43-48, 647, and 650. 186. The method of embodiment 176, wherein the ABE fusion protein comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 8-10 and 14-16, and wherein the ABE fusion protein has an editing window that is shifted compared to a parent ABE base editor, the parent ABE base editor comprising the adenine deaminase fused to the amino terminus of the RGN. 187. The method of embodiment 176, wherein the ABE fusion protein comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 8-10 and 14-16, and wherein the ABE fusion protein has an editing window that is shifted compared to a parent ABE base editor, the parent ABE base editor comprising the adenine deaminase fused to the amino terminus of the RGN. 188. The method of embodiment 176, wherein the ABE fusion protein comprises an amino acid sequence shown in any one of SEQ ID NOs: 8-10 and 14-16. 189. The method of any one of embodiments 176-188, wherein the modified target DNA molecule includes an A＞N mutation of at least one nucleotide in the target DNA molecule, wherein N is C, G, or T. 190. The method of embodiment 189, wherein the modified target DNA molecule includes an A＞G mutation of at least one nucleotide in the target DNA molecule. 191. The method of any of embodiments 157-190, wherein the RGN is a nickase or nuclease inactive RGN. 192. The method of embodiment 191, wherein the RGN nickase comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 49-56, 698 and 699 and retains nickase activity. 193. The method of embodiment 191, wherein the RGN nickase comprises an amino acid sequence of any one of SEQ ID NOs: 49-56, 698 and 699. 194. The method of any one of embodiments 157-193, wherein the RGN and the heterologous polypeptide are directly fused to each other without a linker sequence in between. 195. The method of any one of embodiments 157-194, wherein the fusion protein further comprises at least one nuclear localization signal (NLS). 196. The method of any of embodiments 157-195, wherein the fusion protein is codon-optimized for expression in eukaryotic cells. 197. The method of any one of embodiments 157-196, wherein at least one of the nucleotide sequence encoding one or more guide RNAs and the nucleotide sequence encoding the fusion protein is operably linked to a promoter heterologous to the nucleotide sequence. 198. The method of any one of embodiments 157-197, wherein the target DNA sequence is a eukaryotic target DNA sequence. 199. The method of any of embodiments 157-198, wherein the target DNA sequence is positioned adjacent to a protospacer adjacent motif (PAM) recognized by an RGN. 200. The method of any one of embodiments 157-199, wherein the nucleotide sequence encoding one or more guide RNAs and the nucleotide sequence encoding the fusion protein are located on a vector. 201. The method of any of embodiments 157-200, wherein the target DNA sequence is a eukaryotic target DNA sequence. 202. The method of any of embodiments 157-201, wherein the target DNA molecule is within a cell. 203. The method of embodiment 202, wherein the cell is a eukaryotic cell. 204. The method of embodiment 203, wherein the eukaryotic cell is a plant cell. 205. The method of embodiment 203, wherein the eukaryotic cell is a mammalian cell. 206. The method of embodiment 205, wherein the mammalian cell is a human cell. 207. The method of embodiment 206, wherein the human cell is an immune cell. 208. The method of embodiment 207, wherein the immune cells are stem cells. 209. The method of implementation method 208, wherein the stem cells are induced high-potential stem cells. 210. The method of embodiment 203, wherein the eukaryotic cell is an insect cell. 211. The method of embodiment 202, wherein the cell is a prokaryotic cell. 212. The method of any of embodiments 202-211 further includes selecting cells comprising the modified target DNA molecule. 213. A cell comprising a modified target DNA molecule according to the method of embodiment 212. 214. The cell of embodiment 213, wherein the cell is a eukaryotic cell. 215. The cell of embodiment 214, wherein the eukaryotic cell is a plant cell. 216. A plant comprising cells of implementation method 215. 217. A seed comprising a cell of implementation method 215. 218. The cell of embodiment 214, wherein the eukaryotic cell is a mammalian cell. 219. The cell of embodiment 218, wherein the mammalian cell is a human cell. 220. The cell of embodiment 219, wherein the human cell is an immune cell. 221. The cell of embodiment 220, wherein the immune cell is a stem cell. 222. The cell of embodiment 221, wherein the stem cell is an induced high-potential stem cell. 223. The cell of embodiment 214, wherein the eukaryotic cell is an insect cell. 224. The cell of embodiment 213, wherein the cell is a prokaryotic cell. 225. A pharmaceutical composition comprising a cell of any one of embodiments 218-222 and a pharmaceutically acceptable carrier. 226. A method for treating an individual suffering from or at risk of developing a disease, disorder or symptom, the method comprising: administering to the individual a fusion protein of any of embodiments 1-35 and 232-243, an RNP complex of embodiment 36, a nucleic acid molecule of any of embodiments 37-73 and 244-255, a vector of any of embodiments 74-77, a cell of any of embodiments 84-88, 142-146, and 218-222, a system of any of embodiments 100-139 and 256-267, or a pharmaceutical composition of any of embodiments 94, 152, and 225. 227. The method of embodiment 226, wherein the disease is associated with a causal mutation and the treatment includes correcting the causal mutation. 228. A fusion protein of any one of embodiments 1-35 and 232-243, an RNP complex of embodiment 36, a nucleic acid molecule of any one of embodiments 37-73 and 244-255, a vector of any one of embodiments 74-77, a cell of any one of embodiments 84-88, 142-146, and 218-222, or a system of any one of embodiments 100-139 and 256-267 for treating a disease, disorder or condition in an individual suffering from or at risk of developing the disease, disorder or condition. 229. The use of embodiment 228, wherein the disease is associated with a causal mutation and the treatment comprises correcting the causal mutation. 230. A fusion protein of any one of embodiments 1-35 and 232-243, an RNP complex of embodiment 36, a nucleic acid molecule of any one of embodiments 37-73 and 244-255, a vector of any one of embodiments 74-77, a cell of any one of embodiments 84-88, 142-146, and 218-222, or a system of any one of embodiments 100-139 and 256-267 for use in the manufacture of a drug useful for treating a disease, disorder or condition. 231. The use of embodiment 230, wherein the disease is associated with a causal mutation and an effective amount of the drug corrects the causal mutation. 232 A fusion protein of embodiment 18, wherein the adenine deaminase comprises an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 5, and at least one of the following amino acid residues: a) C at a position corresponding to position 2 of SEQ ID NO: 5; C at a position corresponding to position 2 of SEQ ID NO: 5; b) F or C at a position corresponding to position 22 of SEQ ID NO: 5; c) Q at a position corresponding to position 23 of SEQ ID NO: 5; d) N at a position corresponding to position 35 of SEQ ID NO: 5; e) L at a position corresponding to position 40 of SEQ ID NO: 5; f) Q at a position corresponding to position 46 of SEQ ID NO: 5; g) A or M at a position corresponding to position 68 of SEQ ID NO: 5; h) H at a position corresponding to position 72 of SEQ ID NO: 5; i) W, A, Q, Y, or D at the position corresponding to position 75 of SEQ ID NO: 5; j) G at the position corresponding to position 76 of SEQ ID NO: 5; k) S at the position corresponding to position 81 of SEQ ID NO: 5; l) M at the position corresponding to position 105 of SEQ ID NO: 5; m) H at the position corresponding to position 108 of SEQ ID NO: 5; n) L at the position corresponding to position 109 of SEQ ID NO: 5; o) I or L at the position corresponding to position 117 of SEQ ID NO: 5; p) F at the position corresponding to position 120 of SEQ ID NO: 5; q) E, T, A, G, or V at the position corresponding to position 121 of SEQ ID NO: 5; r) I or H at the position corresponding to position 122 of SEQ ID NO: 5; s) K at the position corresponding to position 125 of SEQ ID NO: 5; t) A at the position corresponding to position 126 of SEQ ID NO: 5; u) H at the position corresponding to position 135 of SEQ ID NO: 5; v) V at the position corresponding to position 137 of SEQ ID NO: 5; w) Y at the position corresponding to position 138 of SEQ ID NO: 5; x) L at the position corresponding to position 139 of SEQ ID NO: 5; y) K or A at the position corresponding to position 142 of SEQ ID NO: 5; z) A, Q, L, or M at the position corresponding to position 145 of SEQ ID NO: 5; aa) K at the position corresponding to position 148 of SEQ ID NO: 5; bb) Q at the position corresponding to position 151 of SEQ ID NO: 5; cc) E or R at the position corresponding to position 153 of SEQ ID NO: 5; dd) NO:5 position corresponding to W; ee) R or V at a position corresponding to SEQ ID NO:5 position corresponding to 156; ff) F at a position corresponding to SEQ ID NO:5 position corresponding to 157; gg) R at a position corresponding to SEQ ID NO:5 position corresponding to 158; hh) Q at a position corresponding to SEQ ID NO:5 position corresponding to 159; ii) D or W at a position corresponding to SEQ ID NO:5 position corresponding to 160; jj) W, H, V, or A at a position corresponding to SEQ ID NO:5 position corresponding to 162; kk) R at a position corresponding to SEQ ID NO:5 position corresponding to 165; and ll) H at a position corresponding to SEQ ID NO:5 position corresponding to 166. 233. The fusion protein of embodiment 232, wherein the adenine deaminase comprises at least one of the following amino acid residues: a) C at a position corresponding to position 2 of SEQ ID NO: 5; b) F or C at a position corresponding to position 22 of SEQ ID NO: 5; c) Q at a position corresponding to position 23 of SEQ ID NO: 5; d) N at a position corresponding to position 35 of SEQ ID NO: 5; e) L at a position corresponding to position 40 of SEQ ID NO: 5; f) A at a position corresponding to position 68 of SEQ ID NO: 5; g) W, A, Q, or Y at a position corresponding to position 75 of SEQ ID NO: 5; h) G at a position corresponding to position 76 of SEQ ID NO: 5; i) S at a position corresponding to position 81 of SEQ ID NO: 5; j) M at a position corresponding to position 105 of SEQ ID NO: 5; k) H at the position corresponding to position 108 of SEQ ID NO: 5; l) L at the position corresponding to position 109 of SEQ ID NO: 5; m) I or L at the position corresponding to position 117 of SEQ ID NO: 5; n) A or G at the position corresponding to position 121 of SEQ ID NO: 5; o) H at the position corresponding to position 122 of SEQ ID NO: 5; p) A at the position corresponding to position 126 of SEQ ID NO: 5; q) H at the position corresponding to position 135 of SEQ ID NO: 5; r) V at the position corresponding to position 137 of SEQ ID NO: 5; s) Y at the position corresponding to position 138 of SEQ ID NO: 5; t) L at the position corresponding to position 139 of SEQ ID NO: 5; u) K or A at the position corresponding to position 142 of SEQ ID NO: 5; v) A, Q, L, or M at a position corresponding to position 145 of SEQ ID NO: 5; w) E or R at a position corresponding to position 153 of SEQ ID NO: 5; x) W at a position corresponding to position 155 of SEQ ID NO: 5; y) R at a position corresponding to position 156 of SEQ ID NO: 5; z) F at a position corresponding to position 157 of SEQ ID NO: 5; aa) R at a position corresponding to position 158 of SEQ ID NO: 5; bb) Q at a position corresponding to position 159 of SEQ ID NO: 5; cc) D or W at a position corresponding to position 160 of SEQ ID NO: 5; dd) A or W at a position corresponding to position 162 of SEQ ID NO: 5; and ee) R at a position corresponding to position 165 of SEQ ID NO: 5. 234. The fusion protein of embodiment 232, wherein the adenine deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5 and W at a position corresponding to position 162 of SEQ ID NO: 5; b) N at a position corresponding to position 35 of SEQ ID NO: 5 and Q at a position corresponding to position 46 of SEQ ID NO: 5; c) S at a position corresponding to position 81 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; d) Q at a position corresponding to position 46 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; e) R at a position corresponding to position 156 of SEQ ID NO: 5 and W at a position corresponding to position 162 of SEQ ID NO: 5; f) A at a position corresponding to position 68 of SEQ ID NO: 5 and R at a position corresponding to position 69 of SEQ ID NO: 5. NO:5 position 81 corresponding to S; g) N corresponding to position 35 of SEQ ID NO:5, S corresponding to position 81 of SEQ ID NO:5, and W corresponding to position 162 of SEQ ID NO:5; h) N corresponding to position 35 of SEQ ID NO:5, Q corresponding to position 46 of SEQ ID NO:5, and W corresponding to position 162 of SEQ ID NO:5; i) W corresponding to position 155 of SEQ ID NO:5, R corresponding to position 156 of SEQ ID NO:5, and W corresponding to position 162 of SEQ ID NO:5; j) N corresponding to position 35 of SEQ ID NO:5, R corresponding to position 156 of SEQ ID NO:5, and W corresponding to position 162 of SEQ ID NO:5; k) N at the position corresponding to position 35 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; l) M at the position corresponding to position 68 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; m) Q at the position corresponding to position 46 of SEQ ID NO: 5, M at the position corresponding to position 68 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; n) NO:5, M at the position corresponding to position 68, S at the position corresponding to position 81, H at the position corresponding to position 108, R at the position corresponding to position 156, and W at the position corresponding to position 162 of SEQ ID NO:5; o) Q at the position corresponding to position 46, N at the position corresponding to position 35, M at the position corresponding to position 68, S at the position corresponding to position 81, H at the position corresponding to position 108, W at the position corresponding to position 155, R at the position corresponding to position 156, and W at the position corresponding to position 162 of SEQ ID NO:5; p) Q at the position corresponding to position 46, N at the position corresponding to position 35, M at the position corresponding to position 68, S at the position corresponding to position 81, and H at the position corresponding to position 108 of SEQ ID NO:5, W at the position corresponding to position 155, R at the position corresponding to position 156, and W at the position corresponding to position 162 of SEQ ID NO:5; NO:5 position 81 corresponding to S, and position 155 corresponding to W; q) SEQ ID NO:5 position 75 corresponding to W, and position 81 corresponding to S; r) SEQ ID NO:5 position 81 corresponding to S, and position 160 corresponding to D; s) SEQ ID NO:5 position 81 corresponding to S, and position 145 corresponding to A; t) SEQ ID NO:5 position 75 corresponding to W, and position 155 corresponding to W; u) SEQ ID NO:5 position 155 corresponding to W, and position 160 corresponding to D; v) SEQ ID NO:5 position 81 corresponding to S, and position 145 corresponding to A; t) SEQ ID NO:5 position 75 corresponding to W, and position 155 corresponding to W; u) SEQ ID NO:5 position 155 corresponding to W, and position 160 corresponding to D; v) SEQ ID NO:5 position 81 corresponding to S, and position 145 corresponding to A; NO:5 position 145 A, and SEQ ID NO:5 position 155 W; w) SEQ ID NO:5 position 75 W, and SEQ ID NO:5 position 160 D; x) SEQ ID NO:5 position 75 W, and SEQ ID NO:5 position 145 A; y) SEQ ID NO:5 position 145 A, and SEQ ID NO:5 position 160 D; z) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 81 S, and SEQ ID NO:5 position 155 W; aa) SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 160 D; NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; bb) S at the position corresponding to SEQ ID NO:5 position 81 corresponding to A, and SEQ ID NO:5 position 145 corresponding to W; cc) W at the position corresponding to SEQ ID NO:5 position 75 corresponding to S, and SEQ ID NO:5 position 81 corresponding to D; dd) W at the position corresponding to SEQ ID NO:5 position 75 corresponding to S, and SEQ ID NO:5 position 81 corresponding to A, and SEQ ID NO:5 position 145 corresponding to D; ee) S at the position corresponding to SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 155 corresponding to W; NO:5 position 145 A, and a position corresponding to position 160 of SEQ ID NO:5; ff) a W at a position corresponding to position 75 of SEQ ID NO:5, a W at a position corresponding to position 155 of SEQ ID NO:5, and a D at a position corresponding to position 160 of SEQ ID NO:5; gg) a W at a position corresponding to position 75 of SEQ ID NO:5, an A at a position corresponding to position 145 of SEQ ID NO:5, and a W at a position corresponding to position 155 of SEQ ID NO:5; hh) an A at a position corresponding to position 145 of SEQ ID NO:5, a W at a position corresponding to position 155 of SEQ ID NO:5, and a D at a position corresponding to position 160 of SEQ ID NO:5; ii) a W at a position corresponding to position 75 of SEQ ID NO:5, a W at a position corresponding to position 155 of SEQ ID NO:5, and a D at a position corresponding to position 160 of SEQ ID NO:5 NO:5 position 145 A, and SEQ ID NO:5 position 160 D; jj) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; kk) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 145 A, and SEQ ID NO:5 position 155 W; ll) SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 145 A, and SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; NO:5 position corresponding to position 160; mm) W at a position corresponding to position 75 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, A at a position corresponding to position 145 of SEQ ID NO:5, and D at a position corresponding to position 160 of SEQ ID NO:5; nn) W at a position corresponding to position 75 of SEQ ID NO:5, A at a position corresponding to position 145 of SEQ ID NO:5, W at a position corresponding to position 155 of SEQ ID NO:5, and D at a position corresponding to position 160 of SEQ ID NO:5; oo) W at a position corresponding to position 75 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, A at a position corresponding to position 145 of SEQ ID NO:5, W at a position corresponding to position 155 of SEQ ID NO:5, and D at a position corresponding to position 160 of SEQ ID NO:5. NO:5 position 160 corresponding to D; pp) L at the position corresponding to SEQ ID NO:5 position 40, and M at the position corresponding to SEQ ID NO:5 position 105 corresponding to M; qq) L at the position corresponding to SEQ ID NO:5 position 40, and V at the position corresponding to SEQ ID NO:5 position 121 corresponding to V; rr) L at the position corresponding to SEQ ID NO:5 position 40, and M at the position corresponding to SEQ ID NO:5 position 145 corresponding to M; ss) L at the position corresponding to SEQ ID NO:5 position 40, and Q at the position corresponding to SEQ ID NO:5 position 159 corresponding to Q; tt) L at the position corresponding to SEQ ID NO:5 position 40, and W at the position corresponding to SEQ ID NO:5 position 160 corresponding to W; uu) M at the position corresponding to SEQ ID NO:5 position 105, and V at the position corresponding to SEQ ID NO:5 position 121 corresponding to V; NO: 5 position 121 corresponding to V; vv) SEQ ID NO: 5 position 105 corresponding to M, and SEQ ID NO: 5 position 145 corresponding to M; ww) SEQ ID NO: 5 position 105 corresponding to M, and SEQ ID NO: 5 position 159 corresponding to Q; xx) SEQ ID NO: 5 position 105 corresponding to M, and SEQ ID NO: 5 position 160 corresponding to W; yy) SEQ ID NO: 5 position 121 corresponding to V, and SEQ ID NO: 5 position 145 corresponding to M; zz) SEQ ID NO: 5 position 121 corresponding to M, and SEQ ID NO: 5 position 159 corresponding to Q; aaa) SEQ ID NO: 5 position 105 corresponding to M, and SEQ ID NO: 5 position 160 corresponding to W; NO: 5 position 121 corresponding to V, and SEQ ID NO: 5 position 160 corresponding to W; bbb) SEQ ID NO: 5 position 145 corresponding to M, and SEQ ID NO: 5 position 159 corresponding to Q; ccc) SEQ ID NO: 5 position 145 corresponding to M, and SEQ ID NO: 5 position 160 corresponding to W; ddd) SEQ ID NO: 5 position 159 corresponding to Q, and SEQ ID NO: 5 position 160 corresponding to W; eee) SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 145 corresponding to M, and SEQ ID NO: 5 position 160 corresponding to W; fff) SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 145 corresponding to Q, and SEQ ID NO: 5 position 160 corresponding to W; NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 159 corresponding to Q; ggg) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 81 corresponding to S; hhh) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; iii) SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; jjj) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 76 corresponding to G; kkk) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 117 corresponding to L; lll) SEQ ID NO:5 position 81 corresponding to S; NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; mmm) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; nnn) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ooo) SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ppp) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to S, and SEQ ID NO:5 position 81 corresponding to L; NO:5 position corresponding to position 117; qqq) A at a position corresponding to position 68 of SEQ ID NO:5, G at a position corresponding to position 76 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, and L at a position corresponding to position 117 of SEQ ID NO:5; rrr) S at a position corresponding to position 81 of SEQ ID NO:5, L at a position corresponding to position 109 of SEQ ID NO:5, E at a position corresponding to position 153 of SEQ ID NO:5, W at a position corresponding to position 155 of SEQ ID NO:5, and D at a position corresponding to position 160 of SEQ ID NO:5; sss) A at a position corresponding to position 75 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, L at a position corresponding to position 117 of SEQ ID NO:5, and D at a position corresponding to position 160 of SEQ ID NO:5. A at a position corresponding to position 121 of SEQ ID NO: 5, A at a position corresponding to position 145 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; ttt) Q at a position corresponding to position 75 of SEQ ID NO: 5, S at a position corresponding to position 81 of SEQ ID NO: 5, I at a position corresponding to position 117 of SEQ ID NO: 5, Q at a position corresponding to position 145 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; uuu) Y at a position corresponding to position 75 of SEQ ID NO: 5, S at a position corresponding to position 81 of SEQ ID NO: 5, L at a position corresponding to position 117 of SEQ ID NO: 5, NO:5 position 121 G, SEQ ID NO:5 position 145 L, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; vvv) SEQ ID NO:5 position 22 C, SEQ ID NO:5 position 68 A, SEQ ID NO:5 position 75 Y, SEQ ID NO:5 position 76 G, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 108 H, SEQ ID NO:5 position 117 L, SEQ ID NO:5 position 122 H, SEQ ID NO:5 position 138 Y, SEQ ID NO:5 position 140 S, SEQ ID NO:5 position 141 H, SEQ ID NO:5 position 143 L, SEQ ID NO:5 position 147 H, SEQ ID NO:5 position 149 S, SEQ ID NO:5 position 150 S, SEQ ID NO:5 position 151 S, SEQ ID NO:5 position 152 S, SEQ ID NO:5 position 153 S, SEQ ID NO:5 position 154 S, SEQ ID NO:5 position 155 S, SEQ ID NO:5 position 156 S, SEQ ID NO:5 position 157 S, SEQ ID NO:5 position 158 S, SEQ ID NO:5 position 159 S, SEQ ID NO:5 position 160 L at a position corresponding to position 139 of SEQ ID NO: 5, A at a position corresponding to position 142 of SEQ ID NO: 5, A at a position corresponding to position 145 of SEQ ID NO: 5, R at a position corresponding to position 153 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, D at a position corresponding to position 160 of SEQ ID NO: 5, and H at a position corresponding to position 162 of SEQ ID NO: 5; or www) S at a position corresponding to position 81 of SEQ ID NO: 5. 235. The fusion protein of embodiment 232, wherein the adenine deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5 and Q at a position corresponding to position 46 of SEQ ID NO: 5; b) S at a position corresponding to position 81 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; c) Q at a position corresponding to position 46 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; d) N at a position corresponding to position 35 of SEQ ID NO: 5, Q at a position corresponding to position 46 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; e) W at a position corresponding to position 155 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, and R at a position corresponding to position 163 of SEQ ID NO: 5. NO:5 position 162 corresponding to W; f) N at the position corresponding to SEQ ID NO:5 position 35, R at the position corresponding to SEQ ID NO:5 position 156, and W at the position corresponding to SEQ ID NO:5 position 162; g) N at the position corresponding to SEQ ID NO:5 position 35, S at the position corresponding to SEQ ID NO:5 position 81, R at the position corresponding to SEQ ID NO:5 position 156, and W at the position corresponding to SEQ ID NO:5 position 162; h) M at the position corresponding to SEQ ID NO:5 position 68, S at the position corresponding to SEQ ID NO:5 position 81, H at the position corresponding to SEQ ID NO:5 position 108, R at the position corresponding to SEQ ID NO:5 position 156, and W at the position corresponding to SEQ ID NO:5 position 162; i) Q at the position corresponding to position 46 of SEQ ID NO: 5, N at the position corresponding to position 35, M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; j) S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; k) W at the position corresponding to position 75 of SEQ ID NO: 5, and S at the position corresponding to position 81 of SEQ ID NO: 5; l) S at the position corresponding to position 81 of SEQ ID NO: 5, and R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; NO:5 position 160 corresponding to D; m) S at the position corresponding to SEQ ID NO:5 position 81, and A at the position corresponding to SEQ ID NO:5 position 145 corresponding to A; n) W at the position corresponding to SEQ ID NO:5 position 75, and W at the position corresponding to SEQ ID NO:5 position 155 corresponding to W; o) W at the position corresponding to SEQ ID NO:5 position 75, and A at the position corresponding to SEQ ID NO:5 position 145 corresponding to A; p) A at the position corresponding to SEQ ID NO:5 position 145, and D at the position corresponding to SEQ ID NO:5 position 160 corresponding to A; q) W at the position corresponding to SEQ ID NO:5 position 75, S at the position corresponding to SEQ ID NO:5 position 81, and W at the position corresponding to SEQ ID NO:5 position 155 corresponding to A; r) W at the position corresponding to SEQ ID NO:5 position 75, S at the position corresponding to SEQ ID NO:5 position 81, and W at the position corresponding to SEQ ID NO:5 position 155 corresponding to A; NO:5 position 81 S, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; s) SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 145 A, and SEQ ID NO:5 position 155 W; t) SEQ ID NO:5 position 40 L, and SEQ ID NO:5 position 105 M; u) SEQ ID NO:5 position 40 L, and SEQ ID NO:5 position 145 M; v) SEQ ID NO:5 position 40 L, and SEQ ID NO:5 position 159 Q; w) SEQ ID NO:5 position 40 A, and SEQ ID NO:5 position 159 B; NO:5 position 40 corresponding to L, and SEQ ID NO:5 position 160 corresponding to W; x) SEQ ID NO:5 position 105 corresponding to M, and SEQ ID NO:5 position 145 corresponding to M; y) SEQ ID NO:5 position 105 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; z) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 159 corresponding to Q; aa) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; bb) SEQ ID NO:5 position 159 corresponding to Q, and SEQ ID NO:5 position 160 corresponding to W; cc) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; NO:5 position 81 S, SEQ ID NO:5 position 145 M, and SEQ ID NO:5 position 160 W; dd) SEQ ID NO:5 position 68 A, and SEQ ID NO:5 position 81 S; ee) SEQ ID NO:5 position 76 G, and SEQ ID NO:5 position 81 S; ff) SEQ ID NO:5 position 81 S, and SEQ ID NO:5 position 117 L; gg) SEQ ID NO:5 position 68 A, and SEQ ID NO:5 position 76 G; hh) SEQ ID NO:5 position 68 A, and SEQ ID NO:5 position 81 S; ff) SEQ ID NO:5 position 81 S, and SEQ ID NO:5 position 117 L; gg) SEQ ID NO:5 position 68 A, and SEQ ID NO:5 position 76 G; hh) SEQ ID NO:5 position 68 A, and SEQ ID NO:5 position 81 S; NO:5 position 117 corresponding to L; ii) G at a position corresponding to position 76 of SEQ ID NO:5, and L at a position corresponding to position 117 of SEQ ID NO:5; jj) A at a position corresponding to position 68 of SEQ ID NO:5, G at a position corresponding to position 76 of SEQ ID NO:5, and S at a position corresponding to position 81 of SEQ ID NO:5; kk) A at a position corresponding to position 68 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, and L at a position corresponding to position 117 of SEQ ID NO:5; ll) G at a position corresponding to position 76 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, and L at a position corresponding to position 117 of SEQ ID NO:5; mm) A at a position corresponding to position 68 of SEQ ID NO:5, A at the position corresponding to position 68 of SEQ ID NO: 5, G at the position corresponding to position 76 of SEQ ID NO: 5, and L at the position corresponding to position 117 of SEQ ID NO: 5; nn) A at the position corresponding to position 68 of SEQ ID NO: 5, G at the position corresponding to position 76 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and L at the position corresponding to position 117 of SEQ ID NO: 5; oo) A at the position corresponding to position 68 of SEQ ID NO: 5, and S at the position corresponding to position 81 of SEQ ID NO: 5; pp) S at the position corresponding to position 81 of SEQ ID NO: 5, L at the position corresponding to position 109 of SEQ ID NO: 5, E at the position corresponding to position 153 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and L at the position corresponding to position 117 of SEQ ID NO: 5. NO:5 position corresponding to position 160; qq) A at a position corresponding to position 75 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, L at a position corresponding to position 117 of SEQ ID NO:5, A at a position corresponding to position 121 of SEQ ID NO:5, A at a position corresponding to position 145 of SEQ ID NO:5, W at a position corresponding to position 155 of SEQ ID NO:5, and D at a position corresponding to position 160 of SEQ ID NO:5; rr) Q at a position corresponding to position 75 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, I at a position corresponding to position 117 of SEQ ID NO:5, Q at a position corresponding to position 145 of SEQ ID NO:5, W at a position corresponding to position 155 of SEQ ID NO:5, and D at a position corresponding to position 160 of SEQ ID NO:5. NO:5 position 160 D; ss) Y at a position corresponding to SEQ ID NO:5 position 75, S at a position corresponding to SEQ ID NO:5 position 81, L at a position corresponding to SEQ ID NO:5 position 117, G at a position corresponding to SEQ ID NO:5 position 121, L at a position corresponding to SEQ ID NO:5 position 145, W at a position corresponding to SEQ ID NO:5 position 155, and D at a position corresponding to SEQ ID NO:5 position 160; tt) C at a position corresponding to SEQ ID NO:5 position 22, A at a position corresponding to SEQ ID NO:5 position 68, Y at a position corresponding to SEQ ID NO:5 position 75, G at a position corresponding to SEQ ID NO:5 position 76, S at a position corresponding to SEQ ID NO:5 position 81, and D at a position corresponding to SEQ ID NO:5 position 160; NO:5, H at a position corresponding to position 108, L at a position corresponding to position 117, H at a position corresponding to position 122, Y at a position corresponding to position 138, L at a position corresponding to position 139, A at a position corresponding to position 142, A at a position corresponding to position 145, R at a position corresponding to position 153, W at a position corresponding to position 155, R at a position corresponding to position 156, D at a position corresponding to position 160, and H at a position corresponding to position 162 of SEQ ID NO:5; uu) S at a position corresponding to position 81 of SEQ ID NO:5; or vv) at a position corresponding to position 82 of SEQ ID NO:5; W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. 236. A fusion protein of any one of embodiments 232, 234, and 235, wherein the adenine deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5, S at a position corresponding to position 81 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; b) W at a position corresponding to position 75 of SEQ ID NO: 5, and W at a position corresponding to position 155 of SEQ ID NO: 5; c) S at a position corresponding to position 81 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; d) S at a position corresponding to position 81 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; NO:5 position 145 A, and SEQ ID NO:5 position 155 W; e) SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 145 M, and SEQ ID NO:5 position 160 W; f) SEQ ID NO:5 position 76 G, and SEQ ID NO:5 position 81 S; g) SEQ ID NO:5 position 81 S, and SEQ ID NO:5 position 117 L; h) SEQ ID NO:5 position 68 A, and SEQ ID NO:5 position 81 S; i) SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 109 L, and SEQ ID NO:5 position 117 L; NO:5 position 153 E, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; j) SEQ ID NO:5 position 75 A, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 117 L, SEQ ID NO:5 position 121 A, SEQ ID NO:5 position 145 A, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; k) SEQ ID NO:5 position 75 Q, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 117 I, SEQ ID NO:5 position 121 A, SEQ ID NO:5 position 145 A, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; NO:5 position 145 corresponding to Q, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; l) SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; m) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; m) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to 5, G at a position corresponding to position 76 of SEQ ID NO: 5, S at a position corresponding to position 81 of SEQ ID NO: 5, H at a position corresponding to position 108 of SEQ ID NO: 5, L at a position corresponding to position 117 of SEQ ID NO: 5, H at a position corresponding to position 122 of SEQ ID NO: 5, Y at a position corresponding to position 138 of SEQ ID NO: 5, L at a position corresponding to position 139 of SEQ ID NO: 5, A at a position corresponding to position 142 of SEQ ID NO: 5, A at a position corresponding to position 145 of SEQ ID NO: 5, R at a position corresponding to position 153 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, D at a position corresponding to position 160 of SEQ ID NO: 5, and H at the position corresponding to position 162 of SEQ ID NO: 5; n) S at the position corresponding to position 81 of SEQ ID NO: 5; or o) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. 237. A fusion protein of any one of embodiments 232-236, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 300-414, 596-598, and 720-723. 238. A fusion protein of any one of embodiments 232-236, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 300-414, 596-598, and 720-723. 239. A fusion protein of any one of embodiments 232-236, wherein the deaminase has an amino acid sequence as shown in any one of SEQ ID NOs: 300-414, 596-598, and 720-723. 240. The fusion protein of any one of embodiments 232-239, wherein the fusion protein is selected from the group consisting of: a) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; b) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 52; c) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 319 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: NO:50 having an amino acid sequence with at least 90% sequence identity after the amino acid position corresponding to position 922 of SEQ ID NO:2; d) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:319 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:52; e) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:375 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; f) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:375 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; NO:375 has an amino acid sequence with at least 90% sequence identity and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; g) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:319 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; h) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:597 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; i) A fusion protein wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 319 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; j) A fusion protein wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 406 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; k) A fusion protein wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; NO: 2 after the amino acid position corresponding to position 678; l) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 596 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; m) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 406 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 52; n) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: NO:52 has an amino acid sequence with at least 90% sequence identity after the amino acid position corresponding to position 910 of SEQ ID NO:4; o) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; p) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:596 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:52; q) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; NO:596 has an amino acid sequence with at least 90% sequence identity and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; r) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; s) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:596 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; and t) A fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49. 241. The fusion protein of any one of embodiments 232-239, wherein the fusion protein is selected from the group consisting of: a) a fusion protein, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 50; b) a fusion protein, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 52; c) a fusion protein, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 319 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: NO:50 has an amino acid sequence with at least 95% sequence identity after the amino acid position corresponding to position 922 of SEQ ID NO:2; d) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:319 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:52; e) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:375 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:49; f) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:375 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:49; NO:375 has an amino acid sequence with at least 95% sequence identity and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:50; g) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:319 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:49; h) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:597 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:50; i) A fusion protein wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 319 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 50; j) A fusion protein wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 406 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 50; k) A fusion protein wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 50; NO: 2 after the amino acid position corresponding to position 678; l) a fusion protein, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 596 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 50; m) a fusion protein, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 406 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 52; n) a fusion protein, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: NO:52 has an amino acid sequence with at least 95% sequence identity after the amino acid position corresponding to position 910 of SEQ ID NO:4; o) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:50; p) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:596 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:52; q) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:50; NO:596 has an amino acid sequence with at least 95% sequence identity and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:50; r) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:49; s) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:596 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:49; and t) A fusion protein, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49. 242. A fusion protein of any one of embodiments 232-239, wherein the fusion protein is selected from the group consisting of: a) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having an amino acid sequence as shown in SEQ ID NO: 50; b) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence as shown in SEQ ID NO: 52; c) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 319 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having an amino acid sequence as shown in SEQ ID NO: 50; d) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 319 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence as shown in SEQ ID NO: 52; e) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence as shown in SEQ ID NO: 49; f) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence as shown in SEQ ID NO: 50; g) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 319 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence as shown in SEQ ID NO: NO:49 after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having the amino acid sequence shown in SEQ ID NO:597; h) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:597 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:50; i) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:319 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:50; j) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:50; k) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having the amino acid sequence as shown in SEQ ID NO: 50; l) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 596 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having the amino acid sequence as shown in SEQ ID NO: 50; m) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 406 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having the amino acid sequence as shown in SEQ ID NO: 52; n) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having the amino acid sequence as shown in SEQ ID NO: NO:52 after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having the amino acid sequence shown in SEQ ID NO:52; o) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:50; p) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:596 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having the amino acid sequence shown in SEQ ID NO:52; q) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:596 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:50; r) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 406 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence as shown in SEQ ID NO: 49; s) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 596 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence as shown in SEQ ID NO: 49; and t) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence as shown in SEQ ID NO: 49. 243. The fusion protein of embodiment 242, wherein the fusion protein has a sequence shown in any one of SEQ ID NOs: 599, 600, 602, 603, 606, 610, 612, 614, 615, 617, 619-624, 626, and 630-632. 244. The nucleic acid molecule of embodiment 54, wherein the adenine deaminase comprises an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 5, and comprises at least one of the following amino acid residues: a) C at a position corresponding to position 2 of SEQ ID NO: 5; b) F or C at a position corresponding to position 22 of SEQ ID NO: 5; c) Q at a position corresponding to position 23 of SEQ ID NO: 5; d) N at a position corresponding to position 35 of SEQ ID NO: 5; e) L at a position corresponding to position 40 of SEQ ID NO: 5; f) Q at a position corresponding to position 46 of SEQ ID NO: 5; g) A or M at a position corresponding to position 68 of SEQ ID NO: 5; h) H at a position corresponding to position 72 of SEQ ID NO: 5; i) W, A, Q, Y, or D at the position corresponding to position 75 of SEQ ID NO: 5; j) G at the position corresponding to position 76 of SEQ ID NO: 5; k) S at the position corresponding to position 81 of SEQ ID NO: 5; l) M at the position corresponding to position 105 of SEQ ID NO: 5; m) H at the position corresponding to position 108 of SEQ ID NO: 5; n) L at the position corresponding to position 109 of SEQ ID NO: 5; o) I or L at the position corresponding to position 117 of SEQ ID NO: 5; p) F at the position corresponding to position 120 of SEQ ID NO: 5; q) E, T, A, G, or V at the position corresponding to position 121 of SEQ ID NO: 5; r) I or H at the position corresponding to position 122 of SEQ ID NO: 5; s) K at the position corresponding to position 125 of SEQ ID NO: 5; t) A at the position corresponding to position 126 of SEQ ID NO: 5; u) H at the position corresponding to position 135 of SEQ ID NO: 5; v) V at the position corresponding to position 137 of SEQ ID NO: 5; w) Y at the position corresponding to position 138 of SEQ ID NO: 5; x) L at the position corresponding to position 139 of SEQ ID NO: 5; y) K or A at the position corresponding to position 142 of SEQ ID NO: 5; z) A, Q, L, or M at the position corresponding to position 145 of SEQ ID NO: 5; aa) K at the position corresponding to position 148 of SEQ ID NO: 5; bb) Q at the position corresponding to position 151 of SEQ ID NO: 5; cc) E or R at the position corresponding to position 153 of SEQ ID NO: 5; dd) NO:5 position corresponding to W; ee) R or V at a position corresponding to SEQ ID NO:5 position corresponding to 156; ff) F at a position corresponding to SEQ ID NO:5 position corresponding to 157; gg) R at a position corresponding to SEQ ID NO:5 position corresponding to 158; hh) Q at a position corresponding to SEQ ID NO:5 position corresponding to 159; ii) D or W at a position corresponding to SEQ ID NO:5 position corresponding to 160; jj) W, H, V, or A at a position corresponding to SEQ ID NO:5 position corresponding to 162; kk) R at a position corresponding to SEQ ID NO:5 position corresponding to 165; and ll) H at a position corresponding to SEQ ID NO:5 position corresponding to 166. 245. A nucleic acid molecule of embodiment 244, wherein the adenine deaminase comprises at least one of the following amino acid residues: a) C at a position corresponding to position 2 of SEQ ID NO: 5; b) F or C at a position corresponding to position 22 of SEQ ID NO: 5; c) Q at a position corresponding to position 23 of SEQ ID NO: 5; d) N at a position corresponding to position 35 of SEQ ID NO: 5; e) L at a position corresponding to position 40 of SEQ ID NO: 5; f) A at a position corresponding to position 68 of SEQ ID NO: 5; g) W, A, Q, or Y at a position corresponding to position 75 of SEQ ID NO: 5; h) G at a position corresponding to position 76 of SEQ ID NO: 5; i) S at a position corresponding to position 81 of SEQ ID NO: 5; j) M at a position corresponding to position 105 of SEQ ID NO: 5; k) H at the position corresponding to position 108 of SEQ ID NO: 5; l) L at the position corresponding to position 109 of SEQ ID NO: 5; m) I or L at the position corresponding to position 117 of SEQ ID NO: 5; n) A or G at the position corresponding to position 121 of SEQ ID NO: 5; o) H at the position corresponding to position 122 of SEQ ID NO: 5; p) A at the position corresponding to position 126 of SEQ ID NO: 5; q) H at the position corresponding to position 135 of SEQ ID NO: 5; r) V at the position corresponding to position 137 of SEQ ID NO: 5; s) Y at the position corresponding to position 138 of SEQ ID NO: 5; t) L at the position corresponding to position 139 of SEQ ID NO: 5; u) K or A at the position corresponding to position 142 of SEQ ID NO: 5; v) A, Q, L, or M at a position corresponding to position 145 of SEQ ID NO: 5; w) E or R at a position corresponding to position 153 of SEQ ID NO: 5; x) W at a position corresponding to position 155 of SEQ ID NO: 5; y) R at a position corresponding to position 156 of SEQ ID NO: 5; z) F at a position corresponding to position 157 of SEQ ID NO: 5; aa) R at a position corresponding to position 158 of SEQ ID NO: 5; bb) Q at a position corresponding to position 159 of SEQ ID NO: 5; cc) D or W at a position corresponding to position 160 of SEQ ID NO: 5; dd) A or W at a position corresponding to position 162 of SEQ ID NO: 5; and ee) R at a position corresponding to position 165 of SEQ ID NO: 5. 246. The nucleic acid molecule of embodiment 244, wherein the adenine deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5, N at a position corresponding to position 35 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; b) N at a position corresponding to position 35 of SEQ ID NO: 5, and Q at a position corresponding to position 46 of SEQ ID NO: 5; c) S at a position corresponding to position 81 of SEQ ID NO: 5, and R at a position corresponding to position 156 of SEQ ID NO: 5; d) Q at a position corresponding to position 46 of SEQ ID NO: 5, and R at a position corresponding to position 156 of SEQ ID NO: 5; e) R at a position corresponding to position 156 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; f) A at the position corresponding to position 68 of SEQ ID NO: 5 and S at the position corresponding to position 81 of SEQ ID NO: 5; g) N at the position corresponding to position 35 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; h) N at the position corresponding to position 35 of SEQ ID NO: 5, Q at the position corresponding to position 46 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; i) W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; j) N at the position corresponding to position 35 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5 NO:5 position 162 corresponding to W; k) N at the position corresponding to SEQ ID NO:5 position 35, S at the position corresponding to SEQ ID NO:5 position 81, R at the position corresponding to SEQ ID NO:5 position 156, and W at the position corresponding to SEQ ID NO:5 position 162; l) M at the position corresponding to SEQ ID NO:5 position 68, H at the position corresponding to SEQ ID NO:5 position 108, R at the position corresponding to SEQ ID NO:5 position 156, and W at the position corresponding to SEQ ID NO:5 position 162; m) Q at the position corresponding to SEQ ID NO:5 position 46, M at the position corresponding to SEQ ID NO:5 position 68, H at the position corresponding to SEQ ID NO:5 position 108, R at the position corresponding to SEQ ID NO:5 position 156, and W at the position corresponding to SEQ ID NO:5 position 162; NO:5 at a position corresponding to position 162; n) M at a position corresponding to position 68 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, H at a position corresponding to position 108 of SEQ ID NO:5, R at a position corresponding to position 156 of SEQ ID NO:5, and W at a position corresponding to position 162 of SEQ ID NO:5; o) Q at a position corresponding to position 46 of SEQ ID NO:5, N at a position corresponding to position 35, M at a position corresponding to position 68 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, H at a position corresponding to position 108 of SEQ ID NO:5, W at a position corresponding to position 155 of SEQ ID NO:5, R at a position corresponding to position 156 of SEQ ID NO:5, and W at a position corresponding to position 162 of SEQ ID NO:5; p) S at a position corresponding to position 81 of SEQ ID NO: 5, and W at a position corresponding to position 155 of SEQ ID NO: 5; q) W at a position corresponding to position 75 of SEQ ID NO: 5, and S at a position corresponding to position 81 of SEQ ID NO: 5; r) S at a position corresponding to position 81 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; s) S at a position corresponding to position 81 of SEQ ID NO: 5, and A at a position corresponding to position 145 of SEQ ID NO: 5; t) W at a position corresponding to position 75 of SEQ ID NO: 5, and W at a position corresponding to position 155 of SEQ ID NO: 5; u) W at a position corresponding to position 155 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; v) NO:5 position 145 A, and SEQ ID NO:5 position 155 W; w) SEQ ID NO:5 position 75 W, and SEQ ID NO:5 position 160 D; x) SEQ ID NO:5 position 75 W, and SEQ ID NO:5 position 145 A; y) SEQ ID NO:5 position 145 A, and SEQ ID NO:5 position 160 D; z) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 81 S, and SEQ ID NO:5 position 155 W; aa) SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 160 D; NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; bb) S at the position corresponding to SEQ ID NO:5 position 81 corresponding to A, and SEQ ID NO:5 position 145 corresponding to W; cc) W at the position corresponding to SEQ ID NO:5 position 75 corresponding to S, and SEQ ID NO:5 position 81 corresponding to D; dd) W at the position corresponding to SEQ ID NO:5 position 75 corresponding to S, and SEQ ID NO:5 position 81 corresponding to A, and SEQ ID NO:5 position 145 corresponding to D; ee) S at the position corresponding to SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 155 corresponding to W; NO:5 position 145 A, and a position corresponding to position 160 of SEQ ID NO:5; ff) a W at a position corresponding to position 75 of SEQ ID NO:5, a W at a position corresponding to position 155 of SEQ ID NO:5, and a D at a position corresponding to position 160 of SEQ ID NO:5; gg) a W at a position corresponding to position 75 of SEQ ID NO:5, an A at a position corresponding to position 145 of SEQ ID NO:5, and a W at a position corresponding to position 155 of SEQ ID NO:5; hh) an A at a position corresponding to position 145 of SEQ ID NO:5, a W at a position corresponding to position 155 of SEQ ID NO:5, and a D at a position corresponding to position 160 of SEQ ID NO:5; ii) a W at a position corresponding to position 75 of SEQ ID NO:5, a W at a position corresponding to position 155 of SEQ ID NO:5, and a D at a position corresponding to position 160 of SEQ ID NO:5 NO:5 position 145 A, and SEQ ID NO:5 position 160 D; jj) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; kk) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 145 A, and SEQ ID NO:5 position 155 W; ll) SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 145 A, and SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; NO:5 position corresponding to position 160; mm) W at a position corresponding to position 75 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, A at a position corresponding to position 145 of SEQ ID NO:5, and D at a position corresponding to position 160 of SEQ ID NO:5; nn) W at a position corresponding to position 75 of SEQ ID NO:5, A at a position corresponding to position 145 of SEQ ID NO:5, W at a position corresponding to position 155 of SEQ ID NO:5, and D at a position corresponding to position 160 of SEQ ID NO:5; oo) W at a position corresponding to position 75 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, A at a position corresponding to position 145 of SEQ ID NO:5, W at a position corresponding to position 155 of SEQ ID NO:5, and D at a position corresponding to position 160 of SEQ ID NO:5. NO:5 position 160 corresponding to D; pp) L at the position corresponding to SEQ ID NO:5 position 40, and M at the position corresponding to SEQ ID NO:5 position 105 corresponding to M; qq) L at the position corresponding to SEQ ID NO:5 position 40, and V at the position corresponding to SEQ ID NO:5 position 121 corresponding to V; rr) L at the position corresponding to SEQ ID NO:5 position 40, and M at the position corresponding to SEQ ID NO:5 position 145 corresponding to M; ss) L at the position corresponding to SEQ ID NO:5 position 40, and Q at the position corresponding to SEQ ID NO:5 position 159 corresponding to Q; tt) L at the position corresponding to SEQ ID NO:5 position 40, and W at the position corresponding to SEQ ID NO:5 position 160 corresponding to W; uu) M at the position corresponding to SEQ ID NO:5 position 105, and V at the position corresponding to SEQ ID NO:5 position 121 corresponding to V; NO: 5 position 121 corresponding to V; vv) SEQ ID NO: 5 position 105 corresponding to M, and SEQ ID NO: 5 position 145 corresponding to M; ww) SEQ ID NO: 5 position 105 corresponding to M, and SEQ ID NO: 5 position 159 corresponding to Q; xx) SEQ ID NO: 5 position 105 corresponding to M, and SEQ ID NO: 5 position 160 corresponding to W; yy) SEQ ID NO: 5 position 121 corresponding to V, and SEQ ID NO: 5 position 145 corresponding to M; zz) SEQ ID NO: 5 position 121 corresponding to M, and SEQ ID NO: 5 position 159 corresponding to Q; aaa) SEQ ID NO: 5 position 105 corresponding to M, and SEQ ID NO: 5 position 160 corresponding to W; NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 160 corresponding to W; bbb) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 159 corresponding to Q; ccc) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; ddd) SEQ ID NO:5 position 159 corresponding to Q, and SEQ ID NO:5 position 160 corresponding to W; eee) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; fff) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to Q, and SEQ ID NO:5 position 160 corresponding to W; NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 159 corresponding to Q; ggg) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 81 corresponding to S; hhh) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; iii) SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; jjj) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 76 corresponding to G; kkk) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 117 corresponding to L; lll) SEQ ID NO:5 position 81 corresponding to S; NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; mmm) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; nnn) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ooo) SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ppp) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to S, and SEQ ID NO:5 position 81 corresponding to L; NO:5 position corresponding to position 117; qqq) A at a position corresponding to position 68 of SEQ ID NO:5, G at a position corresponding to position 76 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, and L at a position corresponding to position 117 of SEQ ID NO:5; rrr) S at a position corresponding to position 81 of SEQ ID NO:5, L at a position corresponding to position 109 of SEQ ID NO:5, E at a position corresponding to position 153 of SEQ ID NO:5, W at a position corresponding to position 155 of SEQ ID NO:5, and D at a position corresponding to position 160 of SEQ ID NO:5; sss) A at a position corresponding to position 75 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, L at a position corresponding to position 117 of SEQ ID NO:5, and D at a position corresponding to position 160 of SEQ ID NO:5. A at a position corresponding to position 121 of SEQ ID NO: 5, A at a position corresponding to position 145 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; ttt) Q at a position corresponding to position 75 of SEQ ID NO: 5, S at a position corresponding to position 81 of SEQ ID NO: 5, I at a position corresponding to position 117 of SEQ ID NO: 5, Q at a position corresponding to position 145 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; uuu) Y at a position corresponding to position 75 of SEQ ID NO: 5, S at a position corresponding to position 81 of SEQ ID NO: 5, L at a position corresponding to position 117 of SEQ ID NO: 5, NO:5 position 121 G, SEQ ID NO:5 position 145 L, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; vvv) SEQ ID NO:5 position 22 C, SEQ ID NO:5 position 68 A, SEQ ID NO:5 position 75 Y, SEQ ID NO:5 position 76 G, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 108 H, SEQ ID NO:5 position 117 L, SEQ ID NO:5 position 122 H, SEQ ID NO:5 position 138 Y, SEQ ID NO:5 position 140 S, SEQ ID NO:5 position 141 H, SEQ ID NO:5 position 143 L, SEQ ID NO:5 position 147 H, SEQ ID NO:5 position 149 S, SEQ ID NO:5 position 150 S, SEQ ID NO:5 position 151 S, SEQ ID NO:5 position 152 S, SEQ ID NO:5 position 153 S, SEQ ID NO:5 position 154 S, SEQ ID NO:5 position 155 S, SEQ ID NO:5 position 156 S, SEQ ID NO:5 position 157 S, SEQ ID NO:5 position 158 S, SEQ ID NO:5 position 159 S, SEQ ID NO:5 position 160 L at a position corresponding to position 139 of SEQ ID NO: 5, A at a position corresponding to position 142 of SEQ ID NO: 5, A at a position corresponding to position 145 of SEQ ID NO: 5, R at a position corresponding to position 153 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, D at a position corresponding to position 160 of SEQ ID NO: 5, and H at a position corresponding to position 162 of SEQ ID NO: 5; or www) S at a position corresponding to position 81 of SEQ ID NO: 5. 247. The nucleic acid molecule of embodiment 244, wherein the adenine deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5 and Q at a position corresponding to position 46 of SEQ ID NO: 5; b) S at a position corresponding to position 81 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; c) Q at a position corresponding to position 46 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; d) N at a position corresponding to position 35 of SEQ ID NO: 5, Q at a position corresponding to position 46 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; e) W at a position corresponding to position 155 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, and R at a position corresponding to position 163 of SEQ ID NO: 5. NO:5 position 162 corresponding to W; f) N at the position corresponding to SEQ ID NO:5 position 35, R at the position corresponding to SEQ ID NO:5 position 156, and W at the position corresponding to SEQ ID NO:5 position 162; g) N at the position corresponding to SEQ ID NO:5 position 35, S at the position corresponding to SEQ ID NO:5 position 81, R at the position corresponding to SEQ ID NO:5 position 156, and W at the position corresponding to SEQ ID NO:5 position 162; h) M at the position corresponding to SEQ ID NO:5 position 68, S at the position corresponding to SEQ ID NO:5 position 81, H at the position corresponding to SEQ ID NO:5 position 108, R at the position corresponding to SEQ ID NO:5 position 156, and W at the position corresponding to SEQ ID NO:5 position 162; i) Q at the position corresponding to position 46 of SEQ ID NO: 5, N at the position corresponding to position 35, M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; j) S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; k) W at the position corresponding to position 75 of SEQ ID NO: 5, and S at the position corresponding to position 81 of SEQ ID NO: 5; l) S at the position corresponding to position 81 of SEQ ID NO: 5, and R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; NO:5 position 160 corresponding to D; m) S at the position corresponding to SEQ ID NO:5 position 81, and A at the position corresponding to SEQ ID NO:5 position 145 corresponding to A; n) W at the position corresponding to SEQ ID NO:5 position 75, and W at the position corresponding to SEQ ID NO:5 position 155 corresponding to W; o) W at the position corresponding to SEQ ID NO:5 position 75, and A at the position corresponding to SEQ ID NO:5 position 145 corresponding to A; p) A at the position corresponding to SEQ ID NO:5 position 145, and D at the position corresponding to SEQ ID NO:5 position 160 corresponding to A; q) W at the position corresponding to SEQ ID NO:5 position 75, S at the position corresponding to SEQ ID NO:5 position 81, and W at the position corresponding to SEQ ID NO:5 position 155 corresponding to A; r) W at the position corresponding to SEQ ID NO:5 position 75, S at the position corresponding to SEQ ID NO:5 position 81, and W at the position corresponding to SEQ ID NO:5 position 155 corresponding to A; NO:5 position 81 S, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; s) SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 145 A, and SEQ ID NO:5 position 155 W; t) SEQ ID NO:5 position 40 L, and SEQ ID NO:5 position 105 M; u) SEQ ID NO:5 position 40 L, and SEQ ID NO:5 position 145 M; v) SEQ ID NO:5 position 40 L, and SEQ ID NO:5 position 159 Q; w) SEQ ID NO:5 position 40 A, and SEQ ID NO:5 position 159 B; NO:5 position 40 corresponding to L, and SEQ ID NO:5 position 160 corresponding to W; x) SEQ ID NO:5 position 105 corresponding to M, and SEQ ID NO:5 position 145 corresponding to M; y) SEQ ID NO:5 position 105 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; z) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 159 corresponding to Q; aa) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; bb) SEQ ID NO:5 position 159 corresponding to Q, and SEQ ID NO:5 position 160 corresponding to W; cc) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; NO:5 position 81 S, SEQ ID NO:5 position 145 M, and SEQ ID NO:5 position 160 W; dd) SEQ ID NO:5 position 68 A, and SEQ ID NO:5 position 81 S; ee) SEQ ID NO:5 position 76 G, and SEQ ID NO:5 position 81 S; ff) SEQ ID NO:5 position 81 S, and SEQ ID NO:5 position 117 L; gg) SEQ ID NO:5 position 68 A, and SEQ ID NO:5 position 76 G; hh) SEQ ID NO:5 position 68 A, and SEQ ID NO:5 position 81 S; ff) SEQ ID NO:5 position 81 S, and SEQ ID NO:5 position 117 L; gg) SEQ ID NO:5 position 68 A, and SEQ ID NO:5 position 76 G; hh) SEQ ID NO:5 position 68 A, and SEQ ID NO:5 position 81 S; NO:5 position 117 corresponding to L; ii) G at the position corresponding to SEQ ID NO:5 position 76, and L at the position corresponding to SEQ ID NO:5 position 117; jj) A at the position corresponding to SEQ ID NO:5 position 68, G at the position corresponding to SEQ ID NO:5 position 76, and S at the position corresponding to SEQ ID NO:5 position 81; kk) A at the position corresponding to SEQ ID NO:5 position 68, S at the position corresponding to SEQ ID NO:5 position 81, and L at the position corresponding to SEQ ID NO:5 position 117; ll) G at the position corresponding to SEQ ID NO:5 position 76, S at the position corresponding to SEQ ID NO:5 position 81, and L at the position corresponding to SEQ ID NO:5 position 117; mm) A at the position corresponding to SEQ ID NO:5 position 68, S at the position corresponding to SEQ ID NO:5 position 81, and L at the position corresponding to SEQ ID NO:5 position 117; A at the position corresponding to position 68 of SEQ ID NO: 5, G at the position corresponding to position 76 of SEQ ID NO: 5, and L at the position corresponding to position 117 of SEQ ID NO: 5; nn) A at the position corresponding to position 68 of SEQ ID NO: 5, G at the position corresponding to position 76 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and L at the position corresponding to position 117 of SEQ ID NO: 5; oo) A at the position corresponding to position 68 of SEQ ID NO: 5, and S at the position corresponding to position 81 of SEQ ID NO: 5; pp) S at the position corresponding to position 81 of SEQ ID NO: 5, L at the position corresponding to position 109 of SEQ ID NO: 5, E at the position corresponding to position 153 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and L at the position corresponding to position 117 of SEQ ID NO: 5. NO:5 position corresponding to position 160; qq) A at a position corresponding to position 75 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, L at a position corresponding to position 117 of SEQ ID NO:5, A at a position corresponding to position 121 of SEQ ID NO:5, A at a position corresponding to position 145 of SEQ ID NO:5, W at a position corresponding to position 155 of SEQ ID NO:5, and D at a position corresponding to position 160 of SEQ ID NO:5; rr) Q at a position corresponding to position 75 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, I at a position corresponding to position 117 of SEQ ID NO:5, Q at a position corresponding to position 145 of SEQ ID NO:5, W at a position corresponding to position 155 of SEQ ID NO:5, and D at a position corresponding to position 160 of SEQ ID NO:5; NO:5 position 160 D; ss) Y at a position corresponding to SEQ ID NO:5 position 75, S at a position corresponding to SEQ ID NO:5 position 81, L at a position corresponding to SEQ ID NO:5 position 117, G at a position corresponding to SEQ ID NO:5 position 121, L at a position corresponding to SEQ ID NO:5 position 145, W at a position corresponding to SEQ ID NO:5 position 155, and D at a position corresponding to SEQ ID NO:5 position 160; tt) C at a position corresponding to SEQ ID NO:5 position 22, A at a position corresponding to SEQ ID NO:5 position 68, Y at a position corresponding to SEQ ID NO:5 position 75, G at a position corresponding to SEQ ID NO:5 position 76, S at a position corresponding to SEQ ID NO:5 position 81, and D at a position corresponding to SEQ ID NO:5 position 160; NO:5, H at a position corresponding to position 108, L at a position corresponding to position 117, H at a position corresponding to position 122, Y at a position corresponding to position 138, L at a position corresponding to position 139, A at a position corresponding to position 142, A at a position corresponding to position 145, R at a position corresponding to position 153, W at a position corresponding to position 155, R at a position corresponding to position 156, D at a position corresponding to position 160, and H at a position corresponding to position 162 of SEQ ID NO:5; uu) S at a position corresponding to position 81 of SEQ ID NO:5; or vv) at a position corresponding to position 82 of SEQ ID NO:5; W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. 248. A nucleic acid molecule according to any one of embodiments 244, 246, and 247, wherein the adenine deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5, S at a position corresponding to position 81 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; b) W at a position corresponding to position 75 of SEQ ID NO: 5, and W at a position corresponding to position 155 of SEQ ID NO: 5; c) S at a position corresponding to position 81 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; d) S at a position corresponding to position 81 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; NO:5 position 145 A, and SEQ ID NO:5 position 155 W; e) SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 145 M, and SEQ ID NO:5 position 160 W; f) SEQ ID NO:5 position 76 G, and SEQ ID NO:5 position 81 S; g) SEQ ID NO:5 position 81 S, and SEQ ID NO:5 position 117 L; h) SEQ ID NO:5 position 68 A, and SEQ ID NO:5 position 81 S; i) SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 109 L, and SEQ ID NO:5 position 117 L; NO:5 position 153 E, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; j) SEQ ID NO:5 position 75 A, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 117 L, SEQ ID NO:5 position 121 A, SEQ ID NO:5 position 145 A, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; k) SEQ ID NO:5 position 75 Q, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 117 I, SEQ ID NO:5 position 121 A, SEQ ID NO:5 position 145 A, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; NO:5 position 145 corresponding to Q, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; l) SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; m) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; m) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to 5, G at a position corresponding to position 76 of SEQ ID NO: 5, S at a position corresponding to position 81 of SEQ ID NO: 5, H at a position corresponding to position 108 of SEQ ID NO: 5, L at a position corresponding to position 117 of SEQ ID NO: 5, H at a position corresponding to position 122 of SEQ ID NO: 5, Y at a position corresponding to position 138 of SEQ ID NO: 5, L at a position corresponding to position 139 of SEQ ID NO: 5, A at a position corresponding to position 142 of SEQ ID NO: 5, A at a position corresponding to position 145 of SEQ ID NO: 5, R at a position corresponding to position 153 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, D at a position corresponding to position 160 of SEQ ID NO: 5, and H at the position corresponding to position 162 of SEQ ID NO: 5; n) S at the position corresponding to position 81 of SEQ ID NO: 5; or o) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. 249. A nucleic acid molecule of any one of embodiments 244-248, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 300-414, 596-598, and 720-723. 250. A nucleic acid molecule of any one of embodiments 244-248, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 300-414, 596-598, and 720-723. 251. A nucleic acid molecule according to any one of embodiments 244-248, wherein the deaminase has an amino acid sequence as shown in any one of SEQ ID NOs: 300-414, 596-598, and 720-723. 252. The nucleic acid molecule of any one of embodiments 244-248, wherein the fusion protein is selected from the group consisting of: a) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; b) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 52; c) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 319 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: NO:50 having an amino acid sequence with at least 90% sequence identity after the amino acid position corresponding to position 922 of SEQ ID NO:2; d) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:319 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:52; e) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:375 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; f) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:375 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; NO:375 has an amino acid sequence with at least 90% sequence identity and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; g) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:319 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; h) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:597 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; i) A fusion protein wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 319 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; j) A fusion protein wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 406 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; k) A fusion protein wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; NO: 2 after the amino acid position corresponding to position 678; l) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 596 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; m) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 406 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 52; n) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: NO:52 has an amino acid sequence with at least 90% sequence identity after the amino acid position corresponding to position 910 of SEQ ID NO:4; o) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; p) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:596 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:52; q) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; NO:596 has an amino acid sequence with at least 90% sequence identity and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; r) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; s) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:596 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; and t) A fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49. 253. The nucleic acid molecule of any one of embodiments 244-248, wherein the fusion protein is selected from the group consisting of: a) a fusion protein, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 50; b) a fusion protein, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 52; c) a fusion protein, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 319 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: NO:50 has an amino acid sequence with at least 95% sequence identity after the amino acid position corresponding to position 922 of SEQ ID NO:2; d) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:319 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:52; e) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:375 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:49; f) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:375 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:49; NO:375 has an amino acid sequence with at least 95% sequence identity and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:50; g) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:319 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:49; h) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:597 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:50; i) A fusion protein wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 319 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 50; j) A fusion protein wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 406 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 50; k) A fusion protein wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 50; NO: 2 after the amino acid position corresponding to position 678; l) a fusion protein, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 596 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 50; m) a fusion protein, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 406 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 52; n) a fusion protein, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: NO:52 has an amino acid sequence with at least 95% sequence identity after the amino acid position corresponding to position 910 of SEQ ID NO:4; o) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:50; p) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:596 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:52; q) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:50; NO:596 has an amino acid sequence with at least 95% sequence identity and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:50; r) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:49; s) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:596 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:49; and t) A fusion protein, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49. 254. A nucleic acid molecule according to any one of embodiments 244-248, wherein the fusion protein is selected from the group consisting of: a) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having an amino acid sequence as shown in SEQ ID NO: 50; b) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence as shown in SEQ ID NO: 52; c) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 319 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having an amino acid sequence as shown in SEQ ID NO: 50; d) A fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 319 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence as shown in SEQ ID NO: 52; e) A fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence as shown in SEQ ID NO: 49; f) A fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence as shown in SEQ ID NO: 50; g) A fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 319 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence as shown in SEQ ID NO: NO:49 after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having the amino acid sequence shown in SEQ ID NO:597; h) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:597 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:50; i) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:319 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:50; j) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:50; k) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence as shown in SEQ ID NO: 50; l) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 596 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence as shown in SEQ ID NO: 50; m) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 406 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence as shown in SEQ ID NO: 52; n) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence as shown in SEQ ID NO: NO:52 after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having the amino acid sequence shown in SEQ ID NO:52; o) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:50; p) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:596 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having the amino acid sequence shown in SEQ ID NO:52; q) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:596 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:50; r) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 406 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence as shown in SEQ ID NO: 49; s) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 596 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence as shown in SEQ ID NO: 49; and t) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence as shown in SEQ ID NO: 49. 255. The nucleic acid molecule of embodiment 254, wherein the fusion protein has a sequence shown in any one of SEQ ID NOs: 599, 600, 602, 603, 606, 610, 612, 614, 615, 617, 619-624, 626, and 630-632. 256. The system of embodiment 117, wherein the adenine deaminase comprises an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 5, and at least one of the following amino acid residues: a) C at a position corresponding to position 2 of SEQ ID NO: 5; b) F or C at a position corresponding to position 22 of SEQ ID NO: 5; c) Q at a position corresponding to position 23 of SEQ ID NO: 5; d) N at a position corresponding to position 35 of SEQ ID NO: 5; e) L at a position corresponding to position 40 of SEQ ID NO: 5; f) Q at a position corresponding to position 46 of SEQ ID NO: 5; g) A or M at a position corresponding to position 68 of SEQ ID NO: 5; h) H at a position corresponding to position 72 of SEQ ID NO: 5; i) W, A, Q, Y, or D at the position corresponding to position 75 of SEQ ID NO: 5; j) G at the position corresponding to position 76 of SEQ ID NO: 5; k) S at the position corresponding to position 81 of SEQ ID NO: 5; l) M at the position corresponding to position 105 of SEQ ID NO: 5; m) H at the position corresponding to position 108 of SEQ ID NO: 5; n) L at the position corresponding to position 109 of SEQ ID NO: 5; o) I or L at the position corresponding to position 117 of SEQ ID NO: 5; p) F at the position corresponding to position 120 of SEQ ID NO: 5; q) E, T, A, G, or V at the position corresponding to position 121 of SEQ ID NO: 5; r) I or H at the position corresponding to position 122 of SEQ ID NO: 5; s) K at the position corresponding to position 125 of SEQ ID NO: 5; t) A at the position corresponding to position 126 of SEQ ID NO: 5; u) H at the position corresponding to position 135 of SEQ ID NO: 5; v) V at the position corresponding to position 137 of SEQ ID NO: 5; w) Y at the position corresponding to position 138 of SEQ ID NO: 5; x) L at the position corresponding to position 139 of SEQ ID NO: 5; y) K or A at the position corresponding to position 142 of SEQ ID NO: 5; z) A, Q, L, or M at the position corresponding to position 145 of SEQ ID NO: 5; aa) K at the position corresponding to position 148 of SEQ ID NO: 5; bb) Q at the position corresponding to position 151 of SEQ ID NO: 5; cc) E or R at the position corresponding to position 153 of SEQ ID NO: 5; dd) NO:5 position corresponding to W; ee) R or V at a position corresponding to SEQ ID NO:5 position corresponding to 156; ff) F at a position corresponding to SEQ ID NO:5 position corresponding to 157; gg) R at a position corresponding to SEQ ID NO:5 position corresponding to 158; hh) Q at a position corresponding to SEQ ID NO:5 position corresponding to 159; ii) D or W at a position corresponding to SEQ ID NO:5 position corresponding to 160; jj) W, H, V, or A at a position corresponding to SEQ ID NO:5 position corresponding to 162; kk) R at a position corresponding to SEQ ID NO:5 position corresponding to 165; and ll) H at a position corresponding to SEQ ID NO:5 position corresponding to 166. 257. The system of embodiment 256, wherein the adenine deaminase comprises at least one of the following amino acid residues: a) C at a position corresponding to position 2 of SEQ ID NO: 5; b) F or C at a position corresponding to position 22 of SEQ ID NO: 5; c) Q at a position corresponding to position 23 of SEQ ID NO: 5; d) N at a position corresponding to position 35 of SEQ ID NO: 5; e) L at a position corresponding to position 40 of SEQ ID NO: 5; f) A at a position corresponding to position 68 of SEQ ID NO: 5; g) W, A, Q, or Y at a position corresponding to position 75 of SEQ ID NO: 5; h) G at a position corresponding to position 76 of SEQ ID NO: 5; i) S at a position corresponding to position 81 of SEQ ID NO: 5; j) M at a position corresponding to position 105 of SEQ ID NO: 5; k) H at the position corresponding to position 108 of SEQ ID NO: 5; l) L at the position corresponding to position 109 of SEQ ID NO: 5; m) I or L at the position corresponding to position 117 of SEQ ID NO: 5; n) A or G at the position corresponding to position 121 of SEQ ID NO: 5; o) H at the position corresponding to position 122 of SEQ ID NO: 5; p) A at the position corresponding to position 126 of SEQ ID NO: 5; q) H at the position corresponding to position 135 of SEQ ID NO: 5; r) V at the position corresponding to position 137 of SEQ ID NO: 5; s) Y at the position corresponding to position 138 of SEQ ID NO: 5; t) L at the position corresponding to position 139 of SEQ ID NO: 5; u) K or A at the position corresponding to position 142 of SEQ ID NO: 5; v) A, Q, L, or M at a position corresponding to position 145 of SEQ ID NO: 5; w) E or R at a position corresponding to position 153 of SEQ ID NO: 5; x) W at a position corresponding to position 155 of SEQ ID NO: 5; y) R at a position corresponding to position 156 of SEQ ID NO: 5; z) F at a position corresponding to position 157 of SEQ ID NO: 5; aa) R at a position corresponding to position 158 of SEQ ID NO: 5; bb) Q at a position corresponding to position 159 of SEQ ID NO: 5; cc) D or W at a position corresponding to position 160 of SEQ ID NO: 5; dd) A or W at a position corresponding to position 162 of SEQ ID NO: 5; and ee) R at a position corresponding to position 165 of SEQ ID NO: 5. 258. The system of embodiment 256, wherein the adenine deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5 and W at a position corresponding to position 162 of SEQ ID NO: 5; b) N at a position corresponding to position 35 of SEQ ID NO: 5 and Q at a position corresponding to position 46 of SEQ ID NO: 5; c) S at a position corresponding to position 81 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; d) Q at a position corresponding to position 46 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; e) R at a position corresponding to position 156 of SEQ ID NO: 5 and W at a position corresponding to position 162 of SEQ ID NO: 5; f) A at a position corresponding to position 68 of SEQ ID NO: 5 and R at a position corresponding to position 69 of SEQ ID NO: 5. NO:5 position 81 corresponding to S; g) N corresponding to position 35 of SEQ ID NO:5, S corresponding to position 81 of SEQ ID NO:5, and W corresponding to position 162 of SEQ ID NO:5; h) N corresponding to position 35 of SEQ ID NO:5, Q corresponding to position 46 of SEQ ID NO:5, and W corresponding to position 162 of SEQ ID NO:5; i) W corresponding to position 155 of SEQ ID NO:5, R corresponding to position 156 of SEQ ID NO:5, and W corresponding to position 162 of SEQ ID NO:5; j) N corresponding to position 35 of SEQ ID NO:5, R corresponding to position 156 of SEQ ID NO:5, and W corresponding to position 162 of SEQ ID NO:5; k) N at the position corresponding to position 35 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; l) M at the position corresponding to position 68 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; m) Q at the position corresponding to position 46 of SEQ ID NO: 5, M at the position corresponding to position 68 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; n) NO:5, M at the position corresponding to position 68, S at the position corresponding to position 81, H at the position corresponding to position 108, R at the position corresponding to position 156, and W at the position corresponding to position 162 of SEQ ID NO:5; o) Q at the position corresponding to position 46, N at the position corresponding to position 35, M at the position corresponding to position 68, S at the position corresponding to position 81, H at the position corresponding to position 108, W at the position corresponding to position 155, R at the position corresponding to position 156, and W at the position corresponding to position 162 of SEQ ID NO:5; p) Q at the position corresponding to position 46, N at the position corresponding to position 35, M at the position corresponding to position 68, S at the position corresponding to position 81, and H at the position corresponding to position 108 of SEQ ID NO:5, W at the position corresponding to position 155, R at the position corresponding to position 156, and W at the position corresponding to position 162 of SEQ ID NO:5; NO:5 position 81 corresponding to S, and position 155 corresponding to W; q) SEQ ID NO:5 position 75 corresponding to W, and position 81 corresponding to S; r) SEQ ID NO:5 position 81 corresponding to S, and position 160 corresponding to D; s) SEQ ID NO:5 position 81 corresponding to S, and position 145 corresponding to A; t) SEQ ID NO:5 position 75 corresponding to W, and position 155 corresponding to W; u) SEQ ID NO:5 position 155 corresponding to W, and position 160 corresponding to D; v) SEQ ID NO:5 position 81 corresponding to S, and position 145 corresponding to A; t) SEQ ID NO:5 position 75 corresponding to W, and position 155 corresponding to W; u) SEQ ID NO:5 position 155 corresponding to W, and position 160 corresponding to D; v) SEQ ID NO:5 position 81 corresponding to S, and position 145 corresponding to A; A at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; w) W at the position corresponding to position 75 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; x) W at the position corresponding to position 75 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; y) A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; z) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; aa) S at the position corresponding to position 81 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; bb) S at the position corresponding to SEQ ID NO:5 position 81 corresponding to A, and SEQ ID NO:5 position 145 corresponding to W; cc) W at the position corresponding to SEQ ID NO:5 position 75 corresponding to S, and SEQ ID NO:5 position 81 corresponding to D; dd) W at the position corresponding to SEQ ID NO:5 position 75 corresponding to S, and SEQ ID NO:5 position 81 corresponding to A, and SEQ ID NO:5 position 145 corresponding to D; ee) S at the position corresponding to SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 155 corresponding to W; NO:5 position 145 A, and SEQ ID NO:5 position 160 D; ff) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; gg) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 145 A, and SEQ ID NO:5 position 155 W; hh) SEQ ID NO:5 position 145 A, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; ii) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; NO:5 position 145 A, and SEQ ID NO:5 position 160 D; jj) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; kk) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 145 A, and SEQ ID NO:5 position 155 W; ll) SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 145 A, and SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; NO: 5 position corresponding to position 160; mm) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; nn) W at the position corresponding to position 75 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; oo) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. NO:5 position 160 corresponding to D; pp) L at the position corresponding to SEQ ID NO:5 position 40, and M at the position corresponding to SEQ ID NO:5 position 105 corresponding to M; qq) L at the position corresponding to SEQ ID NO:5 position 40, and V at the position corresponding to SEQ ID NO:5 position 121 corresponding to V; rr) L at the position corresponding to SEQ ID NO:5 position 40, and M at the position corresponding to SEQ ID NO:5 position 145 corresponding to M; ss) L at the position corresponding to SEQ ID NO:5 position 40, and Q at the position corresponding to SEQ ID NO:5 position 159 corresponding to Q; tt) L at the position corresponding to SEQ ID NO:5 position 40, and W at the position corresponding to SEQ ID NO:5 position 160 corresponding to W; uu) M at the position corresponding to SEQ ID NO:5 position 105, and V at the position corresponding to SEQ ID NO:5 position 121 corresponding to V; NO: 5 position 121 corresponding to V; vv) SEQ ID NO: 5 position 105 corresponding to M, and SEQ ID NO: 5 position 145 corresponding to M; ww) SEQ ID NO: 5 position 105 corresponding to M, and SEQ ID NO: 5 position 159 corresponding to Q; xx) SEQ ID NO: 5 position 105 corresponding to M, and SEQ ID NO: 5 position 160 corresponding to W; yy) SEQ ID NO: 5 position 121 corresponding to V, and SEQ ID NO: 5 position 145 corresponding to M; zz) SEQ ID NO: 5 position 121 corresponding to M, and SEQ ID NO: 5 position 159 corresponding to Q; aaa) SEQ ID NO: 5 position 105 corresponding to M, and SEQ ID NO: 5 position 160 corresponding to W; NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 160 corresponding to W; bbb) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 159 corresponding to Q; ccc) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; ddd) SEQ ID NO:5 position 159 corresponding to Q, and SEQ ID NO:5 position 160 corresponding to W; eee) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; fff) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to Q, and SEQ ID NO:5 position 160 corresponding to W; NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 159 corresponding to Q; ggg) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 81 corresponding to S; hhh) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; iii) SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; jjj) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 76 corresponding to G; kkk) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 117 corresponding to L; lll) SEQ ID NO:5 position 81 corresponding to S; NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; mmm) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; nnn) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ooo) SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ppp) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to S, and SEQ ID NO:5 position 81 corresponding to L; NO:5 position corresponding to position 117; qqq) A at a position corresponding to position 68 of SEQ ID NO:5, G at a position corresponding to position 76 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, and L at a position corresponding to position 117 of SEQ ID NO:5; rrr) S at a position corresponding to position 81 of SEQ ID NO:5, L at a position corresponding to position 109 of SEQ ID NO:5, E at a position corresponding to position 153 of SEQ ID NO:5, W at a position corresponding to position 155 of SEQ ID NO:5, and D at a position corresponding to position 160 of SEQ ID NO:5; sss) A at a position corresponding to position 75 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, L at a position corresponding to position 117 of SEQ ID NO:5, and D at a position corresponding to position 160 of SEQ ID NO:5. A at a position corresponding to position 121 of SEQ ID NO: 5, A at a position corresponding to position 145 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; ttt) Q at a position corresponding to position 75 of SEQ ID NO: 5, S at a position corresponding to position 81 of SEQ ID NO: 5, I at a position corresponding to position 117 of SEQ ID NO: 5, Q at a position corresponding to position 145 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; uuu) Y at a position corresponding to position 75 of SEQ ID NO: 5, S at a position corresponding to position 81 of SEQ ID NO: 5, L at a position corresponding to position 117 of SEQ ID NO: 5, NO:5 position 121 G, SEQ ID NO:5 position 145 L, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; vvv) SEQ ID NO:5 position 22 C, SEQ ID NO:5 position 68 A, SEQ ID NO:5 position 75 Y, SEQ ID NO:5 position 76 G, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 108 H, SEQ ID NO:5 position 117 L, SEQ ID NO:5 position 122 H, SEQ ID NO:5 position 138 Y, SEQ ID NO:5 position 140 S, SEQ ID NO:5 position 141 H, SEQ ID NO:5 position 143 L, SEQ ID NO:5 position 147 H, SEQ ID NO:5 position 149 S, SEQ ID NO:5 position 150 S, SEQ ID NO:5 position 151 S, SEQ ID NO:5 position 152 S, SEQ ID NO:5 position 153 S, SEQ ID NO:5 position 154 S, SEQ ID NO:5 position 155 S, SEQ ID NO:5 position 156 S, SEQ ID NO:5 position 157 S, SEQ ID NO:5 position 158 S, SEQ ID NO:5 position 159 S, SEQ ID NO:5 position 160 L at a position corresponding to position 139 of SEQ ID NO: 5, A at a position corresponding to position 142 of SEQ ID NO: 5, A at a position corresponding to position 145 of SEQ ID NO: 5, R at a position corresponding to position 153 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, D at a position corresponding to position 160 of SEQ ID NO: 5, and H at a position corresponding to position 162 of SEQ ID NO: 5; or www) S at a position corresponding to position 81 of SEQ ID NO: 5. 259. The system of embodiment 256, wherein the adenine deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5 and Q at a position corresponding to position 46 of SEQ ID NO: 5; b) S at a position corresponding to position 81 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; c) Q at a position corresponding to position 46 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; d) N at a position corresponding to position 35 of SEQ ID NO: 5, Q at a position corresponding to position 46 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; e) W at a position corresponding to position 155 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, and R at a position corresponding to position 163 of SEQ ID NO: 5. NO:5 position 162 corresponding to W; f) N at the position corresponding to SEQ ID NO:5 position 35, R at the position corresponding to SEQ ID NO:5 position 156, and W at the position corresponding to SEQ ID NO:5 position 162; g) N at the position corresponding to SEQ ID NO:5 position 35, S at the position corresponding to SEQ ID NO:5 position 81, R at the position corresponding to SEQ ID NO:5 position 156, and W at the position corresponding to SEQ ID NO:5 position 162; h) M at the position corresponding to SEQ ID NO:5 position 68, S at the position corresponding to SEQ ID NO:5 position 81, H at the position corresponding to SEQ ID NO:5 position 108, R at the position corresponding to SEQ ID NO:5 position 156, and W at the position corresponding to SEQ ID NO:5 position 162; i) Q at the position corresponding to position 46 of SEQ ID NO: 5, N at the position corresponding to position 35, M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; j) S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; k) W at the position corresponding to position 75 of SEQ ID NO: 5, and S at the position corresponding to position 81 of SEQ ID NO: 5; l) S at the position corresponding to position 81 of SEQ ID NO: 5, and R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; NO:5 position 160 corresponding to D; m) S at the position corresponding to SEQ ID NO:5 position 81, and A at the position corresponding to SEQ ID NO:5 position 145 corresponding to A; n) W at the position corresponding to SEQ ID NO:5 position 75, and W at the position corresponding to SEQ ID NO:5 position 155 corresponding to W; o) W at the position corresponding to SEQ ID NO:5 position 75, and A at the position corresponding to SEQ ID NO:5 position 145 corresponding to A; p) A at the position corresponding to SEQ ID NO:5 position 145, and D at the position corresponding to SEQ ID NO:5 position 160 corresponding to A; q) W at the position corresponding to SEQ ID NO:5 position 75, S at the position corresponding to SEQ ID NO:5 position 81, and W at the position corresponding to SEQ ID NO:5 position 155 corresponding to A; r) W at the position corresponding to SEQ ID NO:5 position 75, S at the position corresponding to SEQ ID NO:5 position 81, and W at the position corresponding to SEQ ID NO:5 position 155 corresponding to A; NO:5 position 81 S, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; s) SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 145 A, and SEQ ID NO:5 position 155 W; t) SEQ ID NO:5 position 40 L, and SEQ ID NO:5 position 105 M; u) SEQ ID NO:5 position 40 L, and SEQ ID NO:5 position 145 M; v) SEQ ID NO:5 position 40 L, and SEQ ID NO:5 position 159 Q; w) SEQ ID NO:5 position 40 A, and SEQ ID NO:5 position 159 B; NO:5 position 40 corresponding to L, and SEQ ID NO:5 position 160 corresponding to W; x) SEQ ID NO:5 position 105 corresponding to M, and SEQ ID NO:5 position 145 corresponding to M; y) SEQ ID NO:5 position 105 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; z) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 159 corresponding to Q; aa) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; bb) SEQ ID NO:5 position 159 corresponding to Q, and SEQ ID NO:5 position 160 corresponding to W; cc) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; NO:5 position 81 S, SEQ ID NO:5 position 145 M, and SEQ ID NO:5 position 160 W; dd) SEQ ID NO:5 position 68 A, and SEQ ID NO:5 position 81 S; ee) SEQ ID NO:5 position 76 G, and SEQ ID NO:5 position 81 S; ff) SEQ ID NO:5 position 81 S, and SEQ ID NO:5 position 117 L; gg) SEQ ID NO:5 position 68 A, and SEQ ID NO:5 position 76 G; hh) SEQ ID NO:5 position 68 A, and SEQ ID NO:5 position 81 S; ff) SEQ ID NO:5 position 81 S, and SEQ ID NO:5 position 117 L; gg) SEQ ID NO:5 position 68 A, and SEQ ID NO:5 position 76 G; hh) SEQ ID NO:5 position 68 A, and SEQ ID NO:5 position 81 S; NO:5 position 117 corresponding to L; ii) G at a position corresponding to position 76 of SEQ ID NO:5, and L at a position corresponding to position 117 of SEQ ID NO:5; jj) A at a position corresponding to position 68 of SEQ ID NO:5, G at a position corresponding to position 76 of SEQ ID NO:5, and S at a position corresponding to position 81 of SEQ ID NO:5; kk) A at a position corresponding to position 68 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, and L at a position corresponding to position 117 of SEQ ID NO:5; ll) G at a position corresponding to position 76 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, and L at a position corresponding to position 117 of SEQ ID NO:5; mm) A at a position corresponding to position 68 of SEQ ID NO:5, A at the position corresponding to position 68 of SEQ ID NO: 5, G at the position corresponding to position 76 of SEQ ID NO: 5, and L at the position corresponding to position 117 of SEQ ID NO: 5; nn) A at the position corresponding to position 68 of SEQ ID NO: 5, G at the position corresponding to position 76 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and L at the position corresponding to position 117 of SEQ ID NO: 5; oo) A at the position corresponding to position 68 of SEQ ID NO: 5, and S at the position corresponding to position 81 of SEQ ID NO: 5; pp) S at the position corresponding to position 81 of SEQ ID NO: 5, L at the position corresponding to position 109 of SEQ ID NO: 5, E at the position corresponding to position 153 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and L at the position corresponding to position 117 of SEQ ID NO: 5. NO:5 position corresponding to position 160; qq) A at a position corresponding to position 75 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, L at a position corresponding to position 117 of SEQ ID NO:5, A at a position corresponding to position 121 of SEQ ID NO:5, A at a position corresponding to position 145 of SEQ ID NO:5, W at a position corresponding to position 155 of SEQ ID NO:5, and D at a position corresponding to position 160 of SEQ ID NO:5; rr) Q at a position corresponding to position 75 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, I at a position corresponding to position 117 of SEQ ID NO:5, Q at a position corresponding to position 145 of SEQ ID NO:5, W at a position corresponding to position 155 of SEQ ID NO:5, and D at a position corresponding to position 160 of SEQ ID NO:5. NO:5 position 160 D; ss) Y at a position corresponding to SEQ ID NO:5 position 75, S at a position corresponding to SEQ ID NO:5 position 81, L at a position corresponding to SEQ ID NO:5 position 117, G at a position corresponding to SEQ ID NO:5 position 121, L at a position corresponding to SEQ ID NO:5 position 145, W at a position corresponding to SEQ ID NO:5 position 155, and D at a position corresponding to SEQ ID NO:5 position 160; tt) C at a position corresponding to SEQ ID NO:5 position 22, A at a position corresponding to SEQ ID NO:5 position 68, Y at a position corresponding to SEQ ID NO:5 position 75, G at a position corresponding to SEQ ID NO:5 position 76, S at a position corresponding to SEQ ID NO:5 position 81, and D at a position corresponding to SEQ ID NO:5 position 160; NO:5, H at a position corresponding to position 108, L at a position corresponding to position 117, H at a position corresponding to position 122, Y at a position corresponding to position 138, L at a position corresponding to position 139, A at a position corresponding to position 142, A at a position corresponding to position 145, R at a position corresponding to position 153, W at a position corresponding to position 155, R at a position corresponding to position 156, D at a position corresponding to position 160, and H at a position corresponding to position 162 of SEQ ID NO:5; uu) S at a position corresponding to position 81 of SEQ ID NO:5; or vv) at a position corresponding to position 82 of SEQ ID NO:5; W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. 260. The system of any one of embodiments 256, 258, and 259, wherein the adenine deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5, S at a position corresponding to position 81 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; b) W at a position corresponding to position 75 of SEQ ID NO: 5, and W at a position corresponding to position 155 of SEQ ID NO: 5; c) S at a position corresponding to position 81 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; d) S at a position corresponding to position 81 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; NO:5 position 145 A, and SEQ ID NO:5 position 155 W; e) SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 145 M, and SEQ ID NO:5 position 160 W; f) SEQ ID NO:5 position 76 G, and SEQ ID NO:5 position 81 S; g) SEQ ID NO:5 position 81 S, and SEQ ID NO:5 position 117 L; h) SEQ ID NO:5 position 68 A, and SEQ ID NO:5 position 81 S; i) SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 109 L, and SEQ ID NO:5 position 117 L; NO:5 position 153 E, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; j) SEQ ID NO:5 position 75 A, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 117 L, SEQ ID NO:5 position 121 A, SEQ ID NO:5 position 145 A, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; k) SEQ ID NO:5 position 75 Q, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 117 I, SEQ ID NO:5 position 121 A, SEQ ID NO:5 position 145 A, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; NO:5 position 145 corresponding to Q, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; l) SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; m) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; m) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to 5, G at a position corresponding to position 76 of SEQ ID NO: 5, S at a position corresponding to position 81 of SEQ ID NO: 5, H at a position corresponding to position 108 of SEQ ID NO: 5, L at a position corresponding to position 117 of SEQ ID NO: 5, H at a position corresponding to position 122 of SEQ ID NO: 5, Y at a position corresponding to position 138 of SEQ ID NO: 5, L at a position corresponding to position 139 of SEQ ID NO: 5, A at a position corresponding to position 142 of SEQ ID NO: 5, A at a position corresponding to position 145 of SEQ ID NO: 5, R at a position corresponding to position 153 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, D at a position corresponding to position 160 of SEQ ID NO: 5, and H at the position corresponding to position 162 of SEQ ID NO: 5; n) S at the position corresponding to position 81 of SEQ ID NO: 5; or o) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. 261. The system of any of embodiments 256-260, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with any of SEQ ID NOs: 300-414, 596-598, and 720-723. 262. The system of any of embodiments 256-260, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with any of SEQ ID NOs: 300-414, 596-598, and 720-723. 263. The system of any of embodiments 256-260, wherein the deaminase has an amino acid sequence as shown in any of SEQ ID NOs: 300-414, 596-598, and 720-723. 264. The system of any of embodiments 256-263, wherein the fusion protein is selected from the group consisting of: a) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 375 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; b) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 375 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 52; c) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 375 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 52; NO:319 has an amino acid sequence with at least 90% sequence identity and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; d) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:319 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:52; e) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:375 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; f) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 375 and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; g) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 319 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; h) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; NO: 2 after the amino acid position corresponding to position 922; i) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 319 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; j) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 406 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; k) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: NO:50 has an amino acid sequence with at least 90% sequence identity after the amino acid position corresponding to position 678 of SEQ ID NO:2; l) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:596 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; m) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:52; n) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:596 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; NO:597 has an amino acid sequence with at least 90% sequence identity and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:52; o) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; p) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:596 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:52; q) A fusion protein wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 596 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; r) A fusion protein wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 406 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; s) A fusion protein wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 596 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; NO: 1 after the amino acid position corresponding to position 772; and t) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49. 265. The system of any of embodiments 256-263, wherein the fusion protein is selected from the group consisting of: a) a fusion protein, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 50; b) a fusion protein, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 52; c) a fusion protein, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 319 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: NO:50 has an amino acid sequence with at least 95% sequence identity after the amino acid position corresponding to position 922 of SEQ ID NO:2; d) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:319 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:52; e) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:375 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:49; f) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:375 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:49; NO:375 has an amino acid sequence with at least 95% sequence identity and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:50; g) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:319 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:49; h) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:597 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:50; i) A fusion protein wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 319 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 50; j) A fusion protein wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 406 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 50; k) A fusion protein wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 50; NO: 2 after the amino acid position corresponding to position 678; l) a fusion protein, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 596 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 50; m) a fusion protein, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 406 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 52; n) a fusion protein, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: NO:52 has an amino acid sequence with at least 95% sequence identity after the amino acid position corresponding to position 910 of SEQ ID NO:4; o) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:50; p) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:596 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:52; q) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:50; NO:596 has an amino acid sequence with at least 95% sequence identity and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:50; r) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:49; s) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:596 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:49; and t) A fusion protein, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49. 266. The system of any of embodiments 256-263, wherein the fusion protein is selected from the group consisting of: a) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having an amino acid sequence as shown in SEQ ID NO: 50; b) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence as shown in SEQ ID NO: 52; c) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 319 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having an amino acid sequence as shown in SEQ ID NO: 50; d) A fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 319 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence as shown in SEQ ID NO: 52; e) A fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence as shown in SEQ ID NO: 49; f) A fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence as shown in SEQ ID NO: 50; g) A fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 319 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence as shown in SEQ ID NO: NO:49 after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having the amino acid sequence shown in SEQ ID NO:49; h) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:597 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:50; i) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:319 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:50; j) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:50; k) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence as shown in SEQ ID NO: 50; l) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 596 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence as shown in SEQ ID NO: 50; m) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 406 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence as shown in SEQ ID NO: 52; n) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence as shown in SEQ ID NO: NO:52 after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having the amino acid sequence shown in SEQ ID NO:52; o) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:50; p) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:596 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having the amino acid sequence shown in SEQ ID NO:52; q) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:596 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:50; r) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 406 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence as shown in SEQ ID NO: 49; s) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 596 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence as shown in SEQ ID NO: 49; and t) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence as shown in SEQ ID NO: 49. 267. The system of embodiment 266, wherein the fusion protein has a sequence shown in any one of SEQ ID NOs: 599, 600, 602, 603, 606, 610, 612, 614, 615, 617, 619-624, 626, and 630-632. 268. The method of embodiment 176, wherein the adenine deaminase comprises an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 5, and at least one of the following amino acid residues: a) C at a position corresponding to position 2 of SEQ ID NO: 5; b) F or C at a position corresponding to position 22 of SEQ ID NO: 5; c) Q at a position corresponding to position 23 of SEQ ID NO: 5; d) N at a position corresponding to position 35 of SEQ ID NO: 5; e) L at a position corresponding to position 40 of SEQ ID NO: 5; f) Q at a position corresponding to position 46 of SEQ ID NO: 5; g) A or M at a position corresponding to position 68 of SEQ ID NO: 5; h) H at a position corresponding to position 72 of SEQ ID NO: 5; i) W, A, Q, Y, or D at a position corresponding to position 75 of SEQ ID NO: 5; j) G at a position corresponding to position 76 of SEQ ID NO: 5; k) S at a position corresponding to position 81 of SEQ ID NO: 5; l) M at a position corresponding to position 105 of SEQ ID NO: 5; m) H at a position corresponding to position 108 of SEQ ID NO: 5; n) L at a position corresponding to position 109 of SEQ ID NO: 5; o) I or L at a position corresponding to position 117 of SEQ ID NO: 5; p) F at a position corresponding to position 120 of SEQ ID NO: 5; q) E, T, A, G, or V at a position corresponding to position 121 of SEQ ID NO: 5; r) I or H at a position corresponding to position 122 of SEQ ID NO: 5; s) K at a position corresponding to position 125 of SEQ ID NO: 5; t) A at a position corresponding to position 126 of SEQ ID NO: 5; u) H at the position corresponding to position 135 of SEQ ID NO: 5; v) V at the position corresponding to position 137 of SEQ ID NO: 5; w) Y at the position corresponding to position 138 of SEQ ID NO: 5; x) L at the position corresponding to position 139 of SEQ ID NO: 5; y) K or A at the position corresponding to position 142 of SEQ ID NO: 5; z) A, Q, L, or M at the position corresponding to position 145 of SEQ ID NO: 5; aa) K at the position corresponding to position 148 of SEQ ID NO: 5; bb) Q at the position corresponding to position 151 of SEQ ID NO: 5; cc) E or R at the position corresponding to position 153 of SEQ ID NO: 5; dd) W at the position corresponding to position 155 of SEQ ID NO: 5; ee) A, Q, L, or M at the position corresponding to position 145 of SEQ ID NO: 5; NO:5 at a position corresponding to position 156 of R or V; ff) at a position corresponding to position 157 of SEQ ID NO:5; gg) at a position corresponding to position 158 of SEQ ID NO:5; hh) at a position corresponding to position 159 of SEQ ID NO:5; ii) at a position corresponding to position 160 of SEQ ID NO:5; jj) at a position corresponding to position 162 of SEQ ID NO:5 of W, H, V, or A; kk) at a position corresponding to position 165 of SEQ ID NO:5; and ll) at a position corresponding to position 166 of SEQ ID NO:5 of H. 269. The method of embodiment 268, wherein the adenine deaminase comprises at least one of the following amino acid residues: a) C at a position corresponding to position 2 of SEQ ID NO: 5; b) F or C at a position corresponding to position 22 of SEQ ID NO: 5; c) Q at a position corresponding to position 23 of SEQ ID NO: 5; d) N at a position corresponding to position 35 of SEQ ID NO: 5; e) L at a position corresponding to position 40 of SEQ ID NO: 5; f) A at a position corresponding to position 68 of SEQ ID NO: 5; g) W, A, Q, or Y at a position corresponding to position 75 of SEQ ID NO: 5; h) G at a position corresponding to position 76 of SEQ ID NO: 5; i) S at a position corresponding to position 81 of SEQ ID NO: 5; j) M at a position corresponding to position 105 of SEQ ID NO: 5; k) H at the position corresponding to position 108 of SEQ ID NO: 5; l) L at the position corresponding to position 109 of SEQ ID NO: 5; m) I or L at the position corresponding to position 117 of SEQ ID NO: 5; n) A or G at the position corresponding to position 121 of SEQ ID NO: 5; o) H at the position corresponding to position 122 of SEQ ID NO: 5; p) A at the position corresponding to position 126 of SEQ ID NO: 5; q) H at the position corresponding to position 135 of SEQ ID NO: 5; r) V at the position corresponding to position 137 of SEQ ID NO: 5; s) Y at the position corresponding to position 138 of SEQ ID NO: 5; t) L at the position corresponding to position 139 of SEQ ID NO: 5; u) K or A at the position corresponding to position 142 of SEQ ID NO: 5; v) A, Q, L, or M at a position corresponding to position 145 of SEQ ID NO: 5; w) E or R at a position corresponding to position 153 of SEQ ID NO: 5; x) W at a position corresponding to position 155 of SEQ ID NO: 5; y) R at a position corresponding to position 156 of SEQ ID NO: 5; z) F at a position corresponding to position 157 of SEQ ID NO: 5; aa) R at a position corresponding to position 158 of SEQ ID NO: 5; bb) Q at a position corresponding to position 159 of SEQ ID NO: 5; cc) D or W at a position corresponding to position 160 of SEQ ID NO: 5; dd) A or W at a position corresponding to position 162 of SEQ ID NO: 5; and ee) R at a position corresponding to position 165 of SEQ ID NO: 5. 270. The method of embodiment 268, wherein the adenine deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5 and W at a position corresponding to position 162 of SEQ ID NO: 5; b) N at a position corresponding to position 35 of SEQ ID NO: 5 and Q at a position corresponding to position 46 of SEQ ID NO: 5; c) S at a position corresponding to position 81 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; d) Q at a position corresponding to position 46 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; e) R at a position corresponding to position 156 of SEQ ID NO: 5 and W at a position corresponding to position 162 of SEQ ID NO: 5; f) A at a position corresponding to position 68 of SEQ ID NO: 5 and R at a position corresponding to position 69 of SEQ ID NO: 5. NO:5 position 81 corresponding to S; g) N corresponding to position 35 of SEQ ID NO:5, S corresponding to position 81 of SEQ ID NO:5, and W corresponding to position 162 of SEQ ID NO:5; h) N corresponding to position 35 of SEQ ID NO:5, Q corresponding to position 46 of SEQ ID NO:5, and W corresponding to position 162 of SEQ ID NO:5; i) W corresponding to position 155 of SEQ ID NO:5, R corresponding to position 156 of SEQ ID NO:5, and W corresponding to position 162 of SEQ ID NO:5; j) N corresponding to position 35 of SEQ ID NO:5, R corresponding to position 156 of SEQ ID NO:5, and W corresponding to position 162 of SEQ ID NO:5; k) N at the position corresponding to position 35 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; l) M at the position corresponding to position 68 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; m) Q at the position corresponding to position 46 of SEQ ID NO: 5, M at the position corresponding to position 68 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; n) NO:5, M at the position corresponding to position 68, S at the position corresponding to position 81, H at the position corresponding to position 108, R at the position corresponding to position 156, and W at the position corresponding to position 162 of SEQ ID NO:5; o) Q at the position corresponding to position 46, N at the position corresponding to position 35, M at the position corresponding to position 68, S at the position corresponding to position 81, H at the position corresponding to position 108, W at the position corresponding to position 155, R at the position corresponding to position 156, and W at the position corresponding to position 162 of SEQ ID NO:5; p) Q at the position corresponding to position 46, N at the position corresponding to position 35, M at the position corresponding to position 68, S at the position corresponding to position 81, and H at the position corresponding to position 108 of SEQ ID NO:5, W at the position corresponding to position 155, R at the position corresponding to position 156, and W at the position corresponding to position 162 of SEQ ID NO:5; NO:5 position 81 corresponding to S, and position 155 corresponding to W; q) SEQ ID NO:5 position 75 corresponding to W, and position 81 corresponding to S; r) SEQ ID NO:5 position 81 corresponding to S, and position 160 corresponding to D; s) SEQ ID NO:5 position 81 corresponding to S, and position 145 corresponding to A; t) SEQ ID NO:5 position 75 corresponding to W, and position 155 corresponding to W; u) SEQ ID NO:5 position 155 corresponding to W, and position 160 corresponding to D; v) SEQ ID NO:5 position 81 corresponding to S, and position 145 corresponding to A; t) SEQ ID NO:5 position 75 corresponding to W, and position 155 corresponding to W; u) SEQ ID NO:5 position 155 corresponding to W, and position 160 corresponding to D; v) SEQ ID NO:5 position 81 corresponding to S, and position 145 corresponding to A; A at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; w) W at the position corresponding to position 75 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; x) W at the position corresponding to position 75 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; y) A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; z) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; aa) S at the position corresponding to position 81 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; bb) S at the position corresponding to SEQ ID NO:5 position 81 corresponding to A, and SEQ ID NO:5 position 145 corresponding to W; cc) W at the position corresponding to SEQ ID NO:5 position 75 corresponding to S, and SEQ ID NO:5 position 81 corresponding to D; dd) W at the position corresponding to SEQ ID NO:5 position 75 corresponding to S, and SEQ ID NO:5 position 81 corresponding to A, and SEQ ID NO:5 position 145 corresponding to D; ee) S at the position corresponding to SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 155 corresponding to W; NO:5 position 145 A, and a position corresponding to position 160 of SEQ ID NO:5; ff) a W at a position corresponding to position 75 of SEQ ID NO:5, a W at a position corresponding to position 155 of SEQ ID NO:5, and a D at a position corresponding to position 160 of SEQ ID NO:5; gg) a W at a position corresponding to position 75 of SEQ ID NO:5, an A at a position corresponding to position 145 of SEQ ID NO:5, and a W at a position corresponding to position 155 of SEQ ID NO:5; hh) an A at a position corresponding to position 145 of SEQ ID NO:5, a W at a position corresponding to position 155 of SEQ ID NO:5, and a D at a position corresponding to position 160 of SEQ ID NO:5; ii) a W at a position corresponding to position 75 of SEQ ID NO:5, a W at a position corresponding to position 155 of SEQ ID NO:5, and a D at a position corresponding to position 160 of SEQ ID NO:5 NO:5 position 145 A, and SEQ ID NO:5 position 160 D; jj) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; kk) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 145 A, and SEQ ID NO:5 position 155 W; ll) SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 145 A, and SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; NO:5 position corresponding to position 160; mm) W at the position corresponding to position 75 of SEQ ID NO:5, S at the position corresponding to position 81 of SEQ ID NO:5, A at the position corresponding to position 145 of SEQ ID NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5; nn) W at the position corresponding to position 75 of SEQ ID NO:5, A at the position corresponding to position 145 of SEQ ID NO:5, W at the position corresponding to position 155 of SEQ ID NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5; oo) W at the position corresponding to position 75 of SEQ ID NO:5, S at the position corresponding to position 81 of SEQ ID NO:5, A at the position corresponding to position 145 of SEQ ID NO:5, W at the position corresponding to position 155 of SEQ ID NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5. NO:5 position 160 corresponding to D; pp) L at the position corresponding to SEQ ID NO:5 position 40, and M at the position corresponding to SEQ ID NO:5 position 105 corresponding to M; qq) L at the position corresponding to SEQ ID NO:5 position 40, and V at the position corresponding to SEQ ID NO:5 position 121 corresponding to V; rr) L at the position corresponding to SEQ ID NO:5 position 40, and M at the position corresponding to SEQ ID NO:5 position 145 corresponding to M; ss) L at the position corresponding to SEQ ID NO:5 position 40, and Q at the position corresponding to SEQ ID NO:5 position 159 corresponding to Q; tt) L at the position corresponding to SEQ ID NO:5 position 40, and W at the position corresponding to SEQ ID NO:5 position 160 corresponding to W; uu) M at the position corresponding to SEQ ID NO:5 position 105, and V at the position corresponding to SEQ ID NO:5 position 121 corresponding to V; NO: 5 position 121 corresponding to V; vv) SEQ ID NO: 5 position 105 corresponding to M, and SEQ ID NO: 5 position 145 corresponding to M; ww) SEQ ID NO: 5 position 105 corresponding to M, and SEQ ID NO: 5 position 159 corresponding to Q; xx) SEQ ID NO: 5 position 105 corresponding to M, and SEQ ID NO: 5 position 160 corresponding to W; yy) SEQ ID NO: 5 position 121 corresponding to V, and SEQ ID NO: 5 position 145 corresponding to M; zz) SEQ ID NO: 5 position 121 corresponding to M, and SEQ ID NO: 5 position 159 corresponding to Q; aaa) SEQ ID NO: 5 position 105 corresponding to M, and SEQ ID NO: 5 position 160 corresponding to W; NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 160 corresponding to W; bbb) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 159 corresponding to Q; ccc) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; ddd) SEQ ID NO:5 position 159 corresponding to Q, and SEQ ID NO:5 position 160 corresponding to W; eee) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; fff) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to Q, and SEQ ID NO:5 position 160 corresponding to W; NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 159 corresponding to Q; ggg) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 81 corresponding to S; hhh) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; iii) SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; jjj) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 76 corresponding to G; kkk) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 117 corresponding to L; lll) SEQ ID NO:5 position 81 corresponding to S; NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; mmm) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; nnn) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ooo) SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ppp) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to S, and SEQ ID NO:5 position 81 corresponding to L; NO:5 position corresponding to position 117; qqq) A at a position corresponding to position 68 of SEQ ID NO:5, G at a position corresponding to position 76 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, and L at a position corresponding to position 117 of SEQ ID NO:5; rrr) S at a position corresponding to position 81 of SEQ ID NO:5, L at a position corresponding to position 109 of SEQ ID NO:5, E at a position corresponding to position 153 of SEQ ID NO:5, W at a position corresponding to position 155 of SEQ ID NO:5, and D at a position corresponding to position 160 of SEQ ID NO:5; sss) A at a position corresponding to position 75 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, L at a position corresponding to position 117 of SEQ ID NO:5, and D at a position corresponding to position 160 of SEQ ID NO:5. A at a position corresponding to position 121 of SEQ ID NO: 5, A at a position corresponding to position 145 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; ttt) Q at a position corresponding to position 75 of SEQ ID NO: 5, S at a position corresponding to position 81 of SEQ ID NO: 5, I at a position corresponding to position 117 of SEQ ID NO: 5, Q at a position corresponding to position 145 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; uuu) Y at a position corresponding to position 75 of SEQ ID NO: 5, S at a position corresponding to position 81 of SEQ ID NO: 5, L at a position corresponding to position 117 of SEQ ID NO: 5, NO:5 position 121 G, SEQ ID NO:5 position 145 L, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; vvv) SEQ ID NO:5 position 22 C, SEQ ID NO:5 position 68 A, SEQ ID NO:5 position 75 Y, SEQ ID NO:5 position 76 G, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 108 H, SEQ ID NO:5 position 117 L, SEQ ID NO:5 position 122 H, SEQ ID NO:5 position 138 Y, SEQ ID NO:5 position 140 S, SEQ ID NO:5 position 141 H, SEQ ID NO:5 position 143 L, SEQ ID NO:5 position 147 H, SEQ ID NO:5 position 149 S, SEQ ID NO:5 position 150 S, SEQ ID NO:5 position 151 S, SEQ ID NO:5 position 152 S, SEQ ID NO:5 position 153 S, SEQ ID NO:5 position 154 S, SEQ ID NO:5 position 155 S, SEQ ID NO:5 position 156 S, SEQ ID NO:5 position 157 S, SEQ ID NO:5 position 158 S, SEQ ID NO:5 position 159 S, SEQ ID NO:5 position 160 L at a position corresponding to position 139 of SEQ ID NO: 5, A at a position corresponding to position 142 of SEQ ID NO: 5, A at a position corresponding to position 145 of SEQ ID NO: 5, R at a position corresponding to position 153 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, D at a position corresponding to position 160 of SEQ ID NO: 5, and H at a position corresponding to position 162 of SEQ ID NO: 5; or www) S at a position corresponding to position 81 of SEQ ID NO: 5. 271. The method of embodiment 268, wherein the adenine deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5 and Q at a position corresponding to position 46 of SEQ ID NO: 5; b) S at a position corresponding to position 81 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; c) Q at a position corresponding to position 46 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; d) N at a position corresponding to position 35 of SEQ ID NO: 5, Q at a position corresponding to position 46 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; e) W at a position corresponding to position 155 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, and R at a position corresponding to position 163 of SEQ ID NO: 5. NO:5 position 162 corresponding to W; f) N at the position corresponding to SEQ ID NO:5 position 35, R at the position corresponding to SEQ ID NO:5 position 156, and W at the position corresponding to SEQ ID NO:5 position 162; g) N at the position corresponding to SEQ ID NO:5 position 35, S at the position corresponding to SEQ ID NO:5 position 81, R at the position corresponding to SEQ ID NO:5 position 156, and W at the position corresponding to SEQ ID NO:5 position 162; h) M at the position corresponding to SEQ ID NO:5 position 68, S at the position corresponding to SEQ ID NO:5 position 81, H at the position corresponding to SEQ ID NO:5 position 108, R at the position corresponding to SEQ ID NO:5 position 156, and W at the position corresponding to SEQ ID NO:5 position 162; i) Q at the position corresponding to position 46 of SEQ ID NO: 5, N at the position corresponding to position 35, M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; j) S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; k) W at the position corresponding to position 75 of SEQ ID NO: 5, and S at the position corresponding to position 81 of SEQ ID NO: 5; l) S at the position corresponding to position 81 of SEQ ID NO: 5, and R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; NO:5 position 160 corresponding to D; m) S at the position corresponding to SEQ ID NO:5 position 81, and A at the position corresponding to SEQ ID NO:5 position 145 corresponding to A; n) W at the position corresponding to SEQ ID NO:5 position 75, and W at the position corresponding to SEQ ID NO:5 position 155 corresponding to W; o) W at the position corresponding to SEQ ID NO:5 position 75, and A at the position corresponding to SEQ ID NO:5 position 145 corresponding to A; p) A at the position corresponding to SEQ ID NO:5 position 145, and D at the position corresponding to SEQ ID NO:5 position 160 corresponding to A; q) W at the position corresponding to SEQ ID NO:5 position 75, S at the position corresponding to SEQ ID NO:5 position 81, and W at the position corresponding to SEQ ID NO:5 position 155 corresponding to A; r) W at the position corresponding to SEQ ID NO:5 position 75, S at the position corresponding to SEQ ID NO:5 position 81, and W at the position corresponding to SEQ ID NO:5 position 155 corresponding to A; NO:5 position 81 S, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; s) SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 145 A, and SEQ ID NO:5 position 155 W; t) SEQ ID NO:5 position 40 L, and SEQ ID NO:5 position 105 M; u) SEQ ID NO:5 position 40 L, and SEQ ID NO:5 position 145 M; v) SEQ ID NO:5 position 40 L, and SEQ ID NO:5 position 159 Q; w) SEQ ID NO:5 position 40 A, and SEQ ID NO:5 position 159 B; NO:5 position 40 corresponding to L, and SEQ ID NO:5 position 160 corresponding to W; x) SEQ ID NO:5 position 105 corresponding to M, and SEQ ID NO:5 position 145 corresponding to M; y) SEQ ID NO:5 position 105 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; z) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 159 corresponding to Q; aa) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; bb) SEQ ID NO:5 position 159 corresponding to Q, and SEQ ID NO:5 position 160 corresponding to W; cc) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; NO:5 position 81 S, SEQ ID NO:5 position 145 M, and SEQ ID NO:5 position 160 W; dd) SEQ ID NO:5 position 68 A, and SEQ ID NO:5 position 81 S; ee) SEQ ID NO:5 position 76 G, and SEQ ID NO:5 position 81 S; ff) SEQ ID NO:5 position 81 S, and SEQ ID NO:5 position 117 L; gg) SEQ ID NO:5 position 68 A, and SEQ ID NO:5 position 76 G; hh) SEQ ID NO:5 position 68 A, and SEQ ID NO:5 position 81 S; ff) SEQ ID NO:5 position 81 S, and SEQ ID NO:5 position 117 L; gg) SEQ ID NO:5 position 68 A, and SEQ ID NO:5 position 76 G; hh) SEQ ID NO:5 position 68 A, and SEQ ID NO:5 position 81 S; NO:5 position 117 corresponding to L; ii) G at the position corresponding to SEQ ID NO:5 position 76, and L at the position corresponding to SEQ ID NO:5 position 117; jj) A at the position corresponding to SEQ ID NO:5 position 68, G at the position corresponding to SEQ ID NO:5 position 76, and S at the position corresponding to SEQ ID NO:5 position 81; kk) A at the position corresponding to SEQ ID NO:5 position 68, S at the position corresponding to SEQ ID NO:5 position 81, and L at the position corresponding to SEQ ID NO:5 position 117; ll) G at the position corresponding to SEQ ID NO:5 position 76, S at the position corresponding to SEQ ID NO:5 position 81, and L at the position corresponding to SEQ ID NO:5 position 117; mm) A at the position corresponding to SEQ ID NO:5 position 68, S at the position corresponding to SEQ ID NO:5 position 81, and L at the position corresponding to SEQ ID NO:5 position 117; A at the position corresponding to position 68 of SEQ ID NO: 5, G at the position corresponding to position 76 of SEQ ID NO: 5, and L at the position corresponding to position 117 of SEQ ID NO: 5; nn) A at the position corresponding to position 68 of SEQ ID NO: 5, G at the position corresponding to position 76 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and L at the position corresponding to position 117 of SEQ ID NO: 5; oo) A at the position corresponding to position 68 of SEQ ID NO: 5, and S at the position corresponding to position 81 of SEQ ID NO: 5; pp) S at the position corresponding to position 81 of SEQ ID NO: 5, L at the position corresponding to position 109 of SEQ ID NO: 5, E at the position corresponding to position 153 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and L at the position corresponding to position 117 of SEQ ID NO: 5. NO:5 position corresponding to position 160; qq) A at a position corresponding to position 75 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, L at a position corresponding to position 117 of SEQ ID NO:5, A at a position corresponding to position 121 of SEQ ID NO:5, A at a position corresponding to position 145 of SEQ ID NO:5, W at a position corresponding to position 155 of SEQ ID NO:5, and D at a position corresponding to position 160 of SEQ ID NO:5; rr) Q at a position corresponding to position 75 of SEQ ID NO:5, S at a position corresponding to position 81 of SEQ ID NO:5, I at a position corresponding to position 117 of SEQ ID NO:5, Q at a position corresponding to position 145 of SEQ ID NO:5, W at a position corresponding to position 155 of SEQ ID NO:5, and D at a position corresponding to position 160 of SEQ ID NO:5; NO:5 position 160 D; ss) Y at a position corresponding to SEQ ID NO:5 position 75, S at a position corresponding to SEQ ID NO:5 position 81, L at a position corresponding to SEQ ID NO:5 position 117, G at a position corresponding to SEQ ID NO:5 position 121, L at a position corresponding to SEQ ID NO:5 position 145, W at a position corresponding to SEQ ID NO:5 position 155, and D at a position corresponding to SEQ ID NO:5 position 160; tt) C at a position corresponding to SEQ ID NO:5 position 22, A at a position corresponding to SEQ ID NO:5 position 68, Y at a position corresponding to SEQ ID NO:5 position 75, G at a position corresponding to SEQ ID NO:5 position 76, S at a position corresponding to SEQ ID NO:5 position 81, and D at a position corresponding to SEQ ID NO:5 position 160; NO:5, H at a position corresponding to position 108, L at a position corresponding to position 117, H at a position corresponding to position 122, Y at a position corresponding to position 138, L at a position corresponding to position 139, A at a position corresponding to position 142, A at a position corresponding to position 145, R at a position corresponding to position 153, W at a position corresponding to position 155, R at a position corresponding to position 156, D at a position corresponding to position 160, and H at a position corresponding to position 162 of SEQ ID NO:5; uu) S at a position corresponding to position 81 of SEQ ID NO:5; or vv) at a position corresponding to position 82 of SEQ ID NO:5; W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. 272. The method of any one of embodiments 268, 270, and 272, wherein the adenine deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5, S at a position corresponding to position 81 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; b) W at a position corresponding to position 75 of SEQ ID NO: 5, and W at a position corresponding to position 155 of SEQ ID NO: 5; c) S at a position corresponding to position 81 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; d) S at a position corresponding to position 81 of SEQ ID NO: 5, A at a position corresponding to position 145 of SEQ ID NO: 5, and D at a position corresponding to position 162 of SEQ ID NO: 5; 155 of SEQ ID NO: 5; e) S at a position corresponding to position 81 of SEQ ID NO: 5, M at a position corresponding to position 145 of SEQ ID NO: 5, and W at a position corresponding to position 160 of SEQ ID NO: 5; f) G at a position corresponding to position 76 of SEQ ID NO: 5, and S at a position corresponding to position 81 of SEQ ID NO: 5; g) S at a position corresponding to position 81 of SEQ ID NO: 5, and L at a position corresponding to position 117 of SEQ ID NO: 5; h) A at a position corresponding to position 68 of SEQ ID NO: 5, and S at a position corresponding to position 81 of SEQ ID NO: 5; i) S at a position corresponding to position 81 of SEQ ID NO: 5, L at a position corresponding to position 109 of SEQ ID NO: 5, E at a position corresponding to position 153 of SEQ ID NO: 5, and L at a position corresponding to position 117 of SEQ ID NO: 5; NO: 5, W at the position corresponding to position 155, and D at the position corresponding to position 160 of SEQ ID NO: 5; j) A at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, L at the position corresponding to position 117 of SEQ ID NO: 5, A at the position corresponding to position 121 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; k) Q at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, I at the position corresponding to position 117 of SEQ ID NO: 5, Q at the position corresponding to position 145 of SEQ ID NO: 5, NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; l) SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; m) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 121 corresponding to L, SEQ ID NO:5 position 145 corresponding to W, and SEQ ID NO:5 position 155 corresponding to D; m) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 121 corresponding to L, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; S at the position corresponding to position 81 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, L at the position corresponding to position 117 of SEQ ID NO: 5, H at the position corresponding to position 122 of SEQ ID NO: 5, Y at the position corresponding to position 138 of SEQ ID NO: 5, L at the position corresponding to position 139 of SEQ ID NO: 5, A at the position corresponding to position 142 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, R at the position corresponding to position 153 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, D at the position corresponding to position 160 of SEQ ID NO: 5, and H at the position corresponding to position 162 of SEQ ID NO: 5; n) at the position corresponding to position 160 of SEQ ID NO: 5, and H at the position corresponding to position 162 of SEQ ID NO: 5; S at the position corresponding to position 81 of SEQ ID NO: 5; or o) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. 273. The method of any of embodiments 268-272, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with any of SEQ ID NOs: 300-414, 596-598, and 720-723. 274. The method of any of embodiments 268-272, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with any of SEQ ID NOs: 300-414, 596-598, and 720-723. 275. The method of any one of embodiments 268-272, wherein the deaminase has an amino acid sequence as shown in any one of SEQ ID NOs: 300-414, 596-598, and 720-723. 276. The method of any of embodiments 268-272, wherein the fusion protein is selected from the group consisting of: a) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; b) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 52; c) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 319 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: NO:50 having an amino acid sequence with at least 90% sequence identity after the amino acid position corresponding to position 922 of SEQ ID NO:2; d) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:319 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:52; e) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:375 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; f) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:375 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; NO:375 has an amino acid sequence with at least 90% sequence identity and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; g) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:319 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; h) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:597 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; i) A fusion protein wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 319 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; j) A fusion protein wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 406 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; k) A fusion protein wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; NO: 2 after the amino acid position corresponding to position 678; l) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 596 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; m) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 406 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 52; n) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: NO:52 has an amino acid sequence with at least 90% sequence identity after the amino acid position corresponding to position 910 of SEQ ID NO:4; o) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; p) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:596 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:52; q) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; NO:596 has an amino acid sequence with at least 90% sequence identity and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; r) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; s) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:596 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; and t) A fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49. 277. The method of any of embodiments 268-272, wherein the fusion protein is selected from the group consisting of: a) a fusion protein, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 50; b) a fusion protein, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 52; c) a fusion protein, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 319 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: NO:50 has an amino acid sequence with at least 95% sequence identity after the amino acid position corresponding to position 922 of SEQ ID NO:2; d) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:319 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:52; e) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:375 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:49; f) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:375 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:49; NO:375 has an amino acid sequence with at least 95% sequence identity and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:50; g) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:319 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:49; h) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:597 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:50; i) A fusion protein wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 319 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 50; j) A fusion protein wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 406 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 50; k) A fusion protein wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 50; NO: 2 after the amino acid position corresponding to position 678; l) a fusion protein, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 596 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 50; m) a fusion protein, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 4069 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 52; n) a fusion protein, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: NO:52 has an amino acid sequence with at least 95% sequence identity after the amino acid position corresponding to position 910 of SEQ ID NO:4; o) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:50; p) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:596 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:52; q) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:50; NO:596 has an amino acid sequence with at least 95% sequence identity and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:50; r) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:49; s) a fusion protein, wherein the deaminase has an amino acid sequence with at least 95% sequence identity to SEQ ID NO:596 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 95% sequence identity to SEQ ID NO:49; and t) A fusion protein, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49. 278. The method of any one of embodiments 268-272, wherein the fusion protein is selected from the group consisting of: a) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having an amino acid sequence as shown in SEQ ID NO: 50; b) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence as shown in SEQ ID NO: 52; c) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 319 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having an amino acid sequence as shown in SEQ ID NO: 50; d) A fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 319 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence as shown in SEQ ID NO: 52; e) A fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence as shown in SEQ ID NO: 49; f) A fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 375 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence as shown in SEQ ID NO: 50; g) A fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 319 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence as shown in SEQ ID NO: NO:49 after the amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having the amino acid sequence shown in SEQ ID NO:597; h) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:597 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:50; i) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:319 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:50; j) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:50; k) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having the amino acid sequence as shown in SEQ ID NO: 50; l) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 596 and is inserted after the amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having the amino acid sequence as shown in SEQ ID NO: 50; m) a fusion protein, wherein the deaminase has an amino acid sequence as shown in SEQ ID NO: 406 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having the amino acid sequence as shown in SEQ ID NO: 52; n) a deaminase has an amino acid sequence as shown in SEQ ID NO: 597 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having the amino acid sequence as shown in SEQ ID NO: NO:52 after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having the amino acid sequence shown in SEQ ID NO:52; o) a deaminase having the amino acid sequence shown in SEQ ID NO:406 and inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:50; p) a deaminase having the amino acid sequence shown in SEQ ID NO:596 and inserted after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having the amino acid sequence shown in SEQ ID NO:52; q) a deaminase having the amino acid sequence shown in SEQ ID NO:596 and inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:50; r) a deaminase having the amino acid sequence shown in SEQ ID NO:596 and inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:50; NO:406, and inserted into a fusion protein after the amino acid position corresponding to position 772 of SEQ ID NO:1 in a RGN having an amino acid sequence as shown in SEQ ID NO:49; s) a deaminase having an amino acid sequence as shown in SEQ ID NO:596, and inserted into a fusion protein after the amino acid position corresponding to position 772 of SEQ ID NO:1 in a RGN having an amino acid sequence as shown in SEQ ID NO:49; and t) a deaminase having an amino acid sequence as shown in SEQ ID NO:597, and inserted into a fusion protein after the amino acid position corresponding to position 772 of SEQ ID NO:1 in a RGN having an amino acid sequence as shown in SEQ ID NO:49. 279. The method of embodiment 268, wherein the fusion protein has a sequence as shown in any one of SEQ ID NOs: 599, 600, 602, 603, 606, 610, 612, 614, 615, 617, 619-624, 626 and 630-632.

and 1. A deaminase comprising an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 5, and at least one of the following amino acid residues: a) C at a position corresponding to position 2 of SEQ ID NO: 5; b) F or C at a position corresponding to position 22 of SEQ ID NO: 5; c) Q at a position corresponding to position 23 of SEQ ID NO: 5; d) N at a position corresponding to position 35 of SEQ ID NO: 5; e) L at a position corresponding to position 40 of SEQ ID NO: 5; f) Q at a position corresponding to position 46 of SEQ ID NO: 5; g) A or M at a position corresponding to position 68 of SEQ ID NO: 5; h) H at a position corresponding to position 72 of SEQ ID NO: 5; i) W, A, Q, Y, or D at a position corresponding to position 75 of SEQ ID NO: 5; j) NO:5 position 76 corresponding to G; k) SEQ ID NO:5 position 81 corresponding to S; l) SEQ ID NO:5 position 105 corresponding to M; m) SEQ ID NO:5 position 108 corresponding to H; n) SEQ ID NO:5 position 109 corresponding to L; o) SEQ ID NO:5 position 117 corresponding to I or L; p) SEQ ID NO:5 position 120 corresponding to F; q) SEQ ID NO:5 position 121 corresponding to E, T, A, G, or V; r) SEQ ID NO:5 position 122 corresponding to I or H; s) SEQ ID NO:5 position 125 corresponding to K; t) SEQ ID NO:5 position 126 corresponding to A; u) SEQ ID NO:5 position 127 corresponding to F; NO:5 position 135 corresponding to H; v) SEQ ID NO:5 position 137 corresponding to V; w) SEQ ID NO:5 position 138 corresponding to Y; x) SEQ ID NO:5 position 139 corresponding to L; y) SEQ ID NO:5 position 142 corresponding to K or A; z) SEQ ID NO:5 position 145 corresponding to A, Q, L, or M; aa) SEQ ID NO:5 position 148 corresponding to K; bb) SEQ ID NO:5 position 151 corresponding to Q; cc) SEQ ID NO:5 position 153 corresponding to E or R; dd) SEQ ID NO:5 position 155 corresponding to W; ee) SEQ ID NO:5 position 156 corresponding to R or V; ff) F at the position corresponding to position 157 of SEQ ID NO: 5; gg) R at the position corresponding to position 158 of SEQ ID NO: 5; hh) Q at the position corresponding to position 159 of SEQ ID NO: 5; ii) D or W at the position corresponding to position 160 of SEQ ID NO: 5; jj) W, H, V, or A at the position corresponding to position 162 of SEQ ID NO: 5; kk) R at the position corresponding to position 165 of SEQ ID NO: 5; and ll) H at the position corresponding to position 166 of SEQ ID NO: 5. 2. The deaminase of embodiment 1, wherein the deaminase comprises at least one of the following amino acid residues: a) C at the position corresponding to position 2 of SEQ ID NO: 5; b) F or C at the position corresponding to position 22 of SEQ ID NO: 5; c) Q at the position corresponding to position 23 of SEQ ID NO: 5; d) N at the position corresponding to position 35 of SEQ ID NO: 5; e) L at the position corresponding to position 40 of SEQ ID NO: 5; f) A at the position corresponding to position 68 of SEQ ID NO: 5; g) W, A, Q, or Y at the position corresponding to position 75 of SEQ ID NO: 5; h) G at the position corresponding to position 76 of SEQ ID NO: 5; i) S at the position corresponding to position 81 of SEQ ID NO: 5; j) M at the position corresponding to position 105 of SEQ ID NO: 5; k) NO:5 position 108 corresponding to H; l) SEQ ID NO:5 position 109 corresponding to L; m) SEQ ID NO:5 position 117 corresponding to I or L; n) SEQ ID NO:5 position 121 corresponding to A or G; o) SEQ ID NO:5 position 122 corresponding to H; p) SEQ ID NO:5 position 126 corresponding to A; q) SEQ ID NO:5 position 135 corresponding to H; r) SEQ ID NO:5 position 137 corresponding to V; s) SEQ ID NO:5 position 138 corresponding to Y; t) SEQ ID NO:5 position 139 corresponding to L; u) SEQ ID NO:5 position 142 corresponding to K or A; v) SEQ ID NO:5 position 143 corresponding to V; s) SEQ ID NO:5 position 144 corresponding to Y; t) SEQ ID NO:5 position 145 corresponding to L; u) SEQ ID NO:5 position 146 corresponding to K or A; v) SEQ ID NO:5 position 147 corresponding to V; A, Q, L, or M at the position corresponding to position 145 of SEQ ID NO: 5; w) E or R at the position corresponding to position 153 of SEQ ID NO: 5; x) W at the position corresponding to position 155 of SEQ ID NO: 5; y) R at the position corresponding to position 156 of SEQ ID NO: 5; z) F at the position corresponding to position 157 of SEQ ID NO: 5; aa) R at the position corresponding to position 158 of SEQ ID NO: 5; bb) Q at the position corresponding to position 159 of SEQ ID NO: 5; cc) D or W at the position corresponding to position 160 of SEQ ID NO: 5; dd) A or W at the position corresponding to position 162 of SEQ ID NO: 5; and ee) R at the position corresponding to position 165 of SEQ ID NO: 5. 3. The deaminase of embodiment 1, wherein the deaminase comprises: a) N at the position corresponding to position 35 of SEQ ID NO: 5 and W at the position corresponding to position 162 of SEQ ID NO: 5; b) N at the position corresponding to position 35 of SEQ ID NO: 5 and Q at the position corresponding to position 46 of SEQ ID NO: 5; c) S at the position corresponding to position 81 of SEQ ID NO: 5 and R at the position corresponding to position 156 of SEQ ID NO: 5; d) Q at the position corresponding to position 46 of SEQ ID NO: 5 and R at the position corresponding to position 156 of SEQ ID NO: 5; e) R at the position corresponding to position 156 of SEQ ID NO: 5 and W at the position corresponding to position 162 of SEQ ID NO: 5; f) A at the position corresponding to position 68 of SEQ ID NO: 5 and S at the position corresponding to position 81 of SEQ ID NO: 5; g) NO:5 position corresponding to N at position 35, SEQ ID NO:5 position corresponding to S at position 81, and SEQ ID NO:5 position corresponding to W at position 162; h) N at position corresponding to SEQ ID NO:5 position corresponding to Q at position 46, and SEQ ID NO:5 position corresponding to W at position 162; i) W at position corresponding to SEQ ID NO:5 position corresponding to R at position 156, and SEQ ID NO:5 position corresponding to W at position 162; j) N at position corresponding to SEQ ID NO:5 position corresponding to N at position 35, SEQ ID NO:5 position corresponding to R at position 156, and SEQ ID NO:5 position corresponding to W at position 162; k) N at position corresponding to SEQ ID NO:5 position corresponding to S at position 81, SEQ ID NO:5 position corresponding to Q at position 46, and SEQ ID NO:5 position corresponding to W at position 162; NO: 5, R at the position corresponding to position 156, and W at the position corresponding to position 162 of SEQ ID NO: 5; l) M at the position corresponding to position 68 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; m) Q at the position corresponding to position 46 of SEQ ID NO: 5, M at the position corresponding to position 68 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; n) M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5 NO:5 position 108 corresponding to H, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; o) N corresponding to position 35, Q corresponding to position 46, SEQ ID NO:5 position 68 corresponding to M, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 155 corresponding to W, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; p) S corresponding to position 81, SEQ ID NO:5 position 155 corresponding to W; q) W corresponding to position 75, SEQ ID NO:5 position 76 corresponding to M, SEQ ID NO:5 position 87 corresponding to H, SEQ ID NO:5 position 88 corresponding to W, SEQ ID NO:5 position 89 corresponding to R, and SEQ ID NO:5 position 90 corresponding to W; NO:5 at the position corresponding to position 81; r) a at the position corresponding to position 81 of SEQ ID NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5; s) S at the position corresponding to position 81 of SEQ ID NO:5, and A at the position corresponding to position 145 of SEQ ID NO:5; t) W at the position corresponding to position 75 of SEQ ID NO:5, and W at the position corresponding to position 155 of SEQ ID NO:5; u) W at the position corresponding to position 155 of SEQ ID NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5; v) A at the position corresponding to position 145 of SEQ ID NO:5, and W at the position corresponding to position 155 of SEQ ID NO:5; w) W at the position corresponding to position 75 of SEQ ID NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5; x) W at the position corresponding to position 75 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; y) A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; z) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; aa) S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; bb) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; cc) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; dd) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; ee) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ff) W at the position corresponding to position 75 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; gg) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5 NO:5 position 145 A, and SEQ ID NO:5 position 155 W; hh) SEQ ID NO:5 position 145 A, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; ii) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 145 A, and SEQ ID NO:5 position 160 D; jj) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; kk) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 155 S, and SEQ ID NO:5 position 160 D; NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, and SEQ ID NO:5 position 155 corresponding to W; ll) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; mm) SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, and SEQ ID NO:5 position 160 corresponding to D; nn)  SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 155 corresponding to D, and SEQ ID NO:5 position 160 corresponding to D; NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; oo) SEQ ID NO: 5 position 75 corresponding to W, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; pp) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 105 corresponding to M; qq) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 121 corresponding to V; rr) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 145 corresponding to M; ss) L at the position corresponding to position 40 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; tt) L at the position corresponding to position 40 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; uu) M at the position corresponding to position 105 of SEQ ID NO: 5, and V at the position corresponding to position 121 of SEQ ID NO: 5; vv) M at the position corresponding to position 105 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; ww) M at the position corresponding to position 105 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; xx) M at the position corresponding to position 105 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; yy) NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 145 corresponding to M; zz) SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 159 corresponding to Q; aaa) SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 160 corresponding to W; bbb) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 159 corresponding to Q; ccc) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; ddd) SEQ ID NO:5 position 159 corresponding to Q, and SEQ ID NO:5 position 160 corresponding to W; eee) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; fff) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 159 corresponding to Q; ggg) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 81 corresponding to S; hhh) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; iii) SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; jjj) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 81 corresponding to S; NO:5 position 76 corresponding to G; kkk) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 117 corresponding to L; lll) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; mmm) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; nnn) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ooo) SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; NO:5 position corresponding to L at position 117; ppp) A at position corresponding to position 68 of SEQ ID NO:5, G at position corresponding to position 76 of SEQ ID NO:5, and L at position corresponding to position 117 of SEQ ID NO:5; qqq) A at position corresponding to position 68 of SEQ ID NO:5, G at position corresponding to position 76 of SEQ ID NO:5, S at position corresponding to position 81 of SEQ ID NO:5, and L at position corresponding to position 117 of SEQ ID NO:5; rrr) S at position corresponding to position 81 of SEQ ID NO:5, L at position corresponding to position 109 of SEQ ID NO:5, E at position corresponding to position 153 of SEQ ID NO:5, W at position corresponding to position 155 of SEQ ID NO:5, and D at position corresponding to position 160 of SEQ ID NO:5; sss) A at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, L at the position corresponding to position 117 of SEQ ID NO: 5, A at the position corresponding to position 121 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ttt) Q at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, I at the position corresponding to position 117 of SEQ ID NO: 5, Q at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; uuu) NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; vvv) a position corresponding to SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 160 corresponding to D; vvv) a position corresponding to SEQ ID NO:5 position 22 corresponding to A, SEQ ID NO:5 position 68 corresponding to Y, SEQ ID NO:5 position 75 corresponding to G, SEQ ID NO:5 position 76 corresponding to S, SEQ ID NO:5 position 81 corresponding to H, SEQ ID NO:5 position 108 corresponding to L, SEQ ID NO:5 position 117 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; H at the position corresponding to position 122 of SEQ ID NO: 5, Y at the position corresponding to position 138 of SEQ ID NO: 5, L at the position corresponding to position 139 of SEQ ID NO: 5, A at the position corresponding to position 142 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, R at the position corresponding to position 153 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, D at the position corresponding to position 160 of SEQ ID NO: 5, and H at the position corresponding to position 162 of SEQ ID NO: 5; or www) S at the position corresponding to position 81 of SEQ ID NO: 5. 4. The deaminase of embodiment 1 or 3, wherein the deaminase comprises: a) N at the position corresponding to position 35 of SEQ ID NO: 5 and Q at the position corresponding to position 46 of SEQ ID NO: 5; b) S at the position corresponding to position 81 of SEQ ID NO: 5 and R at the position corresponding to position 156 of SEQ ID NO: 5; c) Q at the position corresponding to position 46 of SEQ ID NO: 5 and R at the position corresponding to position 156 of SEQ ID NO: 5; d) N at the position corresponding to position 35 of SEQ ID NO: 5, Q at the position corresponding to position 46 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; e) W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; f) N at the position corresponding to position 35 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; g) N at the position corresponding to position 35 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; h) M at the position corresponding to position 68, S at the position corresponding to position 81 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; i) N at the position corresponding to position 35 of SEQ ID NO: 5, Q at the position corresponding to position 46 of SEQ ID NO: 5, and Q at the position corresponding to position 47 of SEQ ID NO: 5. M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; j) S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; k) W at the position corresponding to position 75 of SEQ ID NO: 5, and S at the position corresponding to position 81 of SEQ ID NO: 5; l) S at the position corresponding to position 81 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; m) S at the position corresponding to position 81 of SEQ ID NO: 5, and R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; A at the position corresponding to position 145 of SEQ ID NO: 5; n) W at the position corresponding to position 75 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; o) W at the position corresponding to position 75 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; p) A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; q) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; r) S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; s) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; t) L at the position corresponding to position 40 of SEQ ID NO: 5, and M at the position corresponding to position 105 of SEQ ID NO: 5; u) L at the position corresponding to position 40 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; v) L at the position corresponding to position 40 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; w) L at the position corresponding to position 40 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; x) M at the position corresponding to position 105 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; y) M at the position corresponding to position 105 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; z) M at the position corresponding to position 145 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; aa) M at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; bb) Q at the position corresponding to position 159 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; cc) S at the position corresponding to position 81 of SEQ ID NO: 5, M at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; dd) A at the position corresponding to position 68 of SEQ ID NO: 5, and Q at the position corresponding to position 160 of SEQ ID NO: 5; NO:5 position 81 corresponding to S; ee) SEQ ID NO:5 position 76 corresponding to S, and SEQ ID NO:5 position 81 corresponding to S; ff) SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; gg) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 76 corresponding to G; hh) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 117 corresponding to L; ii) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; jj) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; ID NO:5 position 81 corresponding to S; kk) SEQ ID NO:5 position 68 corresponding to S, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ll) SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; mm) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; nn) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; NO:5 position 117 corresponding to L; oo) A corresponding to position 68 of SEQ ID NO:5 and S corresponding to position 81 of SEQ ID NO:5; pp) S corresponding to position 81 of SEQ ID NO:5, L corresponding to position 109 of SEQ ID NO:5, E corresponding to position 153 of SEQ ID NO:5, W corresponding to position 155 of SEQ ID NO:5, and D corresponding to position 160 of SEQ ID NO:5; qq) A corresponding to position 75 of SEQ ID NO:5, S corresponding to position 81 of SEQ ID NO:5, L corresponding to position 117 of SEQ ID NO:5, A corresponding to position 121 of SEQ ID NO:5, A corresponding to position 145 of SEQ ID NO:5, and D corresponding to position 160 of SEQ ID NO:5; NO: 5, W at the position corresponding to position 155, and D at the position corresponding to position 160 of SEQ ID NO: 5; rr) Q at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, I at the position corresponding to position 117 of SEQ ID NO: 5, Q at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ss) Y at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, L at the position corresponding to position 117 of SEQ ID NO: 5, G at the position corresponding to position 121 of SEQ ID NO: 5, L at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; tt) SEQ ID NO: 5 position 22 corresponding to W, SEQ ID NO: 5 position 68 corresponding to A, SEQ ID NO: 5 position 75 corresponding to Y, SEQ ID NO: 5 position 76 corresponding to G, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 108 corresponding to H, SEQ ID NO: 5 position 117 corresponding to L, SEQ ID NO: 5 position 122 corresponding to H, SEQ ID NO: 5 position 138 corresponding to Y, SEQ ID NO: 5 position 139 corresponding to L, SEQ ID NO: 5 position 142 corresponding to A, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 150 corresponding to L, SEQ ID NO: 5 position 151 corresponding to L, SEQ ID NO: 5 position 152 corresponding to L, SEQ ID NO: 5 position 153 corresponding to L, SEQ ID NO: 5 position 154 corresponding to L, SEQ ID NO: 5 position 156 corresponding to L, SEQ ID NO: 5 position 157 corresponding to L, SEQ ID NO: 5 position 158 corresponding to L, SEQ ID NO: 5 position 159 corresponding to L, SEQ ID NO: 5 position 160 corresponding to L, SEQ ID NO: 5 position 161 corresponding to L, SEQ ID NO: 5 position 162 corresponding to L, SEQ ID NO: 5 position 163 corresponding to L, SEQ ID NO: 5 position 164 corresponding to L, SEQ ID NO: 5 position 165 corresponding to L, SEQ ID NO: 5 position 166 corresponding to L, SEQ ID NO: 5 position 167 corresponding to L, SEQ ID NO: 5 position 168 corresponding to L R at the position corresponding to position 153 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, D at the position corresponding to position 160 of SEQ ID NO: 5, and H at the position corresponding to position 162 of SEQ ID NO: 5; uu) S at the position corresponding to position 81 of SEQ ID NO: 5; or vv) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. 5. The deaminase of any one of embodiments 1, 3 and 4, wherein the deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5, S at a position corresponding to position 81 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; b) W at a position corresponding to position 75 of SEQ ID NO: 5, and W at a position corresponding to position 155 of SEQ ID NO: 5; c) S at a position corresponding to position 81 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; d) S at a position corresponding to position 81 of SEQ ID NO: 5, A at a position corresponding to position 145 of SEQ ID NO: 5, and D at a position corresponding to position 162 of SEQ ID NO: 5; NO:5 position 155 corresponding to W; e) S corresponding to position 81 of SEQ ID NO:5, M corresponding to position 145 of SEQ ID NO:5, and W corresponding to position 160 of SEQ ID NO:5; f) G corresponding to position 76 of SEQ ID NO:5, and S corresponding to position 81 of SEQ ID NO:5; g) S corresponding to position 81 of SEQ ID NO:5, and L corresponding to position 117 of SEQ ID NO:5; h) A corresponding to position 68 of SEQ ID NO:5, and S corresponding to position 81 of SEQ ID NO:5; i) S corresponding to position 81 of SEQ ID NO:5, L corresponding to position 109 of SEQ ID NO:5, E corresponding to position 153 of SEQ ID NO:5, and L corresponding to position 117 of SEQ ID NO:5; NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; j) SEQ ID NO: 5 position 75 corresponding to A, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 117 corresponding to L, SEQ ID NO: 5 position 121 corresponding to A, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; k) SEQ ID NO: 5 position 75 corresponding to Q, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 117 corresponding to I, SEQ ID NO: 5 position 145 corresponding to Q, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; NO:5 position 160 corresponding to D; l) SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; m) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 110 corresponding to H, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; m) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 121 corresponding to NO:5 position 117 corresponding to L, SEQ ID NO:5 position 122 corresponding to H, SEQ ID NO:5 position 138 corresponding to Y, SEQ ID NO:5 position 139 corresponding to L, SEQ ID NO:5 position 142 corresponding to A, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 153 corresponding to R, SEQ ID NO:5 position 155 corresponding to W, SEQ ID NO:5 position 156 corresponding to R, SEQ ID NO:5 position 160 corresponding to D, and SEQ ID NO:5 position 162 corresponding to H; n) SEQ ID NO:5 position 81 corresponding to S; or o) SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 163 corresponding to H; W at the position corresponding to position 155 of NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. 6. The deaminase of any one of embodiments 1-5, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 300-414, 596-598, and 720-723. 7. The deaminase of any one of embodiments 1-5, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 300-414, 596-598, and 720-723. 8. The deaminase of any one of embodiments 1-5, wherein the deaminase comprises an amino acid sequence of any one of SEQ ID NOs: 300-414, 596-598, and 720-723. 9. The deaminase of any one of embodiments 1-8, wherein the deaminase has improved deaminase activity when compared to SEQ ID NO: 5. 10. The deaminase of any one of embodiments 1-9, wherein the deaminase is adenine deaminase. 11. A nucleic acid molecule comprising a polynucleotide encoding a deaminase having at least 85% sequence identity with SEQ ID NO: 5, wherein the deaminase comprises at least one of the following amino acid residues: a) C at a position corresponding to position 2 of SEQ ID NO: 5; b) F or C at a position corresponding to position 22 of SEQ ID NO: 5; c) Q at a position corresponding to position 23 of SEQ ID NO: 5; d) N at a position corresponding to position 35 of SEQ ID NO: 5; e) L at a position corresponding to position 40 of SEQ ID NO: 5; f) Q at a position corresponding to position 46 of SEQ ID NO: 5; g) A or M at a position corresponding to position 68 of SEQ ID NO: 5; h) H at a position corresponding to position 72 of SEQ ID NO: 5; i) W, A, Q, Y, or D at a position corresponding to position 75 of SEQ ID NO: 5; j) G at the position corresponding to position 76 of SEQ ID NO: 5; k) S at the position corresponding to position 81 of SEQ ID NO: 5; l) M at the position corresponding to position 105 of SEQ ID NO: 5; m) H at the position corresponding to position 108 of SEQ ID NO: 5; n) L at the position corresponding to position 109 of SEQ ID NO: 5; o) I or L at the position corresponding to position 117 of SEQ ID NO: 5; p) F at the position corresponding to position 120 of SEQ ID NO: 5; q) E, T, A, G, or V at the position corresponding to position 121 of SEQ ID NO: 5; r) I or H at the position corresponding to position 122 of SEQ ID NO: 5; s) K at the position corresponding to position 125 of SEQ ID NO: 5; t) A at the position corresponding to position 126 of SEQ ID NO: 5; u) H at the position corresponding to position 135 of SEQ ID NO: 5; v) V at the position corresponding to position 137 of SEQ ID NO: 5; w) Y at the position corresponding to position 138 of SEQ ID NO: 5; x) L at the position corresponding to position 139 of SEQ ID NO: 5; y) K or A at the position corresponding to position 142 of SEQ ID NO: 5; z) A, Q, L, or M at the position corresponding to position 145 of SEQ ID NO: 5; aa) K at the position corresponding to position 148 of SEQ ID NO: 5; bb) Q at the position corresponding to position 151 of SEQ ID NO: 5; cc) E or R at the position corresponding to position 153 of SEQ ID NO: 5; dd) W at the position corresponding to position 155 of SEQ ID NO: 5; ee) NO: 5 at position 156 corresponding to R or V; ff) SEQ ID NO: 5 at position 157 corresponding to F; gg) SEQ ID NO: 5 at position 158 corresponding to Q; hh) SEQ ID NO: 5 at position 159 corresponding to Q; ii) SEQ ID NO: 5 at position 160 corresponding to D or W; jj) SEQ ID NO: 5 at position 162 corresponding to W, H, V, or A; kk) SEQ ID NO: 5 at position 165 corresponding to R; and ll) SEQ ID NO: 5 at position 166 corresponding to H. 12. The nucleic acid molecule of embodiment 11, wherein the deaminase comprises at least one of the following amino acid residues: a) C at the position corresponding to position 2 of SEQ ID NO: 5; b) F or C at the position corresponding to position 22 of SEQ ID NO: 5; c) Q at the position corresponding to position 23 of SEQ ID NO: 5; d) N at the position corresponding to position 35 of SEQ ID NO: 5; e) L at the position corresponding to position 40 of SEQ ID NO: 5; f) A at the position corresponding to position 68 of SEQ ID NO: 5; g) W, A, Q, or Y at the position corresponding to position 75 of SEQ ID NO: 5; h) G at the position corresponding to position 76 of SEQ ID NO: 5; i) S at the position corresponding to position 81 of SEQ ID NO: 5; j) M at the position corresponding to position 105 of SEQ ID NO: 5; k) NO:5 position 108 corresponding to H; l) SEQ ID NO:5 position 109 corresponding to L; m) SEQ ID NO:5 position 117 corresponding to I or L; n) SEQ ID NO:5 position 121 corresponding to A or G; o) SEQ ID NO:5 position 122 corresponding to H; p) SEQ ID NO:5 position 126 corresponding to A; q) SEQ ID NO:5 position 135 corresponding to H; r) SEQ ID NO:5 position 137 corresponding to V; s) SEQ ID NO:5 position 138 corresponding to Y; t) SEQ ID NO:5 position 139 corresponding to L; u) SEQ ID NO:5 position 142 corresponding to K or A; v) SEQ ID NO:5 position 143 corresponding to V; s) SEQ ID NO:5 position 144 corresponding to Y; t) SEQ ID NO:5 position 145 corresponding to L; u) SEQ ID NO:5 position 146 corresponding to K or A; v) SEQ ID NO:5 position 147 corresponding to V; A, Q, L, or M at the position corresponding to position 145 of SEQ ID NO: 5; w) E or R at the position corresponding to position 153 of SEQ ID NO: 5; x) W at the position corresponding to position 155 of SEQ ID NO: 5; y) R at the position corresponding to position 156 of SEQ ID NO: 5; z) F at the position corresponding to position 157 of SEQ ID NO: 5; aa) R at the position corresponding to position 158 of SEQ ID NO: 5; bb) Q at the position corresponding to position 159 of SEQ ID NO: 5; cc) D or W at the position corresponding to position 160 of SEQ ID NO: 5; dd) A or W at the position corresponding to position 162 of SEQ ID NO: 5; and ee) R at the position corresponding to position 165 of SEQ ID NO: 5. 13. The nucleic acid molecule of embodiment 11, wherein the deaminase comprises: a) N at the position corresponding to position 35 of SEQ ID NO: 5 and W at the position corresponding to position 162 of SEQ ID NO: 5; b) N at the position corresponding to position 35 of SEQ ID NO: 5 and Q at the position corresponding to position 46 of SEQ ID NO: 5; c) S at the position corresponding to position 81 of SEQ ID NO: 5 and R at the position corresponding to position 156 of SEQ ID NO: 5; d) Q at the position corresponding to position 46 of SEQ ID NO: 5 and R at the position corresponding to position 156 of SEQ ID NO: 5; e) R at the position corresponding to position 156 of SEQ ID NO: 5 and W at the position corresponding to position 162 of SEQ ID NO: 5; f) A at the position corresponding to position 68 of SEQ ID NO: 5 and S at the position corresponding to position 81 of SEQ ID NO: 5; g) NO:5 position corresponding to N at position 35, SEQ ID NO:5 position corresponding to S at position 81, and SEQ ID NO:5 position corresponding to W at position 162; h) N at position corresponding to SEQ ID NO:5 position corresponding to N at position 35, SEQ ID NO:5 position corresponding to Q at position 46, and SEQ ID NO:5 position corresponding to W at position 162; i) W at position corresponding to SEQ ID NO:5 position corresponding to R at position 156, and SEQ ID NO:5 position corresponding to W at position 162; j) N at position corresponding to SEQ ID NO:5 position corresponding to N at position 35, SEQ ID NO:5 position corresponding to R at position 156, and SEQ ID NO:5 position corresponding to W at position 162; k) N at position corresponding to SEQ ID NO:5 position corresponding to S at position 81, SEQ ID NO:5 position corresponding to Q at position 46, and SEQ ID NO:5 position corresponding to W at position 162; NO: 5, R at the position corresponding to position 156, and W at the position corresponding to position 162 of SEQ ID NO: 5; l) M at the position corresponding to position 68 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; m) Q at the position corresponding to position 46 of SEQ ID NO: 5, M at the position corresponding to position 68 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; n) M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and S at the position corresponding to position 162 of SEQ ID NO: 5; NO:5 position 108 corresponding to H, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; o) N corresponding to position 35, Q corresponding to position 46, SEQ ID NO:5 position 68 corresponding to M, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 155 corresponding to W, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; p) S corresponding to position 81, SEQ ID NO:5 position 155 corresponding to W; q) W corresponding to position 75, SEQ ID NO:5 position 76 corresponding to M, SEQ ID NO:5 position 87 corresponding to H, SEQ ID NO:5 position 88 corresponding to W, SEQ ID NO:5 position 89 corresponding to R, and SEQ ID NO:5 position 90 corresponding to W; NO:5 position corresponding to S; r) SEQ ID NO:5 position corresponding to S, and SEQ ID NO:5 position corresponding to D; s) SEQ ID NO:5 position corresponding to S, and SEQ ID NO:5 position corresponding to A; t) SEQ ID NO:5 position corresponding to W, and SEQ ID NO:5 position corresponding to W; u) SEQ ID NO:5 position corresponding to W, and SEQ ID NO:5 position corresponding to D; v) SEQ ID NO:5 position corresponding to A, and SEQ ID NO:5 position corresponding to W; w) SEQ ID NO:5 position corresponding to W, and SEQ ID NO:5 position corresponding to D; x) W at the position corresponding to position 75 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; y) A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; z) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; aa) S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; bb) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; cc) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; dd) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; ee) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ff) W at the position corresponding to position 75 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; gg) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5 NO:5 position 145 A, and SEQ ID NO:5 position 155 W; hh) SEQ ID NO:5 position 145 A, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; ii) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 145 A, and SEQ ID NO:5 position 160 D; jj) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; kk) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 155 S, and SEQ ID NO:5 position 160 D; NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, and SEQ ID NO:5 position 155 corresponding to W; ll) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; mm) SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, and SEQ ID NO:5 position 160 corresponding to D; nn)  SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 155 corresponding to D, and SEQ ID NO:5 position 160 corresponding to D; NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; oo) SEQ ID NO: 5 position 75 corresponding to W, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; pp) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 105 corresponding to M; qq) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 121 corresponding to V; rr) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 145 corresponding to M; ss) L at the position corresponding to position 40 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; tt) L at the position corresponding to position 40 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; uu) M at the position corresponding to position 105 of SEQ ID NO: 5, and V at the position corresponding to position 121 of SEQ ID NO: 5; vv) M at the position corresponding to position 105 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; ww) M at the position corresponding to position 105 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; xx) M at the position corresponding to position 105 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; yy) NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 145 corresponding to M; zz) SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 159 corresponding to Q; aaa) SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 160 corresponding to W; bbb) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 159 corresponding to Q; ccc) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; ddd) SEQ ID NO:5 position 159 corresponding to Q, and SEQ ID NO:5 position 160 corresponding to W; eee) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; fff) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 159 corresponding to Q; ggg) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 81 corresponding to S; hhh) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; iii) SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; jjj) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 81 corresponding to S; NO:5 position 76 corresponding to G; kkk) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 117 corresponding to L; lll) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; mmm) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; nnn) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ooo) SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; NO:5 position corresponding to L at position 117; ppp) A at position corresponding to position 68 of SEQ ID NO:5, G at position corresponding to position 76 of SEQ ID NO:5, and L at position corresponding to position 117 of SEQ ID NO:5; qqq) A at position corresponding to position 68 of SEQ ID NO:5, G at position corresponding to position 76 of SEQ ID NO:5, S at position corresponding to position 81 of SEQ ID NO:5, and L at position corresponding to position 117 of SEQ ID NO:5; rrr) S at position corresponding to position 81 of SEQ ID NO:5, L at position corresponding to position 109 of SEQ ID NO:5, E at position corresponding to position 153 of SEQ ID NO:5, W at position corresponding to position 155 of SEQ ID NO:5, and D at position corresponding to position 160 of SEQ ID NO:5; sss) A at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, L at the position corresponding to position 117 of SEQ ID NO: 5, A at the position corresponding to position 121 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ttt) Q at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, I at the position corresponding to position 117 of SEQ ID NO: 5, Q at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; uuu) NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; vvv) a position corresponding to SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 160 corresponding to D; vvv) a position corresponding to SEQ ID NO:5 position 22 corresponding to A, SEQ ID NO:5 position 68 corresponding to Y, SEQ ID NO:5 position 75 corresponding to G, SEQ ID NO:5 position 76 corresponding to S, SEQ ID NO:5 position 81 corresponding to H, SEQ ID NO:5 position 108 corresponding to L, SEQ ID NO:5 position 117 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; H at the position corresponding to position 122 of SEQ ID NO: 5, Y at the position corresponding to position 138 of SEQ ID NO: 5, L at the position corresponding to position 139 of SEQ ID NO: 5, A at the position corresponding to position 142 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, R at the position corresponding to position 153 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, D at the position corresponding to position 160 of SEQ ID NO: 5, and H at the position corresponding to position 162 of SEQ ID NO: 5; or www) S at the position corresponding to position 81 of SEQ ID NO: 5. 14. The nucleic acid molecule of embodiment 11 or 13, wherein the deaminase comprises: a) N at the position corresponding to position 35 of SEQ ID NO: 5 and Q at the position corresponding to position 46 of SEQ ID NO: 5; b) S at the position corresponding to position 81 of SEQ ID NO: 5 and R at the position corresponding to position 156 of SEQ ID NO: 5; c) Q at the position corresponding to position 46 of SEQ ID NO: 5 and R at the position corresponding to position 156 of SEQ ID NO: 5; d) N at the position corresponding to position 35 of SEQ ID NO: 5, Q at the position corresponding to position 46 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; e) W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; f) N at the position corresponding to position 35 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; g) N at the position corresponding to position 35 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; h) M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; i) N at the position corresponding to position 35, Q at the position corresponding to position 46 of SEQ ID NO: 5, Q at the position corresponding to position 57 of SEQ ID NO: 5, and Q at the position corresponding to position 66 of SEQ ID NO: 5. NO: 5 position 68 corresponding to M, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 108 corresponding to H, SEQ ID NO: 5 position 155 corresponding to W, SEQ ID NO: 5 position 156 corresponding to R, and SEQ ID NO: 5 position 162 corresponding to W; j) SEQ ID NO: 5 position 81 corresponding to S, and SEQ ID NO: 5 position 155 corresponding to W; k) SEQ ID NO: 5 position 75 corresponding to W, and SEQ ID NO: 5 position 81 corresponding to S; l) SEQ ID NO: 5 position 81 corresponding to S, and SEQ ID NO: 5 position 160 corresponding to D; m) SEQ ID NO: 5 position 81 corresponding to S, and SEQ ID NO: 5 position 162 corresponding to R; A at the position corresponding to position 145 of SEQ ID NO: 5; n) W at the position corresponding to position 75 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; o) W at the position corresponding to position 75 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; p) A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; q) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; r) S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; s) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; t) L at the position corresponding to position 40 of SEQ ID NO: 5, and M at the position corresponding to position 105 of SEQ ID NO: 5; u) L at the position corresponding to position 40 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; v) L at the position corresponding to position 40 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; w) L at the position corresponding to position 40 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; x) M at the position corresponding to position 105 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; y) M at the position corresponding to position 105 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; z) M at the position corresponding to position 145 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; aa) M at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; bb) Q at the position corresponding to position 159 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; cc) S at the position corresponding to position 81 of SEQ ID NO: 5, M at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; dd) A at the position corresponding to position 68 of SEQ ID NO: 5, and Q at the position corresponding to position 160 of SEQ ID NO: 5; NO:5 position 81 corresponding to S; ee) SEQ ID NO:5 position 76 corresponding to S, and SEQ ID NO:5 position 81 corresponding to S; ff) SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; gg) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 76 corresponding to G; hh) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 117 corresponding to L; ii) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; jj) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; ID NO:5 position 81 corresponding to S; kk) SEQ ID NO:5 position 68 corresponding to S, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ll) SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; mm) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; nn) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; NO:5 position 117 corresponding to L; oo) SEQ ID NO:5 position 68 corresponding to L and SEQ ID NO:5 position 81 corresponding to S; pp) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 109 corresponding to L, SEQ ID NO:5 position 153 corresponding to E, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; qq) SEQ ID NO:5 position 75 corresponding to A, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to A, SEQ ID NO:5 position 145 corresponding to E, SEQ ID NO:5 position 156 corresponding to W, and SEQ ID NO:5 position 167 corresponding to D; qq) SEQ ID NO:5 position 75 corresponding to A, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to A, SEQ ID NO:5 position 146 corresponding to E, SEQ ID NO:5 position 157 corresponding to W, and SEQ ID NO:5 position 168 corresponding to D; NO: 5, W at the position corresponding to position 155, and D at the position corresponding to position 160 of SEQ ID NO: 5; rr) Q at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, I at the position corresponding to position 117 of SEQ ID NO: 5, Q at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ss) Y at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, L at the position corresponding to position 117 of SEQ ID NO: 5, G at the position corresponding to position 121 of SEQ ID NO: 5, L at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; tt) C at the position corresponding to position 22 of SEQ ID NO: 5, A at the position corresponding to position 68 of SEQ ID NO: 5, Y at the position corresponding to position 75 of SEQ ID NO: 5, G at the position corresponding to position 76 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, L at the position corresponding to position 117 of SEQ ID NO: 5, H at the position corresponding to position 122 of SEQ ID NO: 5, Y at the position corresponding to position 138 of SEQ ID NO: 5, L at the position corresponding to position 139 of SEQ ID NO: 5, A at the position corresponding to position 142 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, R at the position corresponding to position 153 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, D at the position corresponding to position 160 of SEQ ID NO: 5, and H at the position corresponding to position 162 of SEQ ID NO: 5; uu) S at the position corresponding to position 81 of SEQ ID NO: 5; or vv) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. 15. The nucleic acid molecule of any one of embodiments 11, 13 and 14, wherein the deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5, S at a position corresponding to position 81 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; b) W at a position corresponding to position 75 of SEQ ID NO: 5, and W at a position corresponding to position 155 of SEQ ID NO: 5; c) S at a position corresponding to position 81 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; d) S at a position corresponding to position 81 of SEQ ID NO: 5, A at a position corresponding to position 145 of SEQ ID NO: 5, and D at a position corresponding to position 162 of SEQ ID NO: 5; NO:5 position 155 corresponding to W; e) S corresponding to position 81 of SEQ ID NO:5, M corresponding to position 145 of SEQ ID NO:5, and W corresponding to position 160 of SEQ ID NO:5; f) G corresponding to position 76 of SEQ ID NO:5, and S corresponding to position 81 of SEQ ID NO:5; g) S corresponding to position 81 of SEQ ID NO:5, and L corresponding to position 117 of SEQ ID NO:5; h) A corresponding to position 68 of SEQ ID NO:5, and S corresponding to position 81 of SEQ ID NO:5; i) S corresponding to position 81 of SEQ ID NO:5, L corresponding to position 109 of SEQ ID NO:5, E corresponding to position 153 of SEQ ID NO:5, and L corresponding to position 117 of SEQ ID NO:5; NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; j) SEQ ID NO: 5 position 75 corresponding to A, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 117 corresponding to L, SEQ ID NO: 5 position 121 corresponding to A, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; k) SEQ ID NO: 5 position 75 corresponding to Q, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 117 corresponding to I, SEQ ID NO: 5 position 145 corresponding to Q, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; NO:5 position 160 corresponding to D; l) SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; m) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 110 corresponding to H, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; m) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 121 corresponding to NO:5 position 117 corresponding to L, SEQ ID NO:5 position 122 corresponding to H, SEQ ID NO:5 position 138 corresponding to Y, SEQ ID NO:5 position 139 corresponding to L, SEQ ID NO:5 position 142 corresponding to A, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 153 corresponding to R, SEQ ID NO:5 position 155 corresponding to W, SEQ ID NO:5 position 156 corresponding to R, SEQ ID NO:5 position 160 corresponding to D, and SEQ ID NO:5 position 162 corresponding to H; n) SEQ ID NO:5 position 81 corresponding to S; or o) SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 163 corresponding to H; W at the position corresponding to position 155 of NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. 16. A nucleic acid molecule according to any one of embodiments 11-15, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 300-414, 596-598, and 720-723. 17. A nucleic acid molecule according to any one of embodiments 11-15, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 300-414, 596-598, and 720-723. 18. The nucleic acid molecule 11-15 of any of the embodiments, wherein the deaminase comprises an amino acid sequence of any of SEQ ID NOs: 300-414, 596-598, and 720-723. 19. The nucleic acid molecule of any one of embodiments 11-18, wherein the deaminase has improved deaminase activity when compared to SEQ ID NO: 5. 20. A nucleic acid molecule according to any one of embodiments 11-19, wherein the deaminase is adenine deaminase. 21. The nucleic acid molecule of any one of embodiments 11-20 further comprises a heterologous promoter operably linked to the polynucleotide. 22. A vector comprising a nucleic acid molecule of any one of embodiments 11-21. 23. A cell comprising the deaminase of any one of embodiments 1-10, the nucleic acid molecule of any one of embodiments 11-21, or the vector of embodiment 22. 24. A drug composition comprising a pharmaceutically acceptable carrier and a deaminase according to any one of embodiments 1-10, a nucleic acid molecule according to any one of embodiments 11-21, or a carrier according to embodiment 22. 25. A method for producing deaminase, comprising introducing the nucleic acid molecule of any one of embodiments 11-21 or the vector of embodiment 22 into cells, and culturing the cells under conditions that express deaminase. 26. The method of embodiment 25 further comprises purifying the deaminase. 27. A fusion protein comprising a DNA binding polypeptide and a deaminase having at least 85% sequence identity with SEQ ID NO: 5, wherein the deaminase comprises at least one of the following amino acid residues: a) C at a position corresponding to position 2 of SEQ ID NO: 5; b) F or C at a position corresponding to position 22 of SEQ ID NO: 5; c) Q at a position corresponding to position 23 of SEQ ID NO: 5; d) N at a position corresponding to position 35 of SEQ ID NO: 5; e) L at a position corresponding to position 40 of SEQ ID NO: 5; f) Q at a position corresponding to position 46 of SEQ ID NO: 5; g) A or M at a position corresponding to position 68 of SEQ ID NO: 5; h) H at a position corresponding to position 72 of SEQ ID NO: 5; i) W, A, Q, Y, or D at a position corresponding to position 75 of SEQ ID NO: 5; j) G at the position corresponding to position 76 of SEQ ID NO: 5; k) S at the position corresponding to position 81 of SEQ ID NO: 5; l) M at the position corresponding to position 105 of SEQ ID NO: 5; m) H at the position corresponding to position 108 of SEQ ID NO: 5; n) L at the position corresponding to position 109 of SEQ ID NO: 5; o) I or L at the position corresponding to position 117 of SEQ ID NO: 5; p) F at the position corresponding to position 120 of SEQ ID NO: 5; q) E, T, A, G, or V at the position corresponding to position 121 of SEQ ID NO: 5; r) I or H at the position corresponding to position 122 of SEQ ID NO: 5; s) K at the position corresponding to position 125 of SEQ ID NO: 5; t) A at the position corresponding to position 126 of SEQ ID NO: 5; u) H at the position corresponding to position 135 of SEQ ID NO: 5; v) V at the position corresponding to position 137 of SEQ ID NO: 5; w) Y at the position corresponding to position 138 of SEQ ID NO: 5; x) L at the position corresponding to position 139 of SEQ ID NO: 5; y) K or A at the position corresponding to position 142 of SEQ ID NO: 5; z) A, Q, L, or M at the position corresponding to position 145 of SEQ ID NO: 5; aa) K at the position corresponding to position 148 of SEQ ID NO: 5; bb) Q at the position corresponding to position 151 of SEQ ID NO: 5; cc) E or R at the position corresponding to position 153 of SEQ ID NO: 5; dd) W at the position corresponding to position 155 of SEQ ID NO: 5; ee) NO:5 at position 156 corresponding to R or V; ff) at position 157 corresponding to F; gg) at position 158 corresponding to R; hh) at position 159 corresponding to Q; ii) at position 160 corresponding to D or W; jj) at position 162 corresponding to W, H, V, or A; kk) at position 165 corresponding to R; and ll) at position 166 corresponding to H. 28. The fusion protein of embodiment 27, wherein the deaminase comprises at least one of the following amino acid residues: a) C at the position corresponding to position 2 of SEQ ID NO: 5; b) F or C at the position corresponding to position 22 of SEQ ID NO: 5; c) Q at the position corresponding to position 23 of SEQ ID NO: 5; d) N at the position corresponding to position 35 of SEQ ID NO: 5; e) L at the position corresponding to position 40 of SEQ ID NO: 5; f) A at the position corresponding to position 68 of SEQ ID NO: 5; g) W, A, Q, or Y at the position corresponding to position 75 of SEQ ID NO: 5; h) G at the position corresponding to position 76 of SEQ ID NO: 5; i) S at the position corresponding to position 81 of SEQ ID NO: 5; j) M at the position corresponding to position 105 of SEQ ID NO: 5; k) NO:5 position 108 corresponding to H; l) SEQ ID NO:5 position 109 corresponding to L; m) SEQ ID NO:5 position 117 corresponding to I or L; n) SEQ ID NO:5 position 121 corresponding to A or G; o) SEQ ID NO:5 position 122 corresponding to H; p) SEQ ID NO:5 position 126 corresponding to A; q) SEQ ID NO:5 position 135 corresponding to H; r) SEQ ID NO:5 position 137 corresponding to V; s) SEQ ID NO:5 position 138 corresponding to Y; t) SEQ ID NO:5 position 139 corresponding to L; u) SEQ ID NO:5 position 142 corresponding to K or A; v) SEQ ID NO:5 position 143 corresponding to V; s) SEQ ID NO:5 position 144 corresponding to Y; t) SEQ ID NO:5 position 145 corresponding to L; u) SEQ ID NO:5 position 146 corresponding to K or A; v) SEQ ID NO:5 position 147 corresponding to V; A, Q, L, or M at the position corresponding to position 145 of SEQ ID NO: 5; w) E or R at the position corresponding to position 153 of SEQ ID NO: 5; x) W at the position corresponding to position 155 of SEQ ID NO: 5; y) R at the position corresponding to position 156 of SEQ ID NO: 5; z) F at the position corresponding to position 157 of SEQ ID NO: 5; aa) R at the position corresponding to position 158 of SEQ ID NO: 5; bb) Q at the position corresponding to position 159 of SEQ ID NO: 5; cc) D or W at the position corresponding to position 160 of SEQ ID NO: 5; dd) A or W at the position corresponding to position 162 of SEQ ID NO: 5; and ee) R at the position corresponding to position 165 of SEQ ID NO: 5. 29. The fusion protein of embodiment 27, wherein the deaminase comprises: a) N at the position corresponding to position 35 of SEQ ID NO: 5 and W at the position corresponding to position 162 of SEQ ID NO: 5; b) N at the position corresponding to position 35 of SEQ ID NO: 5 and Q at the position corresponding to position 46 of SEQ ID NO: 5; c) S at the position corresponding to position 81 of SEQ ID NO: 5 and R at the position corresponding to position 156 of SEQ ID NO: 5; d) Q at the position corresponding to position 46 of SEQ ID NO: 5 and R at the position corresponding to position 156 of SEQ ID NO: 5; e) R at the position corresponding to position 156 of SEQ ID NO: 5 and W at the position corresponding to position 162 of SEQ ID NO: 5; f) A at the position corresponding to position 68 of SEQ ID NO: 5 and S at the position corresponding to position 81 of SEQ ID NO: 5; g) NO:5 position corresponding to N at position 35, SEQ ID NO:5 position corresponding to S at position 81, and SEQ ID NO:5 position corresponding to W at position 162; h) N at position corresponding to SEQ ID NO:5 position corresponding to N at position 35, SEQ ID NO:5 position corresponding to Q at position 46, and SEQ ID NO:5 position corresponding to W at position 162; i) W at position corresponding to SEQ ID NO:5 position corresponding to R at position 156, and SEQ ID NO:5 position corresponding to W at position 162; j) N at position corresponding to SEQ ID NO:5 position corresponding to N at position 35, SEQ ID NO:5 position corresponding to R at position 156, and SEQ ID NO:5 position corresponding to W at position 162; k) N at position corresponding to SEQ ID NO:5 position corresponding to S at position 81, SEQ ID NO:5 position corresponding to Q at position 46, and SEQ ID NO:5 position corresponding to W at position 162; NO: 5, R at the position corresponding to position 156, and W at the position corresponding to position 162 of SEQ ID NO: 5; l) M at the position corresponding to position 68 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; m) Q at the position corresponding to position 46 of SEQ ID NO: 5, M at the position corresponding to position 68 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; n) M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and S at the position corresponding to position 162 of SEQ ID NO: 5; NO:5 position 108 corresponding to H, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; o) N corresponding to position 35, Q corresponding to position 46, SEQ ID NO:5 position 68 corresponding to M, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 155 corresponding to W, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; p) S corresponding to position 81, SEQ ID NO:5 position 155 corresponding to W; q) W corresponding to position 75, SEQ ID NO:5 position 76 corresponding to M, SEQ ID NO:5 position 87 corresponding to S; SEQ ID NO:5 position 88 corresponding to H, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 155 corresponding to W, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; p) S corresponding to position 81, SEQ ID NO:5 position 155 corresponding to W; q) W corresponding to position 75, SEQ ID NO:5 position 86 corresponding to M, SEQ ID NO:5 position 87 corresponding to S; NO:5 at the position corresponding to position 81; r) S at the position corresponding to position 81 of SEQ ID NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5; s) S at the position corresponding to position 81 of SEQ ID NO:5, and A at the position corresponding to position 145 of SEQ ID NO:5; t) W at the position corresponding to position 75 of SEQ ID NO:5, and W at the position corresponding to position 155 of SEQ ID NO:5; u) W at the position corresponding to position 155 of SEQ ID NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5; v) A at the position corresponding to position 145 of SEQ ID NO:5, and W at the position corresponding to position 155 of SEQ ID NO:5; w) W at the position corresponding to position 75 of SEQ ID NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5; x) W at the position corresponding to position 75 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; y) A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; z) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; aa) S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; bb) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; cc) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; dd) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; ee) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ff) W at the position corresponding to position 75 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; gg) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5 NO:5 position 145 A, and SEQ ID NO:5 position 155 W; hh) SEQ ID NO:5 position 145 A, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; ii) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 145 A, and SEQ ID NO:5 position 160 D; jj) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; kk) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 155 S, and SEQ ID NO:5 position 160 D; NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, and SEQ ID NO:5 position 155 corresponding to W; ll) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; mm) SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, and SEQ ID NO:5 position 160 corresponding to D; nn)  SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 155 corresponding to D, and SEQ ID NO:5 position 160 corresponding to D; NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; oo) SEQ ID NO: 5 position 75 corresponding to W, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; pp) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 105 corresponding to M; qq) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 121 corresponding to V; rr) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 145 corresponding to M; ss) L at the position corresponding to position 40 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; tt) L at the position corresponding to position 40 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; uu) M at the position corresponding to position 105 of SEQ ID NO: 5, and V at the position corresponding to position 121 of SEQ ID NO: 5; vv) M at the position corresponding to position 105 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; ww) M at the position corresponding to position 105 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; xx) M at the position corresponding to position 105 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; yy) NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 145 corresponding to M; zz) SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 159 corresponding to Q; aaa) SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 160 corresponding to W; bbb) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 159 corresponding to Q; ccc) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; ddd) SEQ ID NO:5 position 159 corresponding to Q, and SEQ ID NO:5 position 160 corresponding to W; eee) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; fff) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 159 corresponding to Q; ggg) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 81 corresponding to S; hhh) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; iii) SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; jjj) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 81 corresponding to S; NO:5 position 76 corresponding to G; kkk) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 117 corresponding to L; lll) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; mmm) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; nnn) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ooo) SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; NO:5 position corresponding to L at position 117; ppp) A at position corresponding to position 68 of SEQ ID NO:5, G at position corresponding to position 76 of SEQ ID NO:5, and L at position corresponding to position 117 of SEQ ID NO:5; qqq) A at position corresponding to position 68 of SEQ ID NO:5, G at position corresponding to position 76 of SEQ ID NO:5, S at position corresponding to position 81 of SEQ ID NO:5, and L at position corresponding to position 117 of SEQ ID NO:5; rrr) S at position corresponding to position 81 of SEQ ID NO:5, L at position corresponding to position 109 of SEQ ID NO:5, E at position corresponding to position 153 of SEQ ID NO:5, W at position corresponding to position 155 of SEQ ID NO:5, and D at position corresponding to position 160 of SEQ ID NO:5; sss) A at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, L at the position corresponding to position 117 of SEQ ID NO: 5, A at the position corresponding to position 121 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ttt) Q at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, I at the position corresponding to position 117 of SEQ ID NO: 5, Q at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; uuu) NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; vvv) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 160 corresponding to D; vvv) SEQ ID NO:5 position 22 corresponding to A, SEQ ID NO:5 position 68 corresponding to Y, SEQ ID NO:5 position 75 corresponding to G, SEQ ID NO:5 position 76 corresponding to S, SEQ ID NO:5 position 81 corresponding to H, SEQ ID NO:5 position 108 corresponding to L, SEQ ID NO:5 position 117 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; H at the position corresponding to position 122 of SEQ ID NO: 5, Y at the position corresponding to position 138 of SEQ ID NO: 5, L at the position corresponding to position 139 of SEQ ID NO: 5, A at the position corresponding to position 142 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, R at the position corresponding to position 153 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, D at the position corresponding to position 160 of SEQ ID NO: 5, and H at the position corresponding to position 162 of SEQ ID NO: 5; or www) S at the position corresponding to position 81 of SEQ ID NO: 5. 30. The fusion protein of embodiment 27 or 29, wherein the deaminase comprises: a) N at the position corresponding to position 35 of SEQ ID NO: 5 and Q at the position corresponding to position 46 of SEQ ID NO: 5; b) S at the position corresponding to position 81 of SEQ ID NO: 5 and R at the position corresponding to position 156 of SEQ ID NO: 5; c) Q at the position corresponding to position 46 of SEQ ID NO: 5 and R at the position corresponding to position 156 of SEQ ID NO: 5; d) N at the position corresponding to position 35 of SEQ ID NO: 5, Q at the position corresponding to position 46 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; e) W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; f) N at the position corresponding to position 35 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; g) N at the position corresponding to position 35 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; h) M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; i) N at the position corresponding to position 35, Q at the position corresponding to position 46 of SEQ ID NO: 5, and Q at the position corresponding to position 47 of SEQ ID NO: 5. M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; j) S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; k) W at the position corresponding to position 75 of SEQ ID NO: 5, and S at the position corresponding to position 81 of SEQ ID NO: 5; l) S at the position corresponding to position 81 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; m) S at the position corresponding to position 81 of SEQ ID NO: 5, and R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; A at the position corresponding to position 145 of SEQ ID NO: 5; n) W at the position corresponding to position 75 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; o) W at the position corresponding to position 75 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; p) A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; q) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; r) S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; s) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; t) L at the position corresponding to position 40 of SEQ ID NO: 5, and M at the position corresponding to position 105 of SEQ ID NO: 5; u) L at the position corresponding to position 40 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; v) L at the position corresponding to position 40 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; w) L at the position corresponding to position 40 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; x) M at the position corresponding to position 105 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; y) M at the position corresponding to position 105 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; z) M at the position corresponding to position 145 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; aa) M at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; bb) Q at the position corresponding to position 159 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; cc) S at the position corresponding to position 81 of SEQ ID NO: 5, M at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; dd) A at the position corresponding to position 68 of SEQ ID NO: 5, and Q at the position corresponding to position 160 of SEQ ID NO: 5; NO:5 position 81 corresponding to S; ee) SEQ ID NO:5 position 76 corresponding to S, and SEQ ID NO:5 position 81 corresponding to S; ff) SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; gg) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 76 corresponding to G; hh) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 117 corresponding to L; ii) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; jj) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; ID NO:5 position 81 corresponding to S; kk) SEQ ID NO:5 position 68 corresponding to S, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ll) SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; mm) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; nn) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; NO:5 position 117 corresponding to L; oo) A corresponding to position 68 of SEQ ID NO:5 and S corresponding to position 81 of SEQ ID NO:5; pp) S corresponding to position 81 of SEQ ID NO:5, L corresponding to position 109 of SEQ ID NO:5, E corresponding to position 153 of SEQ ID NO:5, W corresponding to position 155 of SEQ ID NO:5, and D corresponding to position 160 of SEQ ID NO:5; qq) A corresponding to position 75 of SEQ ID NO:5, S corresponding to position 81 of SEQ ID NO:5, L corresponding to position 117 of SEQ ID NO:5, A corresponding to position 121 of SEQ ID NO:5, A corresponding to position 145 of SEQ ID NO:5, and D corresponding to position 160 of SEQ ID NO:5; NO: 5, W at the position corresponding to position 155, and D at the position corresponding to position 160 of SEQ ID NO: 5; rr) Q at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, I at the position corresponding to position 117 of SEQ ID NO: 5, Q at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ss) Y at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, L at the position corresponding to position 117 of SEQ ID NO: 5, G at the position corresponding to position 121 of SEQ ID NO: 5, L at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; tt) SEQ ID NO: 5 position 22 corresponding to W, SEQ ID NO: 5 position 68 corresponding to A, SEQ ID NO: 5 position 75 corresponding to Y, SEQ ID NO: 5 position 76 corresponding to G, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 108 corresponding to H, SEQ ID NO: 5 position 117 corresponding to L, SEQ ID NO: 5 position 122 corresponding to H, SEQ ID NO: 5 position 138 corresponding to Y, SEQ ID NO: 5 position 139 corresponding to L, SEQ ID NO: 5 position 142 corresponding to A, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 150 corresponding to L, SEQ ID NO: 5 position 151 corresponding to L, SEQ ID NO: 5 position 152 corresponding to L, SEQ ID NO: 5 position 153 corresponding to L, SEQ ID NO: 5 position 154 corresponding to L, SEQ ID NO: 5 position 156 corresponding to L, SEQ ID NO: 5 position 157 corresponding to L, SEQ ID NO: 5 position 158 corresponding to L, SEQ ID NO: 5 position 159 corresponding to L, SEQ ID NO: 5 position 160 corresponding to L, SEQ ID NO: 5 position 161 corresponding to L, SEQ ID NO: 5 position 162 corresponding to L, SEQ ID NO: 5 position 163 corresponding to L, SEQ ID NO: 5 position 164 corresponding to L, SEQ ID NO: 5 position 165 corresponding to L, SEQ ID NO: 5 position 166 corresponding to L, SEQ ID NO: 5 position 167 corresponding to L, SEQ ID NO: 5 position 168 corresponding to L R at the position corresponding to position 153 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, D at the position corresponding to position 160 of SEQ ID NO: 5, and H at the position corresponding to position 162 of SEQ ID NO: 5; uu) S at the position corresponding to position 81 of SEQ ID NO: 5; or vv) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. 31. The fusion protein of any one of embodiments 27, 29 and 30, wherein the deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5, S at a position corresponding to position 81 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; b) W at a position corresponding to position 75 of SEQ ID NO: 5, and W at a position corresponding to position 155 of SEQ ID NO: 5; c) S at a position corresponding to position 81 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; d) S at a position corresponding to position 81 of SEQ ID NO: 5, A at a position corresponding to position 145 of SEQ ID NO: 5, and D at a position corresponding to position 162 of SEQ ID NO: 5; NO:5 position 155 corresponding to W; e) S corresponding to position 81 of SEQ ID NO:5, M corresponding to position 145 of SEQ ID NO:5, and W corresponding to position 160 of SEQ ID NO:5; f) G corresponding to position 76 of SEQ ID NO:5, and S corresponding to position 81 of SEQ ID NO:5; g) S corresponding to position 81 of SEQ ID NO:5, and L corresponding to position 117 of SEQ ID NO:5; h) A corresponding to position 68 of SEQ ID NO:5, and S corresponding to position 81 of SEQ ID NO:5; i) S corresponding to position 81 of SEQ ID NO:5, L corresponding to position 109 of SEQ ID NO:5, E corresponding to position 153 of SEQ ID NO:5, and L corresponding to position 117 of SEQ ID NO:5; NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; j) SEQ ID NO: 5 position 75 corresponding to A, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 117 corresponding to L, SEQ ID NO: 5 position 121 corresponding to A, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; k) SEQ ID NO: 5 position 75 corresponding to Q, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 117 corresponding to I, SEQ ID NO: 5 position 145 corresponding to Q, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; NO:5 position 160 corresponding to D; l) SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; m) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 110 corresponding to H, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; m) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 121 corresponding to NO:5 position 117 corresponding to L, SEQ ID NO:5 position 122 corresponding to H, SEQ ID NO:5 position 138 corresponding to Y, SEQ ID NO:5 position 139 corresponding to L, SEQ ID NO:5 position 142 corresponding to A, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 153 corresponding to R, SEQ ID NO:5 position 155 corresponding to W, SEQ ID NO:5 position 156 corresponding to R, SEQ ID NO:5 position 160 corresponding to D, and SEQ ID NO:5 position 162 corresponding to H; n) SEQ ID NO:5 position 81 corresponding to S; or o) SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 163 corresponding to H; W at the position corresponding to position 155 of NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5. 32. A fusion protein of any one of embodiments 27-31, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 300-414, 596-598, and 720-723. 33. A fusion protein of any one of embodiments 27-31, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 300-414, 596-598, and 720-723. 34. A fusion protein of any one of embodiments 27-31, wherein the deaminase comprises an amino acid sequence of any one of SEQ ID NOs: 300-414, 596-598, and 720-723. 35. The fusion protein of any one of embodiments 27-34, wherein the deaminase has improved deaminase activity when compared to SEQ ID NO: 5. 36. A fusion protein according to any one of embodiments 27-35, wherein the deaminase is adenine deaminase. 37. The fusion protein of any one of embodiments 27-36, wherein the DNA binding polypeptide is a large-range nuclease, a zinc finger fusion protein, or a TALEN. 38. A fusion protein according to any one of embodiments 27-36, wherein the DNA binding polypeptide is an RNA-guided DNA binding polypeptide. 39. The fusion protein of embodiment 38, wherein the RNA-guided DNA-binding polypeptide is an RNA-guided nuclease (RGN) polypeptide. 40. The fusion protein of embodiment 39, wherein the RGN is a type II CRISPR-Cas polypeptide. 41. The fusion protein of embodiment 39, wherein the RGN is a V-type CRISPR-Cas polypeptide. 42. The fusion protein of any one of embodiments 39-41, wherein the RGN is an RGN nickase. 43. The fusion protein of embodiment 39, wherein the RGN is Cas9, CasX, CasY, Cpfl, C2cl, C2c2, C2c3, GeoCas9, CjCas9, Casl2a, Casl2b, Casl2g, Casl2h, Casl2i, Casl3b, Casl3c, Casl3d, Casl4, Csn2, xCas9, SpCas9-NG, LbCasl2a, AsCasl2a, Cas9-KKH, circularly arranged Cas9, Argonaute (Ago), SmacCas9, or Spy-macCas9 domain. 44. The fusion protein of embodiment 39, wherein the RGN has an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699. 45. The fusion protein of embodiment 42, wherein the RGN nickase has an amino acid sequence as shown in any one of SEQ ID NOs: 49-52 and 698. 46. A fusion protein according to any one of embodiments 27-45, wherein the fusion protein further comprises at least one nuclear localization signal (NLS). 47. A fusion protein of any one of embodiments 27-31, wherein the fusion protein is selected from the group consisting of: a) a fusion protein comprising a deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 319 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; b) a fusion protein comprising a deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 375 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; c) a fusion protein comprising a deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 406 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; d) A fusion protein comprising a deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 596 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; e) A fusion protein comprising a deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; f) A fusion protein comprising a deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 303 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; g) A fusion protein comprising a deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 303 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; NO:366 having an amino acid sequence with at least 90% sequence identity, and fused to the N-terminus of an RGN comprising an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; and h) a fusion protein comprising a deaminase, wherein the deaminase comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO:720, and fused to the N-terminus of an RGN comprising an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49. 48. A fusion protein of any one of embodiments 27-31, wherein the fusion protein is selected from the group consisting of: a) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 319 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49; b) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 375 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49; c) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 406 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49; d) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 596 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49; e) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 597 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49; f) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 303 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49; g) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 303 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49; NO:366 having an amino acid sequence with at least 95% sequence identity, and fused to the N-terminus of an RGN comprising an amino acid sequence with at least 95% sequence identity to SEQ ID NO:49; and h) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO:720, and fused to the N-terminus of an RGN comprising an amino acid sequence with at least 95% sequence identity to SEQ ID NO:49. 49. A fusion protein of any one of embodiments 27-31, wherein the fusion protein is selected from the group consisting of: a) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence shown in SEQ ID NO: 319 and is fused to the N-terminus of an RGN comprising the amino acid sequence shown in SEQ ID NO: 49; b) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence shown in SEQ ID NO: 375 and is fused to the N-terminus of an RGN comprising the amino acid sequence shown in SEQ ID NO: 49; c) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence shown in SEQ ID NO: 406 and is fused to the N-terminus of an RGN comprising the amino acid sequence shown in SEQ ID NO: 49; d) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence shown in SEQ ID NO: 596 and is fused to the N-terminus of an RGN comprising the amino acid sequence shown in SEQ ID NO: 597; NO:49; e) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO:597 and is fused to the N-terminus of the RGN comprising the amino acid sequence as shown in SEQ ID NO:49; f) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO:303 and is fused to the N-terminus of the RGN comprising the amino acid sequence as shown in SEQ ID NO:49; g) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO:366 and is fused to the N-terminus of the RGN comprising the amino acid sequence as shown in SEQ ID NO:49; and h) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO:720 and is fused to the N-terminus of the RGN comprising the amino acid sequence as shown in SEQ ID NO:49. 50. A fusion protein according to any one of embodiments 47-49, wherein the fusion protein has a sequence as shown in any one of SEQ ID NOs: 577, 578, 582, 584, 588, 593, 594, 604, 605, 616, and 729. 51. A ribonucleoprotein (RNP) complex, comprising a fusion protein of any one of embodiments 38-50 and a guide RNA bound to the fusion protein. 52. A nucleic acid molecule, comprising a polynucleotide encoding a fusion protein, the fusion protein comprising a DNA binding polypeptide and a deaminase, wherein the deaminase comprises at least one of the following amino acid residues: a) C at a position corresponding to position 2 of SEQ ID NO: 5; b) F or C at a position corresponding to position 22 of SEQ ID NO: 5; c) Q at a position corresponding to position 23 of SEQ ID NO: 5; d) N at a position corresponding to position 35 of SEQ ID NO: 5; e) L at a position corresponding to position 40 of SEQ ID NO: 5; f) Q at a position corresponding to position 46 of SEQ ID NO: 5; g) A or M at a position corresponding to position 68 of SEQ ID NO: 5; h) H at a position corresponding to position 72 of SEQ ID NO: 5; i) W, A, Q, Y, or D at a position corresponding to position 75 of SEQ ID NO: 5; j) NO:5 position 76 corresponding to G; k) SEQ ID NO:5 position 81 corresponding to S; l) SEQ ID NO:5 position 105 corresponding to M; m) SEQ ID NO:5 position 108 corresponding to H; n) SEQ ID NO:5 position 109 corresponding to L; o) SEQ ID NO:5 position 117 corresponding to I or L; p) SEQ ID NO:5 position 120 corresponding to F; q) SEQ ID NO:5 position 121 corresponding to E, T, A, G, or V; r) SEQ ID NO:5 position 122 corresponding to I or H; s) SEQ ID NO:5 position 125 corresponding to K; t) SEQ ID NO:5 position 126 corresponding to A; u) SEQ ID NO:5 position 127 corresponding to F; NO: 5 at the position corresponding to position 135; v) V at the position corresponding to position 137 of SEQ ID NO: 5; w) Y at the position corresponding to position 138 of SEQ ID NO: 5; x) L at the position corresponding to position 139 of SEQ ID NO: 5; y) K or A at the position corresponding to position 142 of SEQ ID NO: 5; z) A, Q, L, or M at the position corresponding to position 145 of SEQ ID NO: 5; aa) K at the position corresponding to position 148 of SEQ ID NO: 5; bb) Q at the position corresponding to position 151 of SEQ ID NO: 5; cc) E or R at the position corresponding to position 153 of SEQ ID NO: 5; dd) W at the position corresponding to position 155 of SEQ ID NO: 5; ee) R or V at the position corresponding to position 156 of SEQ ID NO: 5; ff) F at the position corresponding to position 157 of SEQ ID NO: 5; gg) R at the position corresponding to position 158 of SEQ ID NO: 5; hh) Q at the position corresponding to position 159 of SEQ ID NO: 5; ii) D or W at the position corresponding to position 160 of SEQ ID NO: 5; jj) W, H, V, or A at the position corresponding to position 162 of SEQ ID NO: 5; kk) R at the position corresponding to position 165 of SEQ ID NO: 5; and ll) H at the position corresponding to position 166 of SEQ ID NO: 5. 53. The nucleic acid molecule of embodiment 52, wherein the deaminase comprises at least one of the following amino acid residues: a) C at the position corresponding to position 2 of SEQ ID NO: 5; b) F or C at the position corresponding to position 22 of SEQ ID NO: 5; c) Q at the position corresponding to position 23 of SEQ ID NO: 5; d) N at the position corresponding to position 35 of SEQ ID NO: 5; e) L at the position corresponding to position 40 of SEQ ID NO: 5; f) A at the position corresponding to position 68 of SEQ ID NO: 5; g) W, A, Q, or Y at the position corresponding to position 75 of SEQ ID NO: 5; h) G at the position corresponding to position 76 of SEQ ID NO: 5; i) S at the position corresponding to position 81 of SEQ ID NO: 5; j) M at the position corresponding to position 105 of SEQ ID NO: 5; k) NO:5 position 108 corresponding to H; l) SEQ ID NO:5 position 109 corresponding to L; m) SEQ ID NO:5 position 117 corresponding to I or L; n) SEQ ID NO:5 position 121 corresponding to A or G; o) SEQ ID NO:5 position 122 corresponding to H; p) SEQ ID NO:5 position 126 corresponding to A; q) SEQ ID NO:5 position 135 corresponding to H; r) SEQ ID NO:5 position 137 corresponding to V; s) SEQ ID NO:5 position 138 corresponding to Y; t) SEQ ID NO:5 position 139 corresponding to L; u) SEQ ID NO:5 position 142 corresponding to K or A; v) SEQ ID NO:5 position 143 corresponding to V; s) SEQ ID NO:5 position 144 corresponding to Y; t) SEQ ID NO:5 position 145 corresponding to L; u) SEQ ID NO:5 position 146 corresponding to K or A; v) SEQ ID NO:5 position 147 corresponding to V; A, Q, L, or M at the position corresponding to position 145 of SEQ ID NO: 5; w) E or R at the position corresponding to position 153 of SEQ ID NO: 5; x) W at the position corresponding to position 155 of SEQ ID NO: 5; y) R at the position corresponding to position 156 of SEQ ID NO: 5; z) F at the position corresponding to position 157 of SEQ ID NO: 5; aa) R at the position corresponding to position 158 of SEQ ID NO: 5; bb) Q at the position corresponding to position 159 of SEQ ID NO: 5; cc) D or W at the position corresponding to position 160 of SEQ ID NO: 5; dd) A or W at the position corresponding to position 162 of SEQ ID NO: 5; and ee) R at the position corresponding to position 165 of SEQ ID NO: 5. 54. The nucleic acid molecule of embodiment 52, wherein the deaminase comprises: a) N at the position corresponding to position 35 of SEQ ID NO: 5 and W at the position corresponding to position 162 of SEQ ID NO: 5; b) N at the position corresponding to position 35 of SEQ ID NO: 5 and Q at the position corresponding to position 46 of SEQ ID NO: 5; c) S at the position corresponding to position 81 of SEQ ID NO: 5 and R at the position corresponding to position 156 of SEQ ID NO: 5; d) Q at the position corresponding to position 46 of SEQ ID NO: 5 and R at the position corresponding to position 156 of SEQ ID NO: 5; e) R at the position corresponding to position 156 of SEQ ID NO: 5 and W at the position corresponding to position 162 of SEQ ID NO: 5; f) A at the position corresponding to position 68 of SEQ ID NO: 5 and S at the position corresponding to position 81 of SEQ ID NO: 5; g) NO:5 position corresponding to N at position 35, SEQ ID NO:5 position corresponding to S at position 81, and SEQ ID NO:5 position corresponding to W at position 162; h) N at position corresponding to SEQ ID NO:5 position corresponding to N at position 35, SEQ ID NO:5 position corresponding to Q at position 46, and SEQ ID NO:5 position corresponding to W at position 162; i) W at position corresponding to SEQ ID NO:5 position corresponding to R at position 156, and SEQ ID NO:5 position corresponding to W at position 162; j) N at position corresponding to SEQ ID NO:5 position corresponding to N at position 35, SEQ ID NO:5 position corresponding to R at position 156, and SEQ ID NO:5 position corresponding to W at position 162; k) N at position corresponding to SEQ ID NO:5 position corresponding to S at position 81, SEQ ID NO:5 position corresponding to Q at position 46, and SEQ ID NO:5 position corresponding to W at position 162; NO: 5, R at the position corresponding to position 156, and W at the position corresponding to position 162 of SEQ ID NO: 5; l) M at the position corresponding to position 68 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; m) Q at the position corresponding to position 46 of SEQ ID NO: 5, M at the position corresponding to position 68 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; n) M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and S at the position corresponding to position 162 of SEQ ID NO: 5; NO:5 position 108 corresponding to H, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; o) N corresponding to position 35, Q corresponding to position 46, SEQ ID NO:5 position 68 corresponding to M, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 155 corresponding to W, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; p) S corresponding to position 81, SEQ ID NO:5 position 155 corresponding to W; q) W corresponding to position 75, SEQ ID NO:5 position 76 corresponding to M, SEQ ID NO:5 position 87 corresponding to S; SEQ ID NO:5 position 88 corresponding to H, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 155 corresponding to W, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; p) S corresponding to position 81, SEQ ID NO:5 position 155 corresponding to W; q) W corresponding to position 75, SEQ ID NO:5 position 86 corresponding to M, SEQ ID NO:5 position 87 corresponding to S; NO:5 at the position corresponding to position 81; r) S at the position corresponding to position 81 of SEQ ID NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5; s) S at the position corresponding to position 81 of SEQ ID NO:5, and A at the position corresponding to position 145 of SEQ ID NO:5; t) W at the position corresponding to position 75 of SEQ ID NO:5, and W at the position corresponding to position 155 of SEQ ID NO:5; u) W at the position corresponding to position 155 of SEQ ID NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5; v) A at the position corresponding to position 145 of SEQ ID NO:5, and W at the position corresponding to position 155 of SEQ ID NO:5; w) W at the position corresponding to position 75 of SEQ ID NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5; x) W at the position corresponding to position 75 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; y) A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; z) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; aa) S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; bb) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; cc) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; dd) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; ee) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ff) W at the position corresponding to position 75 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; gg) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5 NO:5 position 145 A, and SEQ ID NO:5 position 155 W; hh) SEQ ID NO:5 position 145 A, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; ii) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 145 A, and SEQ ID NO:5 position 160 D; jj) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; kk) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 155 S, and SEQ ID NO:5 position 160 D; NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, and SEQ ID NO:5 position 155 corresponding to W; ll) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; mm) SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, and SEQ ID NO:5 position 160 corresponding to D; nn)  SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 155 corresponding to D, and SEQ ID NO:5 position 160 corresponding to D; NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; oo) SEQ ID NO: 5 position 75 corresponding to W, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; pp) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 105 corresponding to M; qq) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 121 corresponding to V; rr) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 145 corresponding to M; ss) L at the position corresponding to position 40 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; tt) L at the position corresponding to position 40 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; uu) M at the position corresponding to position 105 of SEQ ID NO: 5, and V at the position corresponding to position 121 of SEQ ID NO: 5; vv) M at the position corresponding to position 105 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; ww) M at the position corresponding to position 105 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; xx) M at the position corresponding to position 105 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; yy) NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 145 corresponding to M; zz) SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 159 corresponding to Q; aaa) SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 160 corresponding to W; bbb) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 159 corresponding to Q; ccc) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; ddd) SEQ ID NO:5 position 159 corresponding to Q, and SEQ ID NO:5 position 160 corresponding to W; eee) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; fff) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 159 corresponding to Q; ggg) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 81 corresponding to S; hhh) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; iii) SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; jjj) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 81 corresponding to S; NO:5 position 76 corresponding to G; kkk) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 117 corresponding to L; lll) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; mmm) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; nnn) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ooo) SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; NO:5 position corresponding to L at position 117; ppp) A at position corresponding to position 68 of SEQ ID NO:5, G at position corresponding to position 76 of SEQ ID NO:5, and L at position corresponding to position 117 of SEQ ID NO:5; qqq) A at position corresponding to position 68 of SEQ ID NO:5, G at position corresponding to position 76 of SEQ ID NO:5, S at position corresponding to position 81 of SEQ ID NO:5, and L at position corresponding to position 117 of SEQ ID NO:5; rrr) S at position corresponding to position 81 of SEQ ID NO:5, L at position corresponding to position 109 of SEQ ID NO:5, E at position corresponding to position 153 of SEQ ID NO:5, W at position corresponding to position 155 of SEQ ID NO:5, and D at position corresponding to position 160 of SEQ ID NO:5; sss) A at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, L at the position corresponding to position 117 of SEQ ID NO: 5, A at the position corresponding to position 121 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ttt) Q at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, I at the position corresponding to position 117 of SEQ ID NO: 5, Q at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; uuu) NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; vvv) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 160 corresponding to D; vvv) SEQ ID NO:5 position 22 corresponding to A, SEQ ID NO:5 position 68 corresponding to Y, SEQ ID NO:5 position 75 corresponding to G, SEQ ID NO:5 position 76 corresponding to S, SEQ ID NO:5 position 81 corresponding to H, SEQ ID NO:5 position 108 corresponding to L, SEQ ID NO:5 position 117 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; H at the position corresponding to position 122 of SEQ ID NO: 5, Y at the position corresponding to position 138 of SEQ ID NO: 5, L at the position corresponding to position 139 of SEQ ID NO: 5, A at the position corresponding to position 142 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, R at the position corresponding to position 153 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, D at the position corresponding to position 160 of SEQ ID NO: 5, and H at the position corresponding to position 162 of SEQ ID NO: 5; or www) S at the position corresponding to position 81 of SEQ ID NO: 5. 55. The nucleic acid molecule of embodiment 52 or 54, wherein the deaminase comprises: a) N at the position corresponding to position 35 of SEQ ID NO: 5 and Q at the position corresponding to position 46 of SEQ ID NO: 5; b) S at the position corresponding to position 81 of SEQ ID NO: 5 and R at the position corresponding to position 156 of SEQ ID NO: 5; c) Q at the position corresponding to position 46 of SEQ ID NO: 5 and R at the position corresponding to position 156 of SEQ ID NO: 5; d) N at the position corresponding to position 35 of SEQ ID NO: 5, Q at the position corresponding to position 46 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; e) W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; f) N at the position corresponding to position 35 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; g) N at the position corresponding to position 35 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; h) M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; i) N at the position corresponding to position 35, Q at the position corresponding to position 46 of SEQ ID NO: 5, Q at the position corresponding to position 57 of SEQ ID NO: 5, and Q at the position corresponding to position 66 of SEQ ID NO: 5. NO: 5 position 68 corresponding to M, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 108 corresponding to H, SEQ ID NO: 5 position 155 corresponding to W, SEQ ID NO: 5 position 156 corresponding to R, and SEQ ID NO: 5 position 162 corresponding to W; j) SEQ ID NO: 5 position 81 corresponding to S, and SEQ ID NO: 5 position 155 corresponding to W; k) SEQ ID NO: 5 position 75 corresponding to W, and SEQ ID NO: 5 position 81 corresponding to S; l) SEQ ID NO: 5 position 81 corresponding to S, and SEQ ID NO: 5 position 160 corresponding to D; m) SEQ ID NO: 5 position 81 corresponding to S, and SEQ ID NO: 5 position 162 corresponding to R; A at the position corresponding to position 145 of SEQ ID NO: 5; n) W at the position corresponding to position 75 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; o) W at the position corresponding to position 75 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; p) A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; q) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; r) S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; s) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; t) L at the position corresponding to position 40 of SEQ ID NO: 5, and M at the position corresponding to position 105 of SEQ ID NO: 5; u) L at the position corresponding to position 40 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; v) L at the position corresponding to position 40 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; w) L at the position corresponding to position 40 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; x) M at the position corresponding to position 105 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; y) M at the position corresponding to position 105 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; z) M at the position corresponding to position 145 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; aa) M at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; bb) Q at the position corresponding to position 159 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; cc) S at the position corresponding to position 81 of SEQ ID NO: 5, M at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; dd) A at the position corresponding to position 68 of SEQ ID NO: 5, and Q at the position corresponding to position 160 of SEQ ID NO: 5; NO:5 position 81 corresponding to S; ee) SEQ ID NO:5 position 76 corresponding to S, and SEQ ID NO:5 position 81 corresponding to S; ff) SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; gg) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 76 corresponding to G; hh) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 117 corresponding to L; ii) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; jj) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; ID NO:5 position 81 corresponding to S; kk) SEQ ID NO:5 position 68 corresponding to S, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ll) SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; mm) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; nn) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; NO:5 position 117 corresponding to L; oo) SEQ ID NO:5 position 68 corresponding to L and SEQ ID NO:5 position 81 corresponding to S; pp) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 109 corresponding to L, SEQ ID NO:5 position 153 corresponding to E, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; qq) SEQ ID NO:5 position 75 corresponding to A, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to A, SEQ ID NO:5 position 145 corresponding to E, SEQ ID NO:5 position 156 corresponding to W, and SEQ ID NO:5 position 167 corresponding to D; qq) SEQ ID NO:5 position 75 corresponding to A, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to A, SEQ ID NO:5 position 146 corresponding to E, SEQ ID NO:5 position 157 corresponding to W, and SEQ ID NO:5 position 168 corresponding to D; NO: 5, W at the position corresponding to position 155, and D at the position corresponding to position 160 of SEQ ID NO: 5; rr) Q at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, I at the position corresponding to position 117 of SEQ ID NO: 5, Q at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ss) Y at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, L at the position corresponding to position 117 of SEQ ID NO: 5, G at the position corresponding to position 121 of SEQ ID NO: 5, L at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; tt) SEQ ID NO: 5 position 22 corresponding to W, SEQ ID NO: 5 position 68 corresponding to A, SEQ ID NO: 5 position 75 corresponding to Y, SEQ ID NO: 5 position 76 corresponding to G, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 108 corresponding to H, SEQ ID NO: 5 position 117 corresponding to L, SEQ ID NO: 5 position 122 corresponding to H, SEQ ID NO: 5 position 138 corresponding to Y, SEQ ID NO: 5 position 139 corresponding to L, SEQ ID NO: 5 position 142 corresponding to A, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 150 corresponding to L, SEQ ID NO: 5 position 151 corresponding to L, SEQ ID NO: 5 position 152 corresponding to L, SEQ ID NO: 5 position 153 corresponding to L, SEQ ID NO: 5 position 154 corresponding to L, SEQ ID NO: 5 position 156 corresponding to L, SEQ ID NO: 5 position 157 corresponding to L, SEQ ID NO: 5 position 158 corresponding to L, SEQ ID NO: 5 position 159 corresponding to L, SEQ ID NO: 5 position 160 corresponding to L, SEQ ID NO: 5 position 161 corresponding to L, SEQ ID NO: 5 position 162 corresponding to L, SEQ ID NO: 5 position 163 corresponding to L, SEQ ID NO: 5 position 164 corresponding to L, SEQ ID NO: 5 position 165 corresponding to L, SEQ ID NO: 5 position 166 corresponding to L, SEQ ID NO: 5 position 167 corresponding to L, SEQ ID NO: 5 position 168 corresponding to L R at the position corresponding to position 153 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, D at the position corresponding to position 160 of SEQ ID NO: 5, and H at the position corresponding to position 162 of SEQ ID NO: 5; uu) S at the position corresponding to position 81 of SEQ ID NO: 5; or vv) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. 56. The nucleic acid molecule of any one of embodiments 52, 54 and 55, wherein the deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5, S at a position corresponding to position 81 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; b) W at a position corresponding to position 75 of SEQ ID NO: 5, and W at a position corresponding to position 155 of SEQ ID NO: 5; c) S at a position corresponding to position 81 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; d) S at a position corresponding to position 81 of SEQ ID NO: 5, A at a position corresponding to position 145 of SEQ ID NO: 5, and D at a position corresponding to position 162 of SEQ ID NO: 5; NO:5 position 155 corresponding to W; e) S corresponding to position 81 of SEQ ID NO:5, M corresponding to position 145 of SEQ ID NO:5, and W corresponding to position 160 of SEQ ID NO:5; f) G corresponding to position 76 of SEQ ID NO:5, and S corresponding to position 81 of SEQ ID NO:5; g) S corresponding to position 81 of SEQ ID NO:5, and L corresponding to position 117 of SEQ ID NO:5; h) A corresponding to position 68 of SEQ ID NO:5, and S corresponding to position 81 of SEQ ID NO:5; i) S corresponding to position 81 of SEQ ID NO:5, L corresponding to position 109 of SEQ ID NO:5, E corresponding to position 153 of SEQ ID NO:5, and L corresponding to position 117 of SEQ ID NO:5; NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; j) SEQ ID NO: 5 position 75 corresponding to A, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 117 corresponding to L, SEQ ID NO: 5 position 121 corresponding to A, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; k) SEQ ID NO: 5 position 75 corresponding to Q, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 117 corresponding to I, SEQ ID NO: 5 position 145 corresponding to Q, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; NO:5 position 160 corresponding to D; l) SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; m) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 110 corresponding to H, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; m) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; NO:5 position 117 corresponding to L, SEQ ID NO:5 position 122 corresponding to H, SEQ ID NO:5 position 138 corresponding to Y, SEQ ID NO:5 position 139 corresponding to L, SEQ ID NO:5 position 142 corresponding to A, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 153 corresponding to R, SEQ ID NO:5 position 155 corresponding to W, SEQ ID NO:5 position 156 corresponding to R, SEQ ID NO:5 position 160 corresponding to D, and SEQ ID NO:5 position 162 corresponding to H; n) SEQ ID NO:5 position 81 corresponding to S; or o) SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 163 corresponding to H; W at the position corresponding to position 155 of NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. 57. A nucleic acid molecule according to any one of embodiments 52-56, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 300-414, 596-598, and 720-723. 58. A nucleic acid molecule of any one of embodiments 52-56, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 300-414, 596-598, and 720-723. 59. A nucleic acid molecule of any one of embodiments 52-56, wherein the deaminase comprises an amino acid sequence of any one of SEQ ID NOs: 300-414, 596-598, and 720-723. 60. The nucleic acid molecule of any one of embodiments 52-59, wherein, when compared to SEQ ID NO: 5, it has improved deaminase activity. 61. A nucleic acid molecule according to any one of embodiments 52-60, wherein the deaminase is adenine deaminase. 62. The nucleic acid molecule of any one of embodiments 52-61, wherein the DNA binding polypeptide is a meganuclease, a zinc finger fusion protein, or a TALEN. 63. A nucleic acid molecule according to any one of embodiments 52-61, wherein the DNA binding polypeptide is an RNA-guided DNA binding polypeptide. 64. The nucleic acid molecule of embodiment 63, wherein the RNA-guided DNA-binding polypeptide is an RNA-guided nuclease (RGN) polypeptide. 65. The nucleic acid molecule of embodiment 64, wherein the RGN is a type II CRISPR-Cas polypeptide. 66. The nucleic acid molecule of embodiment 64, wherein the RGN is a V-type CRISPR-Cas polypeptide. 67. The nucleic acid molecule of any one of embodiments 64-66, wherein the RGN is an RGN nickase. 68. Nucleic acid molecule 64 of the embodiment, wherein the RGN polypeptide is Cas9, CasX, CasY, Cpfl, C2cl, C2c2, C2c3, GeoCas9, CjCas9, Casl2a, Casl2b, Casl2g, Casl2h, Casl2i, Casl3b, Casl3c, Casl3d, Casl4, Csn2, xCas9, SpCas9-NG, LbCasl2a, AsCasl2a, Cas9-KKH, circularly arranged Cas9, Argonaute (Ago), SmacCas9, or Spy-macCas9 domain. 69. The nucleic acid molecule of embodiment 64, wherein the RGN has an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699. 70. The nucleic acid molecule of embodiment 67, wherein the RGN nickase has an amino acid sequence as shown in any one of SEQ ID NOs: 49-52 and 698. 71. A nucleic acid molecule according to any one of embodiments 52-70, wherein the fusion protein further comprises at least one nuclear localization signal (NLS). 72. The nucleic acid molecule 52-56 of any of the embodiments, wherein the fusion protein is selected from the group consisting of: a) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 319 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; b) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 375 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; c) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 406 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; d) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 596 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; e) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; f) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 303 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; g) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 303 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; NO:366 has an amino acid sequence with at least 90% sequence identity, and is fused to the N-terminus of an RGN comprising an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; and h) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO:720, and is fused to the N-terminus of an RGN comprising an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49. 73. The nucleic acid molecule of any one of embodiments 52-56, wherein the fusion protein is selected from the group consisting of: a) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 319 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49; b) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 375 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49; c) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 406 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49; d) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 596 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49; e) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 597 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49; f) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 303 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49; g) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 303 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49; NO:366 has an amino acid sequence with at least 95% sequence identity, and is fused to the N-terminus of an RGN comprising an amino acid sequence with at least 95% sequence identity to SEQ ID NO:49; and h) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO:720, and is fused to the N-terminus of an RGN comprising an amino acid sequence with at least 95% sequence identity to SEQ ID NO:49. 74. The nucleic acid molecule of any one of embodiments 52-56, wherein the fusion protein is selected from the group consisting of: a) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence shown in SEQ ID NO: 319 and is fused to the N-terminus of the RGN comprising the amino acid sequence shown in SEQ ID NO: 49; b) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence shown in SEQ ID NO: 375 and is fused to the N-terminus of the RGN comprising the amino acid sequence shown in SEQ ID NO: 49; c) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence shown in SEQ ID NO: 406 and is fused to the N-terminus of the RGN comprising the amino acid sequence shown in SEQ ID NO: 49; d) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence shown in SEQ ID NO: 596 and is fused to the N-terminus of the RGN comprising the amino acid sequence shown in SEQ ID NO: NO:49; e) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO:597 and is fused to the N-terminus of the RGN comprising the amino acid sequence as shown in SEQ ID NO:49; f) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO:303 and is fused to the N-terminus of the RGN comprising the amino acid sequence as shown in SEQ ID NO:49; g) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO:366 and is fused to the N-terminus of the RGN comprising the amino acid sequence as shown in SEQ ID NO:49; and h) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO:720 and is fused to the N-terminus of the RGN comprising the amino acid sequence as shown in SEQ ID NO:49. 75. A nucleic acid molecule according to any one of embodiments 72-74, wherein the fusion protein has a sequence as shown in any one of SEQ ID NOs: 577, 578, 582, 584, 588, 593, 594, 604, 605, 616, and 729. 76. A nucleic acid molecule according to any one of embodiments 52-75, wherein the fusion protein is codon-optimized for expression in eukaryotic cells. 77. A nucleic acid molecule according to any one of embodiments 52-75, wherein the fusion protein is codon-optimized for expression in prokaryotic cells. 78. A vector comprising a nucleic acid molecule of any one of embodiments 52-77. 79. A vector comprising a nucleic acid molecule of any one of embodiments 64-75, further comprising at least one nucleotide sequence encoding a guide RNA capable of hybridizing with a non-target strand of a target sequence. 80. The vector of embodiment 79, wherein the guide RNA is a single guide RNA (sgRNA). 81. The vector of embodiment 79, wherein the guide RNA is a dual guide RNA (sgRNA). 82. A cell comprising a fusion protein of any one of embodiments 27-50 or an RNP complex of embodiment 51. 83. A cell comprising a fusion protein of any one of embodiments 27-50, wherein the cell further comprises a guide RNA. 84. A cell comprising a nucleic acid molecule of any one of embodiments 52-77. 85. A cell comprising a vector of any one of embodiments 78-81. 86. A cell according to any one of embodiments 82-85, wherein the cell is a prokaryotic cell. 87. A cell according to any one of embodiments 82-85, wherein the cell is a eukaryotic cell. 88. The cell of embodiment 87, wherein the eukaryotic cell is a mammalian cell. 89. The cell of embodiment 88, wherein the mammalian cell is a human cell. 90. The cell of embodiment 89, wherein the human cell is an immune cell. 91. The cells of embodiment 90, wherein the immune cells are stem cells. 92. The cell of embodiment 91, wherein the stem cells are induced multipotent stem cells. 93. The cell of embodiment 87, wherein the eukaryotic cell is an insect or bird cell. 94. The cell of embodiment 87, wherein the eukaryotic cell is a fungal cell. 95. The cell of embodiment 87, wherein the eukaryotic cell is a plant cell. 96. A plant comprising the cell of embodiment 95. 97. A seed comprising the cell of implementation method 95. 98. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and a fusion protein of any one of embodiments 27-50, an RNP complex of embodiment 51, a nucleic acid molecule of any one of embodiments 52-77, a vector of any one of embodiments 78-81, or a cell of any one of embodiments 88-92. 99. A method for making a fusion protein, comprising culturing cells of any one of embodiments 82-95 under conditions in which the fusion protein is expressed. 100. A method for producing a fusion protein, comprising introducing a nucleic acid molecule of any one of embodiments 52-77 or a vector of any one of embodiments 78-81 into a cell, and culturing the cell under conditions in which the fusion protein is expressed. 101. The method of embodiment 99 or 100 further comprises purifying the fusion protein. 102. A method for making an RGN fusion ribonucleoprotein complex, comprising introducing a nucleic acid molecule of any one of embodiments 63-70 and 72-75 and a nucleic acid molecule comprising an expression cassette encoding a guide RNA, or a vector of any one of embodiments 79-81 into a cell, and culturing the cell under conditions in which the fusion protein and the gRNA are expressed and form an RGN fusion ribonucleoprotein complex. 103. The method of embodiment 102 further comprises purifying the RGN fusion ribonucleoprotein complex. 104. A system for modifying a target DNA molecule including a target DNA sequence, the system comprising: a) a fusion protein comprising an RNA-guided nuclease polypeptide and a deaminase, wherein the deaminase has an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 5, or a nucleotide sequence encoding the fusion protein, wherein the deaminase comprises at least one of the following amino acid residues: i) C at a position corresponding to position 2 of SEQ ID NO: 5; ii) F or C at a position corresponding to position 22 of SEQ ID NO: 5; iii) Q at a position corresponding to position 23 of SEQ ID NO: 5; iv) N at a position corresponding to position 35 of SEQ ID NO: 5; v) L at a position corresponding to position 40 of SEQ ID NO: 5; vi) Q at a position corresponding to position 46 of SEQ ID NO: 5; vii) NO:5 position corresponding to A or M; viii) SEQ ID NO:5 position corresponding to H; ix) SEQ ID NO:5 position corresponding to W, A, Q, Y, or D; x) SEQ ID NO:5 position corresponding to G; xi) SEQ ID NO:5 position corresponding to S; xii) SEQ ID NO:5 position corresponding to M; xiii) SEQ ID NO:5 position corresponding to H; xiv) SEQ ID NO:5 position corresponding to L; xv) SEQ ID NO:5 position corresponding to I or L; xvi) SEQ ID NO:5 position corresponding to F; xvii) SEQ ID NO:5 position corresponding to M; xiii) SEQ ID NO:5 position corresponding to H; xiv) SEQ ID NO:5 position corresponding to L; xv) SEQ ID NO:5 position corresponding to I or L; xvii) SEQ ID NO:5 position corresponding to F; xvii) SEQ ID NO:5 position corresponding to NO:5 position 121 corresponding to E, T, A, G, or V; xviii) SEQ ID NO:5 position 122 corresponding to I or H; xix) SEQ ID NO:5 position 125 corresponding to K; xx) SEQ ID NO:5 position 126 corresponding to A; xxi) SEQ ID NO:5 position 135 corresponding to H; xxii) SEQ ID NO:5 position 137 corresponding to V; xxiii) SEQ ID NO:5 position 138 corresponding to Y; xxiv) SEQ ID NO:5 position 139 corresponding to L; xxv) SEQ ID NO:5 position 142 corresponding to K or A; xxvi) SEQ ID NO:5 position 145 corresponding to A, Q, L, or M; xxvii) SEQ ID NO:5 position 146 corresponding to A, Q, L, or M; NO:5 position 148 corresponding to K; xxviii) SEQ ID NO:5 position 151 corresponding to Q; xxix) SEQ ID NO:5 position 153 corresponding to E or R; xxx) SEQ ID NO:5 position 155 corresponding to W; xxxi) SEQ ID NO:5 position 156 corresponding to R or V; xxxii) SEQ ID NO:5 position 157 corresponding to F; xxxiii) SEQ ID NO:5 position 158 corresponding to R; xxxiv) SEQ ID NO:5 position 159 corresponding to Q; xxxv) SEQ ID NO:5 position 160 corresponding to D or W; xxxvi) SEQ ID NO:5 position 162 corresponding to W, H, V, or A; xxxvii) SEQ ID NO:5 position 163 corresponding to W, H, V, or A; NO:5 position 165 corresponding to R; and xxxviii) SEQ ID NO:5 position 166 corresponding to H; and b) one or more guide RNAs capable of hybridizing with the non-target strand of the target DNA sequence, or one or more nucleotide sequences encoding the one or more guide RNAs; and wherein the one or more guide RNAs are capable of forming a complex with the fusion protein to guide the fusion protein to bind to the target DNA sequence and modify the target DNA sequence. 105. The system of embodiment 104, wherein the deaminase comprises at least one of the following amino acid residues: a) C at a position corresponding to position 2 of SEQ ID NO: 5; b) F or C at a position corresponding to position 22 of SEQ ID NO: 5; c) Q at a position corresponding to position 23 of SEQ ID NO: 5; d) N at a position corresponding to position 35 of SEQ ID NO: 5; e) L at a position corresponding to position 40 of SEQ ID NO: 5; f) A at a position corresponding to position 68 of SEQ ID NO: 5; g) W, A, Q, or Y at a position corresponding to position 75 of SEQ ID NO: 5; h) G at a position corresponding to position 76 of SEQ ID NO: 5; i) S at a position corresponding to position 81 of SEQ ID NO: 5; j) M at a position corresponding to position 105 of SEQ ID NO: 5; k) ID NO: 5 position 108 corresponding to H; l) SEQ ID NO: 5 position 109 corresponding to L; m) SEQ ID NO: 5 position 117 corresponding to I or L; n) SEQ ID NO: 5 position 121 corresponding to A or G; o) SEQ ID NO: 5 position 122 corresponding to H; p) SEQ ID NO: 5 position 126 corresponding to A; q) SEQ ID NO: 5 position 135 corresponding to H; r) SEQ ID NO: 5 position 137 corresponding to V; s) SEQ ID NO: 5 position 138 corresponding to Y; t) SEQ ID NO: 5 position 139 corresponding to L; u) SEQ ID NO: 5 position 142 corresponding to K or A; v) SEQ ID NO: A, Q, L, or M at the position corresponding to position 145 of SEQ ID NO: 5; w) E or R at the position corresponding to position 153 of SEQ ID NO: 5; x) W at the position corresponding to position 155 of SEQ ID NO: 5; y) R at the position corresponding to position 156 of SEQ ID NO: 5; z) F at the position corresponding to position 157 of SEQ ID NO: 5; aa) R at the position corresponding to position 158 of SEQ ID NO: 5; bb) Q at the position corresponding to position 159 of SEQ ID NO: 5; cc) D or W at the position corresponding to position 160 of SEQ ID NO: 5; dd) A or W at the position corresponding to position 162 of SEQ ID NO: 5; and ee) R at the position corresponding to position 165 of SEQ ID NO: 5. 106.      The system of embodiment 104, wherein the deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5 and W at a position corresponding to position 162 of SEQ ID NO: 5; b) N at a position corresponding to position 35 of SEQ ID NO: 5 and Q at a position corresponding to position 46 of SEQ ID NO: 5; c) S at a position corresponding to position 81 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; d) Q at a position corresponding to position 46 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; e) R at a position corresponding to position 156 of SEQ ID NO: 5 and W at a position corresponding to position 162 of SEQ ID NO: 5; f) A at a position corresponding to position 68 of SEQ ID NO: 5 and S at a position corresponding to position 81 of SEQ ID NO: 5; g) N at the position corresponding to position 35 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position 162; h) N at the position corresponding to position 35 of SEQ ID NO: 5, Q at the position corresponding to position 46 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; i) W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; j) N at the position corresponding to position 35 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; k) N at the position corresponding to position 35 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and Q at the position corresponding to position 162 of SEQ ID NO: 5 NO: 5, R at the position corresponding to position 156, and W at the position corresponding to position 162 of SEQ ID NO: 5; l) M at the position corresponding to position 68 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; m) Q at the position corresponding to position 46 of SEQ ID NO: 5, M at the position corresponding to position 68 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; n) M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and S at the position corresponding to position 162 of SEQ ID NO: 5; NO:5 position 108 corresponding to H, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; o) N corresponding to position 35, Q corresponding to position 46, SEQ ID NO:5 position 68 corresponding to M, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 155 corresponding to W, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; p) S corresponding to position 81, SEQ ID NO:5 position 155 corresponding to W; q) W corresponding to position 75, SEQ ID NO:5 position 76 corresponding to M, SEQ ID NO:5 position 87 corresponding to S; SEQ ID NO:5 position 88 corresponding to H, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 155 corresponding to W, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; p) S corresponding to position 81, SEQ ID NO:5 position 155 corresponding to W; q) W corresponding to position 75, SEQ ID NO:5 position 86 corresponding to M, SEQ ID NO:5 position 87 corresponding to S; NO:5 at the position corresponding to position 81; r) S at the position corresponding to position 81 of SEQ ID NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5; s) S at the position corresponding to position 81 of SEQ ID NO:5, and A at the position corresponding to position 145 of SEQ ID NO:5; t) W at the position corresponding to position 75 of SEQ ID NO:5, and W at the position corresponding to position 155 of SEQ ID NO:5; u) W at the position corresponding to position 155 of SEQ ID NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5; v) A at the position corresponding to position 145 of SEQ ID NO:5, and W at the position corresponding to position 155 of SEQ ID NO:5; w) W at the position corresponding to position 75 of SEQ ID NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5; x) W at the position corresponding to position 75 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; y) A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; z) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; aa) S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; bb) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; cc) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; dd) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; ee) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ff) W at the position corresponding to position 75 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; gg) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5 NO:5 position 145 A, and SEQ ID NO:5 position 155 W; hh) SEQ ID NO:5 position 145 A, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; ii) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 145 A, and SEQ ID NO:5 position 160 D; jj) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; kk) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 155 S, and SEQ ID NO:5 position 160 D; NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, and SEQ ID NO:5 position 155 corresponding to W; ll) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; mm) SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, and SEQ ID NO:5 position 160 corresponding to D; nn)  SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 155 corresponding to D, and SEQ ID NO:5 position 160 corresponding to D; NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; oo) SEQ ID NO: 5 position 75 corresponding to W, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; pp) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 105 corresponding to M; qq) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 121 corresponding to V; rr) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 145 corresponding to M; ss) L at the position corresponding to position 40 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; tt) L at the position corresponding to position 40 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; uu) M at the position corresponding to position 105 of SEQ ID NO: 5, and V at the position corresponding to position 121 of SEQ ID NO: 5; vv) M at the position corresponding to position 105 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; ww) M at the position corresponding to position 105 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; xx) M at the position corresponding to position 105 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; yy) NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 145 corresponding to M; zz) SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 159 corresponding to Q; aaa) SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 160 corresponding to W; bbb) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 159 corresponding to Q; ccc) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; ddd) SEQ ID NO:5 position 159 corresponding to Q, and SEQ ID NO:5 position 160 corresponding to W; eee) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; fff) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 159 corresponding to Q; ggg) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 81 corresponding to S; hhh) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; iii) SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; jjj) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 81 corresponding to S; NO:5 position 76 corresponding to G; kkk) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 117 corresponding to L; lll) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; mmm) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; nnn) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ooo) SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; NO:5 position corresponding to L at position 117; ppp) A at position corresponding to position 68 of SEQ ID NO:5, G at position corresponding to position 76 of SEQ ID NO:5, and L at position corresponding to position 117 of SEQ ID NO:5; qqq) A at position corresponding to position 68 of SEQ ID NO:5, G at position corresponding to position 76 of SEQ ID NO:5, S at position corresponding to position 81 of SEQ ID NO:5, and L at position corresponding to position 117 of SEQ ID NO:5; rrr) S at position corresponding to position 81 of SEQ ID NO:5, L at position corresponding to position 109 of SEQ ID NO:5, E at position corresponding to position 153 of SEQ ID NO:5, W at position corresponding to position 155 of SEQ ID NO:5, and D at position corresponding to position 160 of SEQ ID NO:5; sss) A at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, L at the position corresponding to position 117 of SEQ ID NO: 5, A at the position corresponding to position 121 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ttt) Q at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, I at the position corresponding to position 117 of SEQ ID NO: 5, Q at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; uuu) NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; vvv) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 160 corresponding to D; vvv) SEQ ID NO:5 position 22 corresponding to A, SEQ ID NO:5 position 68 corresponding to Y, SEQ ID NO:5 position 75 corresponding to G, SEQ ID NO:5 position 76 corresponding to S, SEQ ID NO:5 position 81 corresponding to H, SEQ ID NO:5 position 108 corresponding to L, SEQ ID NO:5 position 117 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; H at the position corresponding to position 122 of SEQ ID NO: 5, Y at the position corresponding to position 138 of SEQ ID NO: 5, L at the position corresponding to position 139 of SEQ ID NO: 5, A at the position corresponding to position 142 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, R at the position corresponding to position 153 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, D at the position corresponding to position 160 of SEQ ID NO: 5, and H at the position corresponding to position 162 of SEQ ID NO: 5; or www) S at the position corresponding to position 81 of SEQ ID NO: 5. 107. The system of embodiment 104 or 106, wherein the deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5 and Q at a position corresponding to position 46 of SEQ ID NO: 5; b) S at a position corresponding to position 81 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; c) Q at a position corresponding to position 46 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; d) N at a position corresponding to position 35 of SEQ ID NO: 5, Q at a position corresponding to position 46 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; e) W at a position corresponding to position 155 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; f) N at the position corresponding to position 35 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; g) N at the position corresponding to position 35 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; h) M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; i) N at the position corresponding to position 35, Q at the position corresponding to position 46 of SEQ ID NO: 5, and Q at the position corresponding to position 47 of SEQ ID NO: 5. M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; j) S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; k) W at the position corresponding to position 75 of SEQ ID NO: 5, and S at the position corresponding to position 81 of SEQ ID NO: 5; l) S at the position corresponding to position 81 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; m) S at the position corresponding to position 81 of SEQ ID NO: 5, and R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; A at the position corresponding to position 145 of SEQ ID NO: 5; n) W at the position corresponding to position 75 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; o) W at the position corresponding to position 75 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; p) A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; q) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; r) S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; s) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; t) L at the position corresponding to position 40 of SEQ ID NO: 5, and M at the position corresponding to position 105 of SEQ ID NO: 5; u) L at the position corresponding to position 40 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; v) L at the position corresponding to position 40 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; w) L at the position corresponding to position 40 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; x) M at the position corresponding to position 105 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; y) M at the position corresponding to position 105 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; z) M at the position corresponding to position 145 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; aa) M at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; bb) Q at the position corresponding to position 159 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; cc) S at the position corresponding to position 81 of SEQ ID NO: 5, M at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; dd) A at the position corresponding to position 68 of SEQ ID NO: 5, and Q at the position corresponding to position 160 of SEQ ID NO: 5; NO:5 position 81 corresponding to S; ee) SEQ ID NO:5 position 76 corresponding to S, and SEQ ID NO:5 position 81 corresponding to S; ff) SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; gg) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 76 corresponding to G; hh) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 117 corresponding to L; ii) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; jj) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; ID NO:5 position 81 corresponding to S; kk) SEQ ID NO:5 position 68 corresponding to S, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ll) SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; mm) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; nn) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; NO:5 position 117 corresponding to L; oo) A corresponding to position 68 of SEQ ID NO:5 and S corresponding to position 81 of SEQ ID NO:5; pp) S corresponding to position 81 of SEQ ID NO:5, L corresponding to position 109 of SEQ ID NO:5, E corresponding to position 153 of SEQ ID NO:5, W corresponding to position 155 of SEQ ID NO:5, and D corresponding to position 160 of SEQ ID NO:5; qq) A corresponding to position 75 of SEQ ID NO:5, S corresponding to position 81 of SEQ ID NO:5, L corresponding to position 117 of SEQ ID NO:5, A corresponding to position 121 of SEQ ID NO:5, A corresponding to position 145 of SEQ ID NO:5, and D corresponding to position 160 of SEQ ID NO:5; NO: 5, W at the position corresponding to position 155, and D at the position corresponding to position 160 of SEQ ID NO: 5; rr) Q at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, I at the position corresponding to position 117 of SEQ ID NO: 5, Q at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ss) Y at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, L at the position corresponding to position 117 of SEQ ID NO: 5, G at the position corresponding to position 121 of SEQ ID NO: 5, L at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; tt) SEQ ID NO: 5 position 22 corresponding to W, SEQ ID NO: 5 position 68 corresponding to A, SEQ ID NO: 5 position 75 corresponding to Y, SEQ ID NO: 5 position 76 corresponding to G, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 108 corresponding to H, SEQ ID NO: 5 position 117 corresponding to L, SEQ ID NO: 5 position 122 corresponding to H, SEQ ID NO: 5 position 138 corresponding to Y, SEQ ID NO: 5 position 139 corresponding to L, SEQ ID NO: 5 position 142 corresponding to A, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 150 corresponding to L, SEQ ID NO: 5 position 151 corresponding to L, SEQ ID NO: 5 position 152 corresponding to L, SEQ ID NO: 5 position 153 corresponding to L, SEQ ID NO: 5 position 154 corresponding to L, SEQ ID NO: 5 position 156 corresponding to L, SEQ ID NO: 5 position 157 corresponding to L, SEQ ID NO: 5 position 158 corresponding to L, SEQ ID NO: 5 position 159 corresponding to L, SEQ ID NO: 5 position 160 corresponding to L, SEQ ID NO: 5 position 161 corresponding to L, SEQ ID NO: 5 position 162 corresponding to L, SEQ ID NO: 5 position 163 corresponding to L, SEQ ID NO: 5 position 164 corresponding to L, SEQ ID NO: 5 position 165 corresponding to L, SEQ ID NO: 5 position 166 corresponding to L, SEQ ID NO: 5 position 167 corresponding to L, SEQ ID NO: 5 position 168 corresponding to L R at the position corresponding to position 153 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, D at the position corresponding to position 160 of SEQ ID NO: 5, and H at the position corresponding to position 162 of SEQ ID NO: 5; uu) S at the position corresponding to position 81 of SEQ ID NO: 5; or vv) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. 108. The system of any one of embodiments 104, 106 and 107, wherein the deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5, S at a position corresponding to position 81 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; b) W at a position corresponding to position 75 of SEQ ID NO: 5, and W at a position corresponding to position 155 of SEQ ID NO: 5; c) S at a position corresponding to position 81 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; d) S at a position corresponding to position 81 of SEQ ID NO: 5, A at a position corresponding to position 145 of SEQ ID NO: 5, and D at a position corresponding to position 162 of SEQ ID NO: 5; NO:5 position 155 corresponding to W; e) S corresponding to position 81 of SEQ ID NO:5, M corresponding to position 145 of SEQ ID NO:5, and W corresponding to position 160 of SEQ ID NO:5; f) G corresponding to position 76 of SEQ ID NO:5, and S corresponding to position 81 of SEQ ID NO:5; g) S corresponding to position 81 of SEQ ID NO:5, and L corresponding to position 117 of SEQ ID NO:5; h) A corresponding to position 68 of SEQ ID NO:5, and S corresponding to position 81 of SEQ ID NO:5; i) S corresponding to position 81 of SEQ ID NO:5, L corresponding to position 109 of SEQ ID NO:5, E corresponding to position 153 of SEQ ID NO:5, and L corresponding to position 117 of SEQ ID NO:5; NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; j) SEQ ID NO: 5 position 75 corresponding to A, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 117 corresponding to L, SEQ ID NO: 5 position 121 corresponding to A, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; k) SEQ ID NO: 5 position 75 corresponding to Q, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 117 corresponding to I, SEQ ID NO: 5 position 145 corresponding to Q, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; NO:5 position 160 corresponding to D; l) SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; m) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 110 corresponding to H, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; m) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 121 corresponding to NO:5 position 117 corresponding to L, SEQ ID NO:5 position 122 corresponding to H, SEQ ID NO:5 position 138 corresponding to Y, SEQ ID NO:5 position 139 corresponding to L, SEQ ID NO:5 position 142 corresponding to A, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 153 corresponding to R, SEQ ID NO:5 position 155 corresponding to W, SEQ ID NO:5 position 156 corresponding to R, SEQ ID NO:5 position 160 corresponding to D, and SEQ ID NO:5 position 162 corresponding to H; n) SEQ ID NO:5 position 81 corresponding to S; or o) SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 163 corresponding to H; W at the position corresponding to position 155 of NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5. 109. The system of any of embodiments 104-108, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with any of SEQ ID NOs: 300-414, 596-598, and 720-723. 110. The system of any of embodiments 104-108, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with any of SEQ ID NOs: 300-414, 596-598, and 720-723. 111. The system of any one of embodiments 104-108, wherein the deaminase comprises an amino acid sequence of any one of SEQ ID NOs: 300-414, 596-598, and 720-723. 112. The system of any of embodiments 104-111, wherein the deaminase has improved deaminase activity when compared to SEQ ID NO: 5. 113. The system of any of embodiments 104-111, wherein the deaminase is adenine deaminase. 114. The system of any one of embodiments 104-113, wherein at least one of the nucleotide sequence encoding the one or more guide RNAs and the nucleotide sequence encoding the fusion protein is operably linked to a promoter heterologous to the nucleotide sequence. 115. The system of any of embodiments 104-114, wherein the target DNA sequence is a eukaryotic target DNA sequence. 116. The system of any of embodiments 104-115, wherein the target DNA sequence is positioned adjacent to a pre-spacer adjacent motif (PAM) recognized by the RGN. 117. The system of any of embodiments 104-116, wherein the RGN of the fusion protein is a type II CRISPR-Cas polypeptide. 118. The system of any of embodiments 104-116, wherein the RGN of the fusion protein is a type V CRISPR-Cas polypeptide. 119. The system of any one of embodiments 104-116, wherein the RGN is Cas9, CasX, CasY, Cpfl, C2cl, C2c2, C2c3, GeoCas9, CjCas9, Casl2a, Casl2b, Casl2g, Casl2h, Casl2i, Casl3b, Casl3c, Casl3d, Casl4, Csn2, xCas9, SpCas9-NG, LbCasl2a, AsCasl2a, Cas9-KKH, circularly arranged Cas9, Argonaute (Ago), SmacCas9, or Spy-macCas9 domain. 120. The system of any of embodiments 104-116, wherein the RGN of the fusion protein has an amino acid sequence having at least 95% sequence identity with any of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699. 121. The system of any of embodiments 104-116, wherein the RGN of the fusion protein is an RGN nickase. 122. The system of embodiment 121, wherein the RGN nickase has an amino acid sequence as shown in any one of SEQ ID NOs: 49-52 and 698. 123. The system of any of embodiments 104-122, wherein the fusion protein comprises one or more nuclear localization signals. 124. The system of any one of embodiments 104-108, wherein the fusion protein is selected from the group consisting of: a) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 319 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; b) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 375 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; c) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 406 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; d) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 596 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; e) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; f) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 303 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; g) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 303 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; NO:366 has an amino acid sequence with at least 90% sequence identity, and is fused to the N-terminus of an RGN comprising an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; and h) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO:720, and is fused to the N-terminus of an RGN comprising an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49. 125. The system of any one of embodiments 104-108, wherein the fusion protein is selected from the group consisting of: a) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 319 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49; b) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 375 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49; c) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 406 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49; d) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 596 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49; e) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 597 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49; f) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 303 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49; g) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 303 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49; NO:366 having an amino acid sequence with at least 95% sequence identity, and fused to the N-terminus of an RGN comprising an amino acid sequence with at least 95% sequence identity to SEQ ID NO:49; and h) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO:720, and fused to the N-terminus of an RGN comprising an amino acid sequence with at least 95% sequence identity to SEQ ID NO:49. 126. The system of any one of embodiments 104-108, wherein the fusion protein is selected from the group consisting of: a) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence shown in SEQ ID NO: 319 and is fused to the N-terminus of an RGN comprising the amino acid sequence shown in SEQ ID NO: 49; b) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence shown in SEQ ID NO: 375 and is fused to the N-terminus of an RGN comprising the amino acid sequence shown in SEQ ID NO: 49; c) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence shown in SEQ ID NO: 406 and is fused to the N-terminus of an RGN comprising the amino acid sequence shown in SEQ ID NO: 49; d) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence shown in SEQ ID NO: 596 and is fused to the N-terminus of an RGN comprising the amino acid sequence shown in SEQ ID NO: NO:49; e) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO:597 and is fused to the N-terminus of the RGN comprising the amino acid sequence as shown in SEQ ID NO:49; f) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO:303 and is fused to the N-terminus of the RGN comprising the amino acid sequence as shown in SEQ ID NO:49; g) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO:366 and is fused to the N-terminus of the RGN comprising the amino acid sequence as shown in SEQ ID NO:49; and h) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO:720 and is fused to the N-terminus of the RGN comprising the amino acid sequence as shown in SEQ ID NO:49. 127. The system of any one of embodiments 124-126, wherein the fusion protein has a sequence as shown in any one of SEQ ID NOs: 577, 578, 582, 584, 588, 593, 594, 604, 605, 616, and 729. 128. The system of any of embodiments 104-127, wherein the fusion protein is codon optimized for expression in eukaryotic cells. 129. The system of any one of embodiments 104-128, wherein the nucleotide sequence encoding the one or more guide RNAs and the nucleotide sequence encoding the fusion protein are located on a vector. 130. A cell comprising a system of any one of embodiments 104-129. 131. The cell of embodiment 130, wherein the cell is a eukaryotic cell. 132. The cell of embodiment 131, wherein the eukaryotic cell is a mammalian cell. 133. The cell of embodiment 132, wherein the mammalian cell is a human cell. 134. The cell of embodiment 133, wherein the human cell is an immune cell. 135. The cell of embodiment 134, wherein the immune cell is a stem cell. 136. The cell of embodiment 135, wherein the stem cell is an induced multipotent stem cell. 137. The cell of embodiment 131, wherein the eukaryotic cell is an insect cell. 138. The cell of embodiment 131, wherein the eukaryotic cell is a plant cell. 139. A plant comprising the cell of embodiment 138. 140. A seed comprising a cell of implementation method 138. 141. The cell of embodiment 130, wherein the cell is a prokaryotic cell. 142. A drug composition comprising a pharmaceutically acceptable carrier and a system of any one of embodiments 104-129 or a cell of any one of embodiments 132-136. 143. A method for modifying a target DNA molecule comprising a target DNA sequence, the method comprising delivering a system according to any one of embodiments 104-129 to the target DNA molecule or a cell comprising the target DNA molecule. 144. The method of embodiment 143, wherein the modified target DNA molecule includes an A＞N mutation of at least one nucleotide in the target DNA molecule, wherein N is C, G or T. 145. The method of embodiment 144, wherein the modified target DNA molecule includes an A＞G mutation of at least one nucleotide in the target DNA molecule. 146. A method for modifying a target DNA molecule comprising a target sequence, comprising: a) assembling the RGN deaminase ribonucleotide complex in vitro by binding: i) one or more guide RNAs capable of hybridizing with non-target strands of the target DNA sequence; and ii) a fusion protein comprising an RNA-guided nuclease polypeptide (RGN) and at least one deaminase, wherein the deaminase has an amino acid sequence with at least 85% sequence identity to SEQ ID NO: 5; wherein the deaminase has at least one of the following amino acid residues: A) C at a position corresponding to position 2 of SEQ ID NO: 5; B) F or C at a position corresponding to position 22 of SEQ ID NO: 5; C) Q at a position corresponding to position 23 of SEQ ID NO: 5; D) NO:5 position corresponding to position 35 N; E) SEQ ID NO:5 position corresponding to position 40 L; F) SEQ ID NO:5 position corresponding to position 46 Q; G) SEQ ID NO:5 position corresponding to position 68 A or M; H) SEQ ID NO:5 position corresponding to position 72 H; I) SEQ ID NO:5 position corresponding to position 75 W, A, Q, Y, or D; J) SEQ ID NO:5 position corresponding to position 76 G; K) SEQ ID NO:5 position corresponding to position 81 S; L) SEQ ID NO:5 position corresponding to position 105 M; M) SEQ ID NO:5 position corresponding to position 108 H; N) SEQ ID NO:5 position corresponding to position 109 L; O) SEQ ID NO:5 position corresponding to position 109 NO:5 position 117 corresponding to I or L; P) SEQ ID NO:5 position 120 corresponding to F; Q) SEQ ID NO:5 position 121 corresponding to E, T, A, G, or V; R) SEQ ID NO:5 position 122 corresponding to I or H; S) SEQ ID NO:5 position 125 corresponding to K; T) SEQ ID NO:5 position 126 corresponding to A; U) SEQ ID NO:5 position 135 corresponding to H; V) SEQ ID NO:5 position 137 corresponding to V; W) SEQ ID NO:5 position 138 corresponding to Y; X) SEQ ID NO:5 position 139 corresponding to L; Y) SEQ ID NO:5 position 142 corresponding to K or A; Z) SEQ ID NO:5 position 143 corresponding to L; A, Q, L, or M at the position corresponding to position 145 of SEQ ID NO: 5; AA)      K at the position corresponding to position 148 of SEQ ID NO: 5; BB) Q at the position corresponding to position 151 of SEQ ID NO: 5; CC) E or R at the position corresponding to position 153 of SEQ ID NO: 5; DD) W at the position corresponding to position 155 of SEQ ID NO: 5; EE) R or V at the position corresponding to position 156 of SEQ ID NO: 5; FF) F at the position corresponding to position 157 of SEQ ID NO: 5; GG) R at the position corresponding to position 158 of SEQ ID NO: 5; HH) Q at the position corresponding to position 159 of SEQ ID NO: 5; II) D or W at the position corresponding to position 160 of SEQ ID NO: 5; JJ) NO: 5 corresponding to position 162 W, H, V, or A; KK) SEQ ID NO: 5 corresponding to position 165 R; and LL) SEQ ID NO: 5 corresponding to position 166 H; and b) contacting the target DNA molecule or a cell comprising the target DNA molecule with an RGN deaminase ribonucleotide complex assembled in vitro; wherein the one or more guide RNAs hybridize with the non-target strands of the target DNA sequence, thereby guiding the fusion protein to bind to the target DNA sequence and modifying the target DNA molecule. 147. The method of embodiment 146, wherein the deaminase comprises at least one of the following amino acid residues: a) C at a position corresponding to position 2 of SEQ ID NO: 5; b) F or C at a position corresponding to position 22 of SEQ ID NO: 5; c) Q at a position corresponding to position 23 of SEQ ID NO: 5; d) N at a position corresponding to position 35 of SEQ ID NO: 5; e) L at a position corresponding to position 40 of SEQ ID NO: 5; f) A at a position corresponding to position 68 of SEQ ID NO: 5; g) W, A, Q, or Y at a position corresponding to position 75 of SEQ ID NO: 5; h) G at a position corresponding to position 76 of SEQ ID NO: 5; i) S at a position corresponding to position 81 of SEQ ID NO: 5; j) M at a position corresponding to position 105 of SEQ ID NO: 5; k) NO:5 position 108 corresponding to H; l) SEQ ID NO:5 position 109 corresponding to L; m) SEQ ID NO:5 position 117 corresponding to I or L; n) SEQ ID NO:5 position 121 corresponding to A or G; o) SEQ ID NO:5 position 122 corresponding to H; p) SEQ ID NO:5 position 126 corresponding to A; q) SEQ ID NO:5 position 135 corresponding to H; r) SEQ ID NO:5 position 137 corresponding to V; s) SEQ ID NO:5 position 138 corresponding to Y; t) SEQ ID NO:5 position 139 corresponding to L; u) SEQ ID NO:5 position 142 corresponding to K or A; v) SEQ ID NO:5 position 143 corresponding to V; s) SEQ ID NO:5 position 144 corresponding to Y; t) SEQ ID NO:5 position 145 corresponding to L; u) SEQ ID NO:5 position 146 corresponding to K or A; v) SEQ ID NO:5 position 147 corresponding to V; A, Q, L, or M at the position corresponding to position 145 of SEQ ID NO: 5; w) E or R at the position corresponding to position 153 of SEQ ID NO: 5; x) W at the position corresponding to position 155 of SEQ ID NO: 5; y) R at the position corresponding to position 156 of SEQ ID NO: 5; z) F at the position corresponding to position 157 of SEQ ID NO: 5; aa) R at the position corresponding to position 158 of SEQ ID NO: 5; bb) Q at the position corresponding to position 159 of SEQ ID NO: 5; cc) D or W at the position corresponding to position 160 of SEQ ID NO: 5; dd) A or W at the position corresponding to position 162 of SEQ ID NO: 5; and ee) R at the position corresponding to position 165 of SEQ ID NO: 5. 148. The method of embodiment 146, wherein the deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5 and W at a position corresponding to position 162 of SEQ ID NO: 5; b) N at a position corresponding to position 35 of SEQ ID NO: 5 and Q at a position corresponding to position 46 of SEQ ID NO: 5; c) S at a position corresponding to position 81 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; d) Q at a position corresponding to position 46 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; e) R at a position corresponding to position 156 of SEQ ID NO: 5 and W at a position corresponding to position 162 of SEQ ID NO: 5; f) A at a position corresponding to position 68 of SEQ ID NO: 5 and S at a position corresponding to position 81 of SEQ ID NO: 5; g) NO:5 position corresponding to N at position 35, SEQ ID NO:5 position corresponding to S at position 81, and SEQ ID NO:5 position corresponding to W at position 162; h) N at position corresponding to SEQ ID NO:5 position corresponding to Q at position 46, and SEQ ID NO:5 position corresponding to W at position 162; i) W at position corresponding to SEQ ID NO:5 position corresponding to R at position 156, and SEQ ID NO:5 position corresponding to W at position 162; j) N at position corresponding to SEQ ID NO:5 position corresponding to N at position 35, SEQ ID NO:5 position corresponding to R at position 156, and SEQ ID NO:5 position corresponding to W at position 162; k) N at position corresponding to SEQ ID NO:5 position corresponding to S at position 81, SEQ ID NO:5 position corresponding to Q at position 46, and SEQ ID NO:5 position corresponding to W at position 162; NO: 5, R at the position corresponding to position 156, and W at the position corresponding to position 162 of SEQ ID NO: 5; l) M at the position corresponding to position 68 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; m) Q at the position corresponding to position 46 of SEQ ID NO: 5, M at the position corresponding to position 68 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; n) M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5 NO:5 position 108 corresponding to H, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; o) N corresponding to position 35, Q corresponding to position 46, SEQ ID NO:5 position 68 corresponding to M, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 155 corresponding to W, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; p) S corresponding to position 81, SEQ ID NO:5 position 155 corresponding to W; q) W corresponding to position 75, SEQ ID NO:5 position 76 corresponding to M, SEQ ID NO:5 position 87 corresponding to H, SEQ ID NO:5 position 88 corresponding to W, SEQ ID NO:5 position 89 corresponding to R, and SEQ ID NO:5 position 90 corresponding to W; NO:5 position corresponding to S; r) SEQ ID NO:5 position corresponding to S, and SEQ ID NO:5 position corresponding to D; s) SEQ ID NO:5 position corresponding to S, and SEQ ID NO:5 position corresponding to A; t) SEQ ID NO:5 position corresponding to W, and SEQ ID NO:5 position corresponding to W; u) SEQ ID NO:5 position corresponding to W, and SEQ ID NO:5 position corresponding to D; v) SEQ ID NO:5 position corresponding to A, and SEQ ID NO:5 position corresponding to W; w) SEQ ID NO:5 position corresponding to W, and SEQ ID NO:5 position corresponding to D; x) W at the position corresponding to position 75 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; y) A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; z) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; aa) S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; bb) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; cc) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; dd) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; ee) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ff) W at the position corresponding to position 75 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; gg) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5 NO:5 position 145 A, and SEQ ID NO:5 position 155 W; hh) SEQ ID NO:5 position 145 A, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; ii) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 145 A, and SEQ ID NO:5 position 160 D; jj) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; kk) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 155 S, and SEQ ID NO:5 position 160 D; NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, and SEQ ID NO:5 position 155 corresponding to W; ll) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; mm) SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, and SEQ ID NO:5 position 160 corresponding to D; nn)  SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 155 corresponding to D, and SEQ ID NO:5 position 160 corresponding to D; NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; oo) SEQ ID NO: 5 position 75 corresponding to W, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; pp) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 105 corresponding to M; qq) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 121 corresponding to V; rr) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 145 corresponding to M; ss) L at the position corresponding to position 40 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; tt) L at the position corresponding to position 40 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; uu) M at the position corresponding to position 105 of SEQ ID NO: 5, and V at the position corresponding to position 121 of SEQ ID NO: 5; vv) M at the position corresponding to position 105 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; ww) M at the position corresponding to position 105 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; xx) M at the position corresponding to position 105 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; yy) NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 145 corresponding to M; zz) SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 159 corresponding to Q; aaa) SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 160 corresponding to W; bbb) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 159 corresponding to Q; ccc) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; ddd) SEQ ID NO:5 position 159 corresponding to Q, and SEQ ID NO:5 position 160 corresponding to W; eee) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; fff) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 159 corresponding to Q; ggg) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 81 corresponding to S; hhh) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; iii) SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; jjj) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 81 corresponding to S; NO:5 position 76 corresponding to G; kkk) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 117 corresponding to L; lll) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; mmm) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; nnn) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ooo) SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; NO:5 position corresponding to L at position 117; ppp) A at position corresponding to position 68 of SEQ ID NO:5, G at position corresponding to position 76 of SEQ ID NO:5, and L at position corresponding to position 117 of SEQ ID NO:5; qqq) A at position corresponding to position 68 of SEQ ID NO:5, G at position corresponding to position 76 of SEQ ID NO:5, S at position corresponding to position 81 of SEQ ID NO:5, and L at position corresponding to position 117 of SEQ ID NO:5; rrr) S at position corresponding to position 81 of SEQ ID NO:5, L at position corresponding to position 109 of SEQ ID NO:5, E at position corresponding to position 153 of SEQ ID NO:5, W at position corresponding to position 155 of SEQ ID NO:5, and D at position corresponding to position 160 of SEQ ID NO:5; sss) A at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, L at the position corresponding to position 117 of SEQ ID NO: 5, A at the position corresponding to position 121 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ttt) Q at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, I at the position corresponding to position 117 of SEQ ID NO: 5, Q at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; uuu) NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; vvv) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 160 corresponding to D; vvv) SEQ ID NO:5 position 22 corresponding to A, SEQ ID NO:5 position 68 corresponding to Y, SEQ ID NO:5 position 75 corresponding to G, SEQ ID NO:5 position 76 corresponding to S, SEQ ID NO:5 position 81 corresponding to H, SEQ ID NO:5 position 108 corresponding to L, SEQ ID NO:5 position 117 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; H at the position corresponding to position 122 of SEQ ID NO: 5, Y at the position corresponding to position 138 of SEQ ID NO: 5, L at the position corresponding to position 139 of SEQ ID NO: 5, A at the position corresponding to position 142 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, R at the position corresponding to position 153 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, D at the position corresponding to position 160 of SEQ ID NO: 5, and H at the position corresponding to position 162 of SEQ ID NO: 5; or www) S at the position corresponding to position 81 of SEQ ID NO: 5. 149. The method of embodiment 146 or 148, wherein the deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5 and Q at a position corresponding to position 46 of SEQ ID NO: 5; b) S at a position corresponding to position 81 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; c) Q at a position corresponding to position 46 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; d) N at a position corresponding to position 35 of SEQ ID NO: 5, Q at a position corresponding to position 46 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; e) W at a position corresponding to position 155 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; f) N at the position corresponding to position 35 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; g) N at the position corresponding to position 35 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; h) M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; i) N at the position corresponding to position 35, Q at the position corresponding to position 46 of SEQ ID NO: 5, and Q at the position corresponding to position 47 of SEQ ID NO: 5. M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; j) S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; k) W at the position corresponding to position 75 of SEQ ID NO: 5, and S at the position corresponding to position 81 of SEQ ID NO: 5; l) S at the position corresponding to position 81 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; m) S at the position corresponding to position 81 of SEQ ID NO: 5, and R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; A at the position corresponding to position 145 of SEQ ID NO: 5; n) W at the position corresponding to position 75 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; o) W at the position corresponding to position 75 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; p) A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; q) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; r) S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; s) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; t) L at the position corresponding to position 40 of SEQ ID NO: 5, and M at the position corresponding to position 105 of SEQ ID NO: 5; u) L at the position corresponding to position 40 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; v) L at the position corresponding to position 40 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; w) L at the position corresponding to position 40 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; x) M at the position corresponding to position 105 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; y) M at the position corresponding to position 105 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; z) M at the position corresponding to position 145 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; aa) M at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; bb) Q at the position corresponding to position 159 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; cc) S at the position corresponding to position 81 of SEQ ID NO: 5, M at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; dd) A at the position corresponding to position 68 of SEQ ID NO: 5, and Q at the position corresponding to position 160 of SEQ ID NO: 5; NO:5 position 81 corresponding to S; ee) SEQ ID NO:5 position 76 corresponding to S, and SEQ ID NO:5 position 81 corresponding to S; ff) SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; gg) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 76 corresponding to G; hh) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 117 corresponding to L; ii) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; jj) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; ID NO:5 position 81 corresponding to S; kk) SEQ ID NO:5 position 68 corresponding to S, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ll) SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; mm) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; nn) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; NO:5 position 117 corresponding to L; oo) A corresponding to position 68 of SEQ ID NO:5 and S corresponding to position 81 of SEQ ID NO:5; pp) S corresponding to position 81 of SEQ ID NO:5, L corresponding to position 109 of SEQ ID NO:5, E corresponding to position 153 of SEQ ID NO:5, W corresponding to position 155 of SEQ ID NO:5, and D corresponding to position 160 of SEQ ID NO:5; qq) A corresponding to position 75 of SEQ ID NO:5, S corresponding to position 81 of SEQ ID NO:5, L corresponding to position 117 of SEQ ID NO:5, A corresponding to position 121 of SEQ ID NO:5, A corresponding to position 145 of SEQ ID NO:5, and D corresponding to position 160 of SEQ ID NO:5; NO: 5, W at the position corresponding to position 155, and D at the position corresponding to position 160 of SEQ ID NO: 5; rr) Q at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, I at the position corresponding to position 117 of SEQ ID NO: 5, Q at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ss) Y at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, L at the position corresponding to position 117 of SEQ ID NO: 5, G at the position corresponding to position 121 of SEQ ID NO: 5, L at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; tt) SEQ ID NO: 5 position 22 corresponding to W, SEQ ID NO: 5 position 68 corresponding to A, SEQ ID NO: 5 position 75 corresponding to Y, SEQ ID NO: 5 position 76 corresponding to G, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 108 corresponding to H, SEQ ID NO: 5 position 117 corresponding to L, SEQ ID NO: 5 position 122 corresponding to H, SEQ ID NO: 5 position 138 corresponding to Y, SEQ ID NO: 5 position 139 corresponding to L, SEQ ID NO: 5 position 142 corresponding to A, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 150 corresponding to L, SEQ ID NO: 5 position 151 corresponding to L, SEQ ID NO: 5 position 152 corresponding to L, SEQ ID NO: 5 position 153 corresponding to L, SEQ ID NO: 5 position 154 corresponding to L, SEQ ID NO: 5 position 156 corresponding to L, SEQ ID NO: 5 position 157 corresponding to L, SEQ ID NO: 5 position 158 corresponding to L, SEQ ID NO: 5 position 159 corresponding to L, SEQ ID NO: 5 position 160 corresponding to L, SEQ ID NO: 5 position 161 corresponding to L, SEQ ID NO: 5 position 162 corresponding to L, SEQ ID NO: 5 position 163 corresponding to L, SEQ ID NO: 5 position 164 corresponding to L, SEQ ID NO: 5 position 165 corresponding to L, SEQ ID NO: 5 position 166 corresponding to L, SEQ ID NO: 5 position 167 corresponding to L, SEQ ID NO: 5 position 168 corresponding to L R at the position corresponding to position 153 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, D at the position corresponding to position 160 of SEQ ID NO: 5, and H at the position corresponding to position 162 of SEQ ID NO: 5; uu) S at the position corresponding to position 81 of SEQ ID NO: 5; or vv) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. 150. The method of any one of embodiments 146, 148 and 149, wherein the deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5, S at a position corresponding to position 81 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; b) W at a position corresponding to position 75 of SEQ ID NO: 5, and W at a position corresponding to position 155 of SEQ ID NO: 5; c) S at a position corresponding to position 81 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; d) S at a position corresponding to position 81 of SEQ ID NO: 5, A at a position corresponding to position 145 of SEQ ID NO: 5, and D at a position corresponding to position 162 of SEQ ID NO: 5; NO:5 position 155 corresponding to W; e) S corresponding to position 81 of SEQ ID NO:5, M corresponding to position 145 of SEQ ID NO:5, and W corresponding to position 160 of SEQ ID NO:5; f) G corresponding to position 76 of SEQ ID NO:5, and S corresponding to position 81 of SEQ ID NO:5; g) S corresponding to position 81 of SEQ ID NO:5, and L corresponding to position 117 of SEQ ID NO:5; h) A corresponding to position 68 of SEQ ID NO:5, and S corresponding to position 81 of SEQ ID NO:5; i) S corresponding to position 81 of SEQ ID NO:5, L corresponding to position 109 of SEQ ID NO:5, E corresponding to position 153 of SEQ ID NO:5, and L corresponding to position 117 of SEQ ID NO:5; NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; j) SEQ ID NO: 5 position 75 corresponding to A, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 117 corresponding to L, SEQ ID NO: 5 position 121 corresponding to A, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; k) SEQ ID NO: 5 position 75 corresponding to Q, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 117 corresponding to I, SEQ ID NO: 5 position 145 corresponding to Q, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; NO:5 position 160 corresponding to D; l) SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; m) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 110 corresponding to H, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; m) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 121 corresponding to NO:5 position 117 corresponding to L, SEQ ID NO:5 position 122 corresponding to H, SEQ ID NO:5 position 138 corresponding to Y, SEQ ID NO:5 position 139 corresponding to L, SEQ ID NO:5 position 142 corresponding to A, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 153 corresponding to R, SEQ ID NO:5 position 155 corresponding to W, SEQ ID NO:5 position 156 corresponding to R, SEQ ID NO:5 position 160 corresponding to D, and SEQ ID NO:5 position 162 corresponding to H; n) SEQ ID NO:5 position 81 corresponding to S; or o) SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 163 corresponding to H; W at the position corresponding to position 155 of NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. 151. The method of any of embodiments 146-150, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with any of SEQ ID NOs: 300-414, 596-598, and 720-723. 152. The method of any of embodiments 146-150, wherein the deaminase has an amino acid sequence having at least 95% sequence identity with any of SEQ ID NOs: 300-414, 596-598, and 720-723. 153. Method 146-150 of any of the embodiments, wherein the deaminase has an amino acid sequence of any of SEQ ID NOs: 300-414, 596-598, and 720-723. 154. Method 146-153 of any of the embodiments, wherein the deaminase has improved deaminase activity when compared to SEQ ID NO: 5. 155. The method of any of embodiments 146-154, wherein the deaminase is adenine deaminase. 156. The method of any of embodiments 146-155, wherein the RGN of the fusion protein is a type II CRISPR-Cas polypeptide. 157. The method of any one of embodiments 146-155, wherein the RGN of the fusion protein is a V-type CRISPR-Cas polypeptide. 158. The method of any one of embodiments 146-155, wherein the RGN is Cas9, CasX, CasY, Cpfl, C2cl, C2c2, C2c3, GeoCas9, CjCas9, Casl2a, Casl2b, Casl2g, Casl2h, Casl2i, Casl3b, Casl3c, Casl3d, Casl4, Csn2, xCas9, SpCas9-NG, LbCasl2a, AsCasl2a, Cas9-KKH, circularly arranged Cas9, Argonaute (Ago), SmacCas9, or Spy-macCas9 domain. 159. The method of any one of embodiments 146-155, wherein the RGN of the fusion protein has an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699. 160. The method of any one of embodiments 146-155, wherein the RGN of the fusion protein is an RGN nickase. 161. The method of embodiment 160, wherein the RGN nickase has an amino acid sequence as shown in any one of SEQ ID NOs: 49-52 and 698. 162. The method of any of embodiments 146-161, wherein the fusion protein comprises one or more nuclear localization signals. 163. The method of any one of embodiments 146-162, wherein the fusion protein is selected from the group consisting of: a) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 319 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; b) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 375 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; c) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 406 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; d) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 596 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; e) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; f) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 303 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; g) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 303 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; NO:366 has an amino acid sequence with at least 90% sequence identity, and is fused to the N-terminus of an RGN comprising an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; and h) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO:720, and is fused to the N-terminus of an RGN comprising an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49. 164. The method of any one of embodiments 146-162, wherein the fusion protein is selected from the group consisting of: a) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 319 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49; b) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 375 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49; c) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 406 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49; d) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 596 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49; e) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 597 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49; f) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 303 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49; g) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 303 and fused to the N-terminus of an RGN comprising an amino acid sequence having at least 95% sequence identity with SEQ ID NO: 49; NO:366 has an amino acid sequence with at least 95% sequence identity, and is fused to the N-terminus of an RGN comprising an amino acid sequence with at least 95% sequence identity to SEQ ID NO:49; and h) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence with at least 95% sequence identity to SEQ ID NO:720, and is fused to the N-terminus of an RGN comprising an amino acid sequence with at least 95% sequence identity to SEQ ID NO:49. 165. The method of any one of embodiments 146-162, wherein the fusion protein is selected from the group consisting of: a) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence shown in SEQ ID NO: 319 and is fused to the N-terminus of the RGN comprising the amino acid sequence shown in SEQ ID NO: 49; b) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence shown in SEQ ID NO: 375 and is fused to the N-terminus of the RGN comprising the amino acid sequence shown in SEQ ID NO: 49; c) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence shown in SEQ ID NO: 406 and is fused to the N-terminus of the RGN comprising the amino acid sequence shown in SEQ ID NO: 49; d) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence shown in SEQ ID NO: 596 and is fused to the N-terminus of the RGN comprising the amino acid sequence shown in SEQ ID NO: NO:49; e) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO:597 and is fused to the N-terminus of the RGN comprising the amino acid sequence as shown in SEQ ID NO:49; f) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO:303 and is fused to the N-terminus of the RGN comprising the amino acid as shown in SEQ ID NO:49; g) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO:366 and is fused to the N-terminus of the RGN comprising the amino acid sequence as shown in SEQ ID NO:49; and h) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO:720 and is fused to the N-terminus of the RGN comprising the amino acid sequence as shown in SEQ ID NO:49. 166. The method of any one of embodiments 163-165, wherein the fusion protein has a sequence as shown in any one of SEQ ID NOs: 577, 578, 582, 584, 588, 593, 594, 604, 605, 616, and 729. 167. The method of any of embodiments 146-166, wherein the fusion protein is codon-optimized for expression in eukaryotic cells. 168. The method of any one of embodiments 146-167, wherein the modified target DNA molecule includes an A＞N mutation of at least one nucleotide in the target DNA molecule, wherein N is C, G or T. 169. The method of embodiment 168, wherein the modified target DNA molecule includes an A＞G mutation of at least one nucleotide in the target DNA molecule. 170. The method of any one of embodiments 146-169, wherein the target DNA sequence is a eukaryotic target DNA sequence. 171. The method of any of embodiments 146-170, wherein the target DNA sequence is positioned adjacent to a pre-spacer adjacent motif (PAM). 172. The method of any of embodiments 146-171, wherein the target DNA molecule includes a causal mutation associated with a disease or condition, and wherein the modification of the target DNA molecule corrects the causal mutation. 173. Method 172 of the implementation method, wherein the correction of causal mutations includes correcting meaningless mutations. 174. The method of any of embodiments 146-173, wherein the target DNA molecule is within a cell. 175. The method of embodiment 174, wherein the cell is a eukaryotic cell. 176. The method of embodiment 175, wherein the eukaryotic cell is a plant cell. 177. The method of embodiment 175, wherein the eukaryotic cell is a mammalian cell. 178. The method of embodiment 177, wherein the mammalian cell is a human cell. 179. The method of embodiment 178, wherein the human cell is an immune cell. 180. The method of embodiment 179, wherein the immune cells are stem cells. 181. The method of embodiment 180, wherein the stem cells are induced multipotent stem cells. 182. The method of embodiment 175, wherein the eukaryotic cell is an insect cell. 183. The method of embodiment 174, wherein the cell is a prokaryotic cell. 184. The method of any of embodiments 174-183 further comprises selecting a cell comprising the modified DNA molecule. 185. A cell comprising a modified target DNA sequence according to the method of embodiment 184. 186. The cell of implementation method 185, wherein the cell is a eukaryotic cell. 187. The cell of embodiment 186, wherein the eukaryotic cell is a plant cell. 188. A plant comprising the cell of embodiment 187. 189. A seed comprising a cell of implementation method 187. 190. The cell of embodiment 187, wherein the eukaryotic cell is a mammalian cell. 191. The cell of embodiment 190, wherein the mammalian cell is a human cell. 192. The cell of embodiment 191, wherein the human cell is an immune cell. 193. The cell of embodiment 192, wherein the immune cell is a stem cell. 194. The cell of embodiment 193, wherein the stem cells are induced multipotent stem cells. 195. The cell of embodiment 186, wherein the eukaryotic cell is an insect cell. 196. The cell of implementation method 185, wherein the cell is a prokaryotic cell. 197. A drug composition comprising a cell of any one of embodiments 190-194 and a pharmaceutically acceptable carrier. 198. A composition comprising: a) a fusion protein comprising a DNA binding polypeptide and a first adenine deaminase, or an amino acid molecule encoding the fusion protein; and b) a second adenine deaminase having at least 85% sequence identity with SEQ ID NO: 5; or an amino acid molecule encoding the deaminase, wherein the second deaminase comprises at least one of the following amino acid residues: i) C at a position corresponding to position 2 of SEQ ID NO: 5; ii) F or C at a position corresponding to position 22 of SEQ ID NO: 5; iii) Q at a position corresponding to position 23 of SEQ ID NO: 5; iv) N at a position corresponding to position 35 of SEQ ID NO: 5; v) L at a position corresponding to position 40 of SEQ ID NO: 5; vi) Q at a position corresponding to position 46 of SEQ ID NO: 5; vii) NO:5 position corresponding to A or M; viii) SEQ ID NO:5 position corresponding to H; ix) SEQ ID NO:5 position corresponding to W, A, Q, Y, or D; x) SEQ ID NO:5 position corresponding to G; xi) SEQ ID NO:5 position corresponding to S; xii) SEQ ID NO:5 position corresponding to M; xiii) SEQ ID NO:5 position corresponding to H; xiv) SEQ ID NO:5 position corresponding to L; xv) SEQ ID NO:5 position corresponding to I or L; xvi) SEQ ID NO:5 position corresponding to F; xvii) SEQ ID NO:5 position corresponding to M; xiii) SEQ ID NO:5 position corresponding to H; xiv) SEQ ID NO:5 position corresponding to L; xv) SEQ ID NO:5 position corresponding to I or L; xvii) SEQ ID NO:5 position corresponding to F; xvii) SEQ ID NO:5 position corresponding to NO:5 position 121 corresponding to E, T, A, G, or V; xviii) SEQ ID NO:5 position 122 corresponding to I or H; xix) SEQ ID NO:5 position 125 corresponding to K; xx) SEQ ID NO:5 position 126 corresponding to A; xxi) SEQ ID NO:5 position 135 corresponding to H; xxii) SEQ ID NO:5 position 137 corresponding to V; xxiii) SEQ ID NO:5 position 138 corresponding to Y; xxiv) SEQ ID NO:5 position 139 corresponding to L; xxv) SEQ ID NO:5 position 142 corresponding to K or A; xxvi) SEQ ID NO:5 position 145 corresponding to A, Q, L, or M; xxvii) SEQ ID NO:5 position 146 corresponding to A, Q, L, or M; NO:5 position 148 corresponding to K; xxviii) SEQ ID NO:5 position 151 corresponding to Q; xxix) SEQ ID NO:5 position 153 corresponding to E or R; xxx) SEQ ID NO:5 position 155 corresponding to W; xxxi) SEQ ID NO:5 position 156 corresponding to R or V; xxxii) SEQ ID NO:5 position 157 corresponding to F; xxxiii) SEQ ID NO:5 position 158 corresponding to R; xxxiv) SEQ ID NO:5 position 159 corresponding to Q; xxxv) SEQ ID NO:5 position 160 corresponding to D or W; xxxvi) SEQ ID NO:5 position 162 corresponding to W, H, V, or A; xxxvii) SEQ ID NO:5 position 163 corresponding to W, H, V, or A; R at the position corresponding to position 165 of SEQ ID NO:5; and xxxviii) H at the position corresponding to position 166 of SEQ ID NO:5. 199. The composition of embodiment 198, wherein the second deaminase comprises at least one of the following amino acid residues: a) C at a position corresponding to position 2 of SEQ ID NO: 5; b) F or C at a position corresponding to position 22 of SEQ ID NO: 5; c) Q at a position corresponding to position 23 of SEQ ID NO: 5; d) N at a position corresponding to position 35 of SEQ ID NO: 5; e) L at a position corresponding to position 40 of SEQ ID NO: 5; f) A at a position corresponding to position 68 of SEQ ID NO: 5; g) W, A, Q, or Y at a position corresponding to position 75 of SEQ ID NO: 5; h) G at a position corresponding to position 76 of SEQ ID NO: 5; i) S at a position corresponding to position 81 of SEQ ID NO: 5; j) M at a position corresponding to position 105 of SEQ ID NO: 5; k) H at the position corresponding to position 108 of SEQ ID NO: 5; l) L at the position corresponding to position 109 of SEQ ID NO: 5; m) I or L at the position corresponding to position 117 of SEQ ID NO: 5; n) A or G at the position corresponding to position 121 of SEQ ID NO: 5; o) H at the position corresponding to position 122 of SEQ ID NO: 5; p) A at the position corresponding to position 126 of SEQ ID NO: 5; q) H at the position corresponding to position 135 of SEQ ID NO: 5; r) V at the position corresponding to position 137 of SEQ ID NO: 5; s) Y at the position corresponding to position 138 of SEQ ID NO: 5; t) L at the position corresponding to position 139 of SEQ ID NO: 5; u) K or A at the position corresponding to position 142 of SEQ ID NO: 5; v) A, Q, L, or M at the position corresponding to position 145 of SEQ ID NO: 5; w) E or R at the position corresponding to position 153 of SEQ ID NO: 5; x) W at the position corresponding to position 155 of SEQ ID NO: 5; y) R at the position corresponding to position 156 of SEQ ID NO: 5; z) F at the position corresponding to position 157 of SEQ ID NO: 5; aa) R at the position corresponding to position 158 of SEQ ID NO: 5; bb) Q at the position corresponding to position 159 of SEQ ID NO: 5; cc) D or W at the position corresponding to position 160 of SEQ ID NO: 5; dd) A or W at the position corresponding to position 162 of SEQ ID NO: 5; and ee) R at the position corresponding to position 165 of SEQ ID NO: 5. 200. Composition 198 of the embodiment, wherein the second deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5 and W at a position corresponding to position 162 of SEQ ID NO: 5; b) N at a position corresponding to position 35 of SEQ ID NO: 5 and Q at a position corresponding to position 46 of SEQ ID NO: 5; c) S at a position corresponding to position 81 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; d) Q at a position corresponding to position 46 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; e) R at a position corresponding to position 156 of SEQ ID NO: 5 and W at a position corresponding to position 162 of SEQ ID NO: 5; f) A at a position corresponding to position 68 of SEQ ID NO: 5 and S at a position corresponding to position 81 of SEQ ID NO: 5; g) N at the position corresponding to position 35 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position 162; h) N at the position corresponding to position 35 of SEQ ID NO: 5, Q at the position corresponding to position 46 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; i) W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; j) N at the position corresponding to position 35 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; k) N at the position corresponding to position 35 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and Q at the position corresponding to position 162 of SEQ ID NO: 5 NO: 5, R at the position corresponding to position 156, and W at the position corresponding to position 162 of SEQ ID NO: 5; l) M at the position corresponding to position 68 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; m) Q at the position corresponding to position 46 of SEQ ID NO: 5, M at the position corresponding to position 68 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; n) M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and S at the position corresponding to position 162 of SEQ ID NO: 5; NO:5 position 108 corresponding to H, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; o) N corresponding to position 35, Q corresponding to position 46, SEQ ID NO:5 position 68 corresponding to M, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 155 corresponding to W, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; p) S corresponding to position 81, SEQ ID NO:5 position 155 corresponding to W; q) W corresponding to position 75, SEQ ID NO:5 position 76 corresponding to M, SEQ ID NO:5 position 87 corresponding to S; SEQ ID NO:5 position 88 corresponding to H, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 155 corresponding to W, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; p) S corresponding to position 81, SEQ ID NO:5 position 155 corresponding to W; q) W corresponding to position 75, SEQ ID NO:5 position 86 corresponding to M, SEQ ID NO:5 position 87 corresponding to S; NO:5 at the position corresponding to position 81; r) S at the position corresponding to position 81 of SEQ ID NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5; s) S at the position corresponding to position 81 of SEQ ID NO:5, and A at the position corresponding to position 145 of SEQ ID NO:5; t) W at the position corresponding to position 75 of SEQ ID NO:5, and W at the position corresponding to position 155 of SEQ ID NO:5; u) W at the position corresponding to position 155 of SEQ ID NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5; v) A at the position corresponding to position 145 of SEQ ID NO:5, and W at the position corresponding to position 155 of SEQ ID NO:5; w) W at the position corresponding to position 75 of SEQ ID NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5; x) W at the position corresponding to position 75 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; y) A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; z) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; aa) S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; bb) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; cc) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; dd) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; ee) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ff) W at the position corresponding to position 75 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; gg) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5 NO:5 position 145 A, and SEQ ID NO:5 position 155 W; hh) SEQ ID NO:5 position 145 A, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; ii) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 145 A, and SEQ ID NO:5 position 160 D; jj) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; kk) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 155 S, and SEQ ID NO:5 position 160 D; NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, and SEQ ID NO:5 position 155 corresponding to W; ll) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; mm) SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, and SEQ ID NO:5 position 160 corresponding to D; nn)  SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 155 corresponding to D, and SEQ ID NO:5 position 160 corresponding to D; NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; oo) SEQ ID NO: 5 position 75 corresponding to W, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; pp) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 105 corresponding to M; qq) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 121 corresponding to V; rr) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 145 corresponding to M; ss) L at the position corresponding to position 40 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; tt) L at the position corresponding to position 40 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; uu) M at the position corresponding to position 105 of SEQ ID NO: 5, and V at the position corresponding to position 121 of SEQ ID NO: 5; vv) M at the position corresponding to position 105 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; ww) M at the position corresponding to position 105 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; xx) M at the position corresponding to position 105 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; yy) NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 145 corresponding to M; zz) SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 159 corresponding to Q; aaa) SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 160 corresponding to W; bbb) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 159 corresponding to Q; ccc) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; ddd) SEQ ID NO:5 position 159 corresponding to Q, and SEQ ID NO:5 position 160 corresponding to W; eee) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; fff) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 159 corresponding to Q; ggg) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 81 corresponding to S; hhh) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; iii) SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; jjj) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 81 corresponding to S; NO:5 position 76 corresponding to G; kkk) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 117 corresponding to L; lll) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; mmm) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; nnn) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ooo) SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; NO:5 position corresponding to L at position 117; ppp) A at position corresponding to position 68 of SEQ ID NO:5, G at position corresponding to position 76 of SEQ ID NO:5, and L at position corresponding to position 117 of SEQ ID NO:5; qqq) A at position corresponding to position 68 of SEQ ID NO:5, G at position corresponding to position 76 of SEQ ID NO:5, S at position corresponding to position 81 of SEQ ID NO:5, and L at position corresponding to position 117 of SEQ ID NO:5; rrr) S at position corresponding to position 81 of SEQ ID NO:5, L at position corresponding to position 109 of SEQ ID NO:5, E at position corresponding to position 153 of SEQ ID NO:5, W at position corresponding to position 155 of SEQ ID NO:5, and D at position corresponding to position 160 of SEQ ID NO:5; sss) A at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, L at the position corresponding to position 117 of SEQ ID NO: 5, A at the position corresponding to position 121 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ttt) Q at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, I at the position corresponding to position 117 of SEQ ID NO: 5, Q at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; uuu) NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; vvv) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 160 corresponding to D; vvv) SEQ ID NO:5 position 22 corresponding to A, SEQ ID NO:5 position 68 corresponding to Y, SEQ ID NO:5 position 75 corresponding to G, SEQ ID NO:5 position 76 corresponding to S, SEQ ID NO:5 position 81 corresponding to H, SEQ ID NO:5 position 108 corresponding to L, SEQ ID NO:5 position 117 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; H at the position corresponding to position 122 of SEQ ID NO: 5, Y at the position corresponding to position 138 of SEQ ID NO: 5, L at the position corresponding to position 139 of SEQ ID NO: 5, A at the position corresponding to position 142 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, R at the position corresponding to position 153 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, D at the position corresponding to position 160 of SEQ ID NO: 5, and H at the position corresponding to position 162 of SEQ ID NO: 5; or www) S at the position corresponding to position 81 of SEQ ID NO: 5. 201. The composition of embodiment 198 or 200, wherein the second deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5 and Q at a position corresponding to position 46 of SEQ ID NO: 5; b) S at a position corresponding to position 81 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; c) Q at a position corresponding to position 46 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; d) N at a position corresponding to position 35 of SEQ ID NO: 5, Q at a position corresponding to position 46 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; e) W at a position corresponding to position 155 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; f) N at the position corresponding to position 35 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; g) N at the position corresponding to position 35 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; h) M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; i) N at the position corresponding to position 35, Q at the position corresponding to position 46 of SEQ ID NO: 5, and Q at the position corresponding to position 47 of SEQ ID NO: 5. M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; j) S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; k) W at the position corresponding to position 75 of SEQ ID NO: 5, and S at the position corresponding to position 81 of SEQ ID NO: 5; l) S at the position corresponding to position 81 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; m) S at the position corresponding to position 81 of SEQ ID NO: 5, and R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; A at the position corresponding to position 145 of SEQ ID NO: 5; n) W at the position corresponding to position 75 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; o) W at the position corresponding to position 75 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; p) A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; q) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; r) S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; s) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; t) L at the position corresponding to position 40 of SEQ ID NO: 5, and M at the position corresponding to position 105 of SEQ ID NO: 5; u) L at the position corresponding to position 40 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; v) L at the position corresponding to position 40 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; w) L at the position corresponding to position 40 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; x) M at the position corresponding to position 105 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; y) M at the position corresponding to position 105 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; z) M at the position corresponding to position 145 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; aa) M at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; bb) Q at the position corresponding to position 159 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; cc) S at the position corresponding to position 81 of SEQ ID NO: 5, M at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; dd) A at the position corresponding to position 68 of SEQ ID NO: 5, and Q at the position corresponding to position 160 of SEQ ID NO: 5; NO:5 position 81 corresponding to S; ee) SEQ ID NO:5 position 76 corresponding to S, and SEQ ID NO:5 position 81 corresponding to S; ff) SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; gg) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 76 corresponding to G; hh) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 117 corresponding to L; ii) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; jj) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; ID NO:5 position 81 corresponding to S; kk) SEQ ID NO:5 position 68 corresponding to S, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ll) SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; mm) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; nn) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; NO:5 position 117 corresponding to L; oo) A corresponding to position 68 of SEQ ID NO:5 and S corresponding to position 81 of SEQ ID NO:5; pp) S corresponding to position 81 of SEQ ID NO:5, L corresponding to position 109 of SEQ ID NO:5, E corresponding to position 153 of SEQ ID NO:5, W corresponding to position 155 of SEQ ID NO:5, and D corresponding to position 160 of SEQ ID NO:5; qq) A corresponding to position 75 of SEQ ID NO:5, S corresponding to position 81 of SEQ ID NO:5, L corresponding to position 117 of SEQ ID NO:5, A corresponding to position 121 of SEQ ID NO:5, A corresponding to position 145 of SEQ ID NO:5, and D corresponding to position 160 of SEQ ID NO:5; NO: 5, W at the position corresponding to position 155, and D at the position corresponding to position 160 of SEQ ID NO: 5; rr) Q at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, I at the position corresponding to position 117 of SEQ ID NO: 5, Q at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ss) Y at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, L at the position corresponding to position 117 of SEQ ID NO: 5, G at the position corresponding to position 121 of SEQ ID NO: 5, L at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; tt) SEQ ID NO: 5 position 22 corresponding to W, SEQ ID NO: 5 position 68 corresponding to A, SEQ ID NO: 5 position 75 corresponding to Y, SEQ ID NO: 5 position 76 corresponding to G, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 108 corresponding to H, SEQ ID NO: 5 position 117 corresponding to L, SEQ ID NO: 5 position 122 corresponding to H, SEQ ID NO: 5 position 138 corresponding to Y, SEQ ID NO: 5 position 139 corresponding to L, SEQ ID NO: 5 position 142 corresponding to A, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 150 corresponding to L, SEQ ID NO: 5 position 151 corresponding to L, SEQ ID NO: 5 position 152 corresponding to L, SEQ ID NO: 5 position 153 corresponding to L, SEQ ID NO: 5 position 154 corresponding to L, SEQ ID NO: 5 position 156 corresponding to L, SEQ ID NO: 5 position 157 corresponding to L, SEQ ID NO: 5 position 158 corresponding to L, SEQ ID NO: 5 position 159 corresponding to L, SEQ ID NO: 5 position 160 corresponding to L, SEQ ID NO: 5 position 161 corresponding to L, SEQ ID NO: 5 position 162 corresponding to L, SEQ ID NO: 5 position 163 corresponding to L, SEQ ID NO: 5 position 164 corresponding to L, SEQ ID NO: 5 position 165 corresponding to L, SEQ ID NO: 5 position 166 corresponding to L, SEQ ID NO: 5 position 167 corresponding to L, SEQ ID NO: 5 position 168 corresponding to L R at the position corresponding to position 153 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, D at the position corresponding to position 160 of SEQ ID NO: 5, and H at the position corresponding to position 162 of SEQ ID NO: 5; uu) S at the position corresponding to position 81 of SEQ ID NO: 5; or vv) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. 202. The composition of any one of embodiments 198, 200 and 201, wherein the second deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5, S at a position corresponding to position 81 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; b) W at a position corresponding to position 75 of SEQ ID NO: 5, and W at a position corresponding to position 155 of SEQ ID NO: 5; c) S at a position corresponding to position 81 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; d) S at a position corresponding to position 81 of SEQ ID NO: 5, A at a position corresponding to position 145 of SEQ ID NO: 5, and D at a position corresponding to position 162 of SEQ ID NO: 5; NO:5 position 155 corresponding to W; e) S corresponding to position 81 of SEQ ID NO:5, M corresponding to position 145 of SEQ ID NO:5, and W corresponding to position 160 of SEQ ID NO:5; f) G corresponding to position 76 of SEQ ID NO:5, and S corresponding to position 81 of SEQ ID NO:5; g) S corresponding to position 81 of SEQ ID NO:5, and L corresponding to position 117 of SEQ ID NO:5; h) A corresponding to position 68 of SEQ ID NO:5, and S corresponding to position 81 of SEQ ID NO:5; i) S corresponding to position 81 of SEQ ID NO:5, L corresponding to position 109 of SEQ ID NO:5, E corresponding to position 153 of SEQ ID NO:5, and L corresponding to position 117 of SEQ ID NO:5; NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; j) SEQ ID NO: 5 position 75 corresponding to A, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 117 corresponding to L, SEQ ID NO: 5 position 121 corresponding to A, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; k) SEQ ID NO: 5 position 75 corresponding to Q, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 117 corresponding to I, SEQ ID NO: 5 position 145 corresponding to Q, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; NO:5 position 160 corresponding to D; l) SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; m) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 110 corresponding to H, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; m) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 121 corresponding to NO:5 position 117 corresponding to L, SEQ ID NO:5 position 122 corresponding to H, SEQ ID NO:5 position 138 corresponding to Y, SEQ ID NO:5 position 139 corresponding to L, SEQ ID NO:5 position 142 corresponding to A, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 153 corresponding to R, SEQ ID NO:5 position 155 corresponding to W, SEQ ID NO:5 position 156 corresponding to R, SEQ ID NO:5 position 160 corresponding to D, and SEQ ID NO:5 position 162 corresponding to H; n) SEQ ID NO:5 position 81 corresponding to S; or o) SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 163 corresponding to H; W at the position corresponding to position 155 of NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5. 203. The composition of any of embodiments 198-202, wherein the second adenine deaminase has at least 90% sequence identity with any of SEQ ID NOs: 300-414, 596-598, and 720-723. 204. The composition of any one of embodiments 198-202, wherein the second adenine deaminase has 95% sequence identity with any one of SEQ ID NOs: 300-414, 596-598, and 720-723. 205. The composition of any one of embodiments 198-202, wherein the second adenine deaminase has an amino acid sequence of any one of SEQ ID NOs: 300-414, 596-598, and 720-723. 206. A composition of any one of embodiments 198-205, wherein the first adenine deaminase has at least 85% sequence identity with SEQ ID NO: 5 and includes at least one of the following amino acid residues: a) C at a position corresponding to position 2 of SEQ ID NO: 5; b) F or C at a position corresponding to position 22 of SEQ ID NO: 5; c) Q at a position corresponding to position 23 of SEQ ID NO: 5; d) N at a position corresponding to position 35 of SEQ ID NO: 5; e) L at a position corresponding to position 40 of SEQ ID NO: 5; f) Q at a position corresponding to position 46 of SEQ ID NO: 5; g) A or M at a position corresponding to position 68 of SEQ ID NO: 5; h) H at a position corresponding to position 72 of SEQ ID NO: 5; i) W, A, Q, Y, or D at the position corresponding to position 75 of SEQ ID NO: 5; j) G at the position corresponding to position 76 of SEQ ID NO: 5; k) S at the position corresponding to position 81 of SEQ ID NO: 5; l) M at the position corresponding to position 105 of SEQ ID NO: 5; m) H at the position corresponding to position 108 of SEQ ID NO: 5; n) L at the position corresponding to position 109 of SEQ ID NO: 5; o) I or L at the position corresponding to position 117 of SEQ ID NO: 5; p) F at the position corresponding to position 120 of SEQ ID NO: 5; q) E, T, A, G, or V at the position corresponding to position 121 of SEQ ID NO: 5; r) I or H at the position corresponding to position 122 of SEQ ID NO: 5; s) K at the position corresponding to position 125 of SEQ ID NO: 5; t) A at the position corresponding to position 126 of SEQ ID NO: 5; u) H at the position corresponding to position 135 of SEQ ID NO: 5; v) V at the position corresponding to position 137 of SEQ ID NO: 5; w) Y at the position corresponding to position 138 of SEQ ID NO: 5; x) L at the position corresponding to position 139 of SEQ ID NO: 5; y) K or A at the position corresponding to position 142 of SEQ ID NO: 5; z) A, Q, L, or M at the position corresponding to position 145 of SEQ ID NO: 5; aa) K at the position corresponding to position 148 of SEQ ID NO: 5; bb) Q at the position corresponding to position 151 of SEQ ID NO: 5; cc) E or R at the position corresponding to position 153 of SEQ ID NO: 5; dd) NO:5 corresponding to position 155 W; ee) SEQ ID NO:5 corresponding to position 156 R or V; ff) SEQ ID NO:5 corresponding to position 157 F; gg) SEQ ID NO:5 corresponding to position 158 R; hh) SEQ ID NO:5 corresponding to position 159 Q; ii) SEQ ID NO:5 corresponding to position 160 D or W; jj) SEQ ID NO:5 corresponding to position 162 W, H, V, or A; kk) SEQ ID NO:5 corresponding to position 165 R; and ll) SEQ ID NO:5 corresponding to position 166 H. 207. The composition of embodiment 206, wherein the first deaminase comprises at least one of the following amino acid residues: a) C at a position corresponding to position 2 of SEQ ID NO: 5; b) F or C at a position corresponding to position 22 of SEQ ID NO: 5; c) Q at a position corresponding to position 23 of SEQ ID NO: 5; d) N at a position corresponding to position 35 of SEQ ID NO: 5; e) L at a position corresponding to position 40 of SEQ ID NO: 5; f) A at a position corresponding to position 68 of SEQ ID NO: 5; g) W, A, Q, or Y at a position corresponding to position 75 of SEQ ID NO: 5; h) G at a position corresponding to position 76 of SEQ ID NO: 5; i) S at a position corresponding to position 81 of SEQ ID NO: 5; j) M at a position corresponding to position 105 of SEQ ID NO: 5; k) H at the position corresponding to position 108 of SEQ ID NO: 5; l) L at the position corresponding to position 109 of SEQ ID NO: 5; m) I or L at the position corresponding to position 117 of SEQ ID NO: 5; n) A or G at the position corresponding to position 121 of SEQ ID NO: 5; o) H at the position corresponding to position 122 of SEQ ID NO: 5; p) A at the position corresponding to position 126 of SEQ ID NO: 5; q) H at the position corresponding to position 135 of SEQ ID NO: 5; r) V at the position corresponding to position 137 of SEQ ID NO: 5; s) Y at the position corresponding to position 138 of SEQ ID NO: 5; t) L at the position corresponding to position 139 of SEQ ID NO: 5; u) K or A at the position corresponding to position 142 of SEQ ID NO: 5; v) A, Q, L, or M at the position corresponding to position 145 of SEQ ID NO: 5; w) E or R at the position corresponding to position 153 of SEQ ID NO: 5; x) W at the position corresponding to position 155 of SEQ ID NO: 5; y) R at the position corresponding to position 156 of SEQ ID NO: 5; z) F at the position corresponding to position 157 of SEQ ID NO: 5; aa) R at the position corresponding to position 158 of SEQ ID NO: 5; bb) Q at the position corresponding to position 159 of SEQ ID NO: 5; cc) D or W at the position corresponding to position 160 of SEQ ID NO: 5; dd) A or W at the position corresponding to position 162 of SEQ ID NO: 5; and ee) R at the position corresponding to position 165 of SEQ ID NO: 5. 208. The composition of embodiment 206, wherein the first deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5 and W at a position corresponding to position 162 of SEQ ID NO: 5; b) N at a position corresponding to position 35 of SEQ ID NO: 5 and Q at a position corresponding to position 46 of SEQ ID NO: 5; c) S at a position corresponding to position 81 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; d) Q at a position corresponding to position 46 of SEQ ID NO: 5 and R at a position corresponding to position 156 of SEQ ID NO: 5; e) R at a position corresponding to position 156 of SEQ ID NO: 5 and W at a position corresponding to position 162 of SEQ ID NO: 5; f) A at a position corresponding to position 68 of SEQ ID NO: 5 and S at a position corresponding to position 81 of SEQ ID NO: 5; g) N at the position corresponding to position 35 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position 162; h) N at the position corresponding to position 35 of SEQ ID NO: 5, Q at the position corresponding to position 46 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; i) W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; j) N at the position corresponding to position 35 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; k) N at the position corresponding to position 35 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and Q at the position corresponding to position 162 of SEQ ID NO: 5 NO: 5, R at the position corresponding to position 156, and W at the position corresponding to position 162 of SEQ ID NO: 5; l) M at the position corresponding to position 68 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; m) Q at the position corresponding to position 46 of SEQ ID NO: 5, M at the position corresponding to position 68 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; n) M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and S at the position corresponding to position 162 of SEQ ID NO: 5; NO:5 position 108 corresponding to H, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; o) N corresponding to position 35, Q corresponding to position 46, SEQ ID NO:5 position 68 corresponding to M, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 155 corresponding to W, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; p) S corresponding to position 81, SEQ ID NO:5 position 155 corresponding to W; q) W corresponding to position 75, SEQ ID NO:5 position 76 corresponding to M, SEQ ID NO:5 position 87 corresponding to S; SEQ ID NO:5 position 88 corresponding to H, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 155 corresponding to W, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; p) S corresponding to position 81, SEQ ID NO:5 position 155 corresponding to W; q) W corresponding to position 75, SEQ ID NO:5 position 86 corresponding to M, SEQ ID NO:5 position 87 corresponding to S; NO:5 at the position corresponding to position 81; r) S at the position corresponding to position 81 of SEQ ID NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5; s) S at the position corresponding to position 81 of SEQ ID NO:5, and A at the position corresponding to position 145 of SEQ ID NO:5; t) W at the position corresponding to position 75 of SEQ ID NO:5, and W at the position corresponding to position 155 of SEQ ID NO:5; u) W at the position corresponding to position 155 of SEQ ID NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5; v) A at the position corresponding to position 145 of SEQ ID NO:5, and W at the position corresponding to position 155 of SEQ ID NO:5; w) W at the position corresponding to position 75 of SEQ ID NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5; x) W at the position corresponding to position 75 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; y) A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; z) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; aa) S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; bb) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; cc) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; dd) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; ee) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ff) W at the position corresponding to position 75 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; gg) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5 NO:5 position 145 A, and SEQ ID NO:5 position 155 W; hh) SEQ ID NO:5 position 145 A, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; ii) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 145 A, and SEQ ID NO:5 position 160 D; jj) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; kk) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 155 S, and SEQ ID NO:5 position 160 D; NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, and SEQ ID NO:5 position 155 corresponding to W; ll) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; mm) SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, and SEQ ID NO:5 position 160 corresponding to D; nn)  SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 155 corresponding to D, and SEQ ID NO:5 position 160 corresponding to D; NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; oo) SEQ ID NO: 5 position 75 corresponding to W, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; pp) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 105 corresponding to M; qq) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 121 corresponding to V; rr) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 145 corresponding to M; ss) L at the position corresponding to position 40 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; tt) L at the position corresponding to position 40 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; uu) M at the position corresponding to position 105 of SEQ ID NO: 5, and V at the position corresponding to position 121 of SEQ ID NO: 5; vv) M at the position corresponding to position 105 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; ww) M at the position corresponding to position 105 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; xx) M at the position corresponding to position 105 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; yy) NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 145 corresponding to M; zz) SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 159 corresponding to Q; aaa) SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 160 corresponding to W; bbb) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 159 corresponding to Q; ccc) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; ddd) SEQ ID NO:5 position 159 corresponding to Q, and SEQ ID NO:5 position 160 corresponding to W; eee) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; fff) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 159 corresponding to Q; ggg) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 81 corresponding to S; hhh) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; iii) SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; jjj) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 81 corresponding to S; NO:5 position 76 corresponding to G; kkk) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 117 corresponding to L; lll) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; mmm) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; nnn) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ooo) SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; NO:5 position corresponding to L at position 117; ppp) A at position corresponding to position 68 of SEQ ID NO:5, G at position corresponding to position 76 of SEQ ID NO:5, and L at position corresponding to position 117 of SEQ ID NO:5; qqq) A at position corresponding to position 68 of SEQ ID NO:5, G at position corresponding to position 76 of SEQ ID NO:5, S at position corresponding to position 81 of SEQ ID NO:5, and L at position corresponding to position 117 of SEQ ID NO:5; rrr) S at position corresponding to position 81 of SEQ ID NO:5, L at position corresponding to position 109 of SEQ ID NO:5, E at position corresponding to position 153 of SEQ ID NO:5, W at position corresponding to position 155 of SEQ ID NO:5, and D at position corresponding to position 160 of SEQ ID NO:5; sss) A at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, L at the position corresponding to position 117 of SEQ ID NO: 5, A at the position corresponding to position 121 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ttt) Q at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, I at the position corresponding to position 117 of SEQ ID NO: 5, Q at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; uuu) NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; vvv) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 160 corresponding to D; vvv) SEQ ID NO:5 position 22 corresponding to A, SEQ ID NO:5 position 68 corresponding to Y, SEQ ID NO:5 position 75 corresponding to G, SEQ ID NO:5 position 76 corresponding to S, SEQ ID NO:5 position 81 corresponding to H, SEQ ID NO:5 position 108 corresponding to L, SEQ ID NO:5 position 117 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; H at the position corresponding to position 122 of SEQ ID NO: 5, Y at the position corresponding to position 138 of SEQ ID NO: 5, L at the position corresponding to position 139 of SEQ ID NO: 5, A at the position corresponding to position 142 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, R at the position corresponding to position 153 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, D at the position corresponding to position 160 of SEQ ID NO: 5, and H at the position corresponding to position 162 of SEQ ID NO: 5; or www) S at the position corresponding to position 81 of SEQ ID NO: 5. 209. Embodiment 206 or the composition, wherein the first deaminase comprises: a) N at the position corresponding to position 35 of SEQ ID NO: 5 and Q at the position corresponding to position 46 of SEQ ID NO: 5; b) S at the position corresponding to position 81 of SEQ ID NO: 5 and R at the position corresponding to position 156 of SEQ ID NO: 5; c) Q at the position corresponding to position 46 of SEQ ID NO: 5 and R at the position corresponding to position 156 of SEQ ID NO: 5; d) N at the position corresponding to position 35 of SEQ ID NO: 5, Q at the position corresponding to position 46 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; e) W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; f) N at the position corresponding to position 35 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; g) N at the position corresponding to position 35 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; h) M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; i) N at the position corresponding to position 35, Q at the position corresponding to position 46 of SEQ ID NO: 5, Q at the position corresponding to position 57 of SEQ ID NO: 5, and Q at the position corresponding to position 66 of SEQ ID NO: 5. NO: 5 position 68 corresponding to M, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 108 corresponding to H, SEQ ID NO: 5 position 155 corresponding to W, SEQ ID NO: 5 position 156 corresponding to R, and SEQ ID NO: 5 position 162 corresponding to W; j) SEQ ID NO: 5 position 81 corresponding to S, and SEQ ID NO: 5 position 155 corresponding to W; k) SEQ ID NO: 5 position 75 corresponding to W, and SEQ ID NO: 5 position 81 corresponding to S; l) SEQ ID NO: 5 position 81 corresponding to S, and SEQ ID NO: 5 position 160 corresponding to D; m) SEQ ID NO: 5 position 81 corresponding to S, and SEQ ID NO: 5 position 162 corresponding to R; A at the position corresponding to position 145 of SEQ ID NO: 5; n) W at the position corresponding to position 75 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; o) W at the position corresponding to position 75 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; p) A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; q) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; r) S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; s) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; t) L at the position corresponding to position 40 of SEQ ID NO: 5, and M at the position corresponding to position 105 of SEQ ID NO: 5; u) L at the position corresponding to position 40 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; v) L at the position corresponding to position 40 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; w) L at the position corresponding to position 40 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; x) M at the position corresponding to position 105 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; y) M at the position corresponding to position 105 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; z) M at the position corresponding to position 145 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; aa) M at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; bb) Q at the position corresponding to position 159 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; cc) S at the position corresponding to position 81 of SEQ ID NO: 5, M at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; dd) A at the position corresponding to position 68 of SEQ ID NO: 5, and Q at the position corresponding to position 160 of SEQ ID NO: 5; NO:5 position 81 corresponding to S; ee) SEQ ID NO:5 position 76 corresponding to S, and SEQ ID NO:5 position 81 corresponding to S; ff) SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; gg) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 76 corresponding to G; hh) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 117 corresponding to L; ii) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; jj) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; ID NO:5 position 81 corresponding to S; kk) SEQ ID NO:5 position 68 corresponding to S, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ll) SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; mm) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; nn) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; NO:5 position 117 corresponding to L; oo) SEQ ID NO:5 position 68 corresponding to L and SEQ ID NO:5 position 81 corresponding to S; pp) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 109 corresponding to L, SEQ ID NO:5 position 153 corresponding to E, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; qq) SEQ ID NO:5 position 75 corresponding to A, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to A, SEQ ID NO:5 position 145 corresponding to E, SEQ ID NO:5 position 156 corresponding to W, and SEQ ID NO:5 position 167 corresponding to D; qq) SEQ ID NO:5 position 75 corresponding to A, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to A, SEQ ID NO:5 position 146 corresponding to E, SEQ ID NO:5 position 157 corresponding to W, and SEQ ID NO:5 position 168 corresponding to D; NO: 5, W at the position corresponding to position 155, and D at the position corresponding to position 160 of SEQ ID NO: 5; rr) Q at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, I at the position corresponding to position 117 of SEQ ID NO: 5, Q at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ss) Y at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, L at the position corresponding to position 117 of SEQ ID NO: 5, G at the position corresponding to position 121 of SEQ ID NO: 5, L at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; tt) SEQ ID NO: 5 position 22 corresponding to W, SEQ ID NO: 5 position 68 corresponding to A, SEQ ID NO: 5 position 75 corresponding to Y, SEQ ID NO: 5 position 76 corresponding to G, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 108 corresponding to H, SEQ ID NO: 5 position 117 corresponding to L, SEQ ID NO: 5 position 122 corresponding to H, SEQ ID NO: 5 position 138 corresponding to Y, SEQ ID NO: 5 position 139 corresponding to L, SEQ ID NO: 5 position 142 corresponding to A, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 150 corresponding to L, SEQ ID NO: 5 position 151 corresponding to L, SEQ ID NO: 5 position 152 corresponding to L, SEQ ID NO: 5 position 153 corresponding to L, SEQ ID NO: 5 position 154 corresponding to L, SEQ ID NO: 5 position 156 corresponding to L, SEQ ID NO: 5 position 157 corresponding to L, SEQ ID NO: 5 position 158 corresponding to L, SEQ ID NO: 5 position 159 corresponding to L, SEQ ID NO: 5 position 160 corresponding to L, SEQ ID NO: 5 position 161 corresponding to L, SEQ ID NO: 5 position 162 corresponding to L, SEQ ID NO: 5 position 163 corresponding to L, SEQ ID NO: 5 position 164 corresponding to L, SEQ ID NO: 5 position 165 corresponding to L, SEQ ID NO: 5 position 166 corresponding to L, SEQ ID NO: 5 position 167 corresponding to L, SEQ ID NO: 5 position 168 corresponding to L R at the position corresponding to position 153 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, D at the position corresponding to position 160 of SEQ ID NO: 5, and H at the position corresponding to position 162 of SEQ ID NO: 5; uu) S at the position corresponding to position 81 of SEQ ID NO: 5; or vv) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. 210. The composition of any one of embodiments 206, 208 or 209, wherein the first deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5, S at a position corresponding to position 81 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; b) W at a position corresponding to position 75 of SEQ ID NO: 5, and W at a position corresponding to position 155 of SEQ ID NO: 5; c) S at a position corresponding to position 81 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; d) S at a position corresponding to position 81 of SEQ ID NO: 5, A at a position corresponding to position 145 of SEQ ID NO: 5, and D at a position corresponding to position 162 of SEQ ID NO: 5; NO:5 position 155 corresponding to W; e) S corresponding to position 81 of SEQ ID NO:5, M corresponding to position 145 of SEQ ID NO:5, and W corresponding to position 160 of SEQ ID NO:5; f) G corresponding to position 76 of SEQ ID NO:5, and S corresponding to position 81 of SEQ ID NO:5; g) S corresponding to position 81 of SEQ ID NO:5, and L corresponding to position 117 of SEQ ID NO:5; h) A corresponding to position 68 of SEQ ID NO:5, and S corresponding to position 81 of SEQ ID NO:5; i) S corresponding to position 81 of SEQ ID NO:5, L corresponding to position 109 of SEQ ID NO:5, E corresponding to position 153 of SEQ ID NO:5, and L corresponding to position 117 of SEQ ID NO:5; NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; j) SEQ ID NO: 5 position 75 corresponding to A, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 117 corresponding to L, SEQ ID NO: 5 position 121 corresponding to A, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; k) SEQ ID NO: 5 position 75 corresponding to Q, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 117 corresponding to I, SEQ ID NO: 5 position 145 corresponding to Q, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; NO:5 position 160 corresponding to D; l) SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; m) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 110 corresponding to H, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; m) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 121 corresponding to NO:5 position 117 corresponding to L, SEQ ID NO:5 position 122 corresponding to H, SEQ ID NO:5 position 138 corresponding to Y, SEQ ID NO:5 position 139 corresponding to L, SEQ ID NO:5 position 142 corresponding to A, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 153 corresponding to R, SEQ ID NO:5 position 155 corresponding to W, SEQ ID NO:5 position 156 corresponding to R, SEQ ID NO:5 position 160 corresponding to D, and SEQ ID NO:5 position 162 corresponding to H; n) SEQ ID NO:5 position 81 corresponding to S; or o) SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 163 corresponding to H; W at the position corresponding to position 155 of NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. 211. The composition of any of embodiments 206-210, wherein the first adenine deaminase has at least 90% sequence identity with any of SEQ ID NOs: 300-414, 596, 597 and 598, 720-723. 212. The composition of any one of embodiments 206-210, wherein the first adenine deaminase has 95% sequence identity with any one of SEQ ID NOs: 300-414, 596-598, and 720-723. 213. The composition of any one of embodiments 206-210, wherein the first adenine deaminase has an amino acid sequence of any one of SEQ ID NOs: 300-414, 596-598, and 720-723. 214. The composition of any of embodiments 198-213, wherein the DNA binding polypeptide is a meganuclease, a zinc finger fusion protein, or a TALEN. 215. The composition of any of embodiments 198-213, wherein the DNA binding polypeptide is an RNA-guided DNA binding polypeptide. 216. The composition of embodiment 215, wherein the RNA-guided DNA-binding polypeptide is an RNA-guided nuclease (RGN) polypeptide. 217. The composition of embodiment 216, wherein the RGN is an RGN nickase. 218. A vector comprising a first amino acid molecule encoding a fusion protein and a second amino acid molecule encoding a second deaminase, wherein the fusion protein comprises a DNA binding polypeptide and a first adenine deaminase, wherein the second adenine deaminase has at least 85% sequence identity with SEQ ID NO: 5, and wherein the second adenine deaminase has at least one of the following amino acid residues: a) C at a position corresponding to position 2 of SEQ ID NO: 5; b) F or C at a position corresponding to position 22 of SEQ ID NO: 5; c) Q at a position corresponding to position 23 of SEQ ID NO: 5; d) N at a position corresponding to position 35 of SEQ ID NO: 5; e) L at a position corresponding to position 40 of SEQ ID NO: 5; f) Q at a position corresponding to position 46 of SEQ ID NO: 5; g) A or M at a position corresponding to position 68 of SEQ ID NO: 5; h) NO:5 at the position corresponding to position 72; i) W, A, Q, Y, or D at the position corresponding to position 75 of SEQ ID NO:5; j) G at the position corresponding to position 76 of SEQ ID NO:5; k) S at the position corresponding to position 81 of SEQ ID NO:5; l) M at the position corresponding to position 105 of SEQ ID NO:5; m) H at the position corresponding to position 108 of SEQ ID NO:5; n) L at the position corresponding to position 109 of SEQ ID NO:5; o) I or L at the position corresponding to position 117 of SEQ ID NO:5; p) F at the position corresponding to position 120 of SEQ ID NO:5; q) E, T, A, G, or V at the position corresponding to position 121 of SEQ ID NO:5; r) I or H at the position corresponding to position 122 of SEQ ID NO:5; s) K at the position corresponding to position 125 of SEQ ID NO: 5; t) A at the position corresponding to position 126 of SEQ ID NO: 5; u) H at the position corresponding to position 135 of SEQ ID NO: 5; v) V at the position corresponding to position 137 of SEQ ID NO: 5; w) Y at the position corresponding to position 138 of SEQ ID NO: 5; x) L at the position corresponding to position 139 of SEQ ID NO: 5; y) K or A at the position corresponding to position 142 of SEQ ID NO: 5; z) A, Q, L, or M at the position corresponding to position 145 of SEQ ID NO: 5; aa) K at the position corresponding to position 148 of SEQ ID NO: 5; bb) Q at the position corresponding to position 151 of SEQ ID NO: 5; cc) NO:5 position corresponding to E or R; dd) SEQ ID NO:5 position corresponding to W; ee) SEQ ID NO:5 position corresponding to R or V; ff) SEQ ID NO:5 position corresponding to F; gg) SEQ ID NO:5 position corresponding to R; hh) SEQ ID NO:5 position corresponding to Q; ii) SEQ ID NO:5 position corresponding to D or W; jj) SEQ ID NO:5 position corresponding to W, H, V, or A; kk) SEQ ID NO:5 position corresponding to R; and ll) SEQ ID NO:5 position corresponding to H. 219. The carrier of embodiment 218, wherein the second deaminase comprises at least one of the following amino acid residues: a) C at the position corresponding to position 2 of SEQ ID NO: 5; b) F or C at the position corresponding to position 22 of SEQ ID NO: 5; c) Q at the position corresponding to position 23 of SEQ ID NO: 5; d) N at the position corresponding to position 35 of SEQ ID NO: 5; e) L at the position corresponding to position 40 of SEQ ID NO: 5; f) A at the position corresponding to position 68 of SEQ ID NO: 5; g) W, A, Q, or Y at the position corresponding to position 75 of SEQ ID NO: 5; h) G at the position corresponding to position 76 of SEQ ID NO: 5; i) S at the position corresponding to position 81 of SEQ ID NO: 5; j) M at the position corresponding to position 105 of SEQ ID NO: 5; k) ID NO: 5 position 108 corresponding to H; l) SEQ ID NO: 5 position 109 corresponding to L; m) SEQ ID NO: 5 position 117 corresponding to I or L; n) SEQ ID NO: 5 position 121 corresponding to A or G; o) SEQ ID NO: 5 position 122 corresponding to H; p) SEQ ID NO: 5 position 126 corresponding to A; q) SEQ ID NO: 5 position 135 corresponding to H; r) SEQ ID NO: 5 position 137 corresponding to V; s) SEQ ID NO: 5 position 138 corresponding to Y; t) SEQ ID NO: 5 position 139 corresponding to L; u) SEQ ID NO: 5 position 142 corresponding to K or A; v) SEQ ID NO: A, Q, L, or M at the position corresponding to position 145 of SEQ ID NO: 5; w) E or R at the position corresponding to position 153 of SEQ ID NO: 5; x) W at the position corresponding to position 155 of SEQ ID NO: 5; y) R at the position corresponding to position 156 of SEQ ID NO: 5; z) F at the position corresponding to position 157 of SEQ ID NO: 5; aa) R at the position corresponding to position 158 of SEQ ID NO: 5; bb) Q at the position corresponding to position 159 of SEQ ID NO: 5; cc) D or W at the position corresponding to position 160 of SEQ ID NO: 5; dd) A or W at the position corresponding to position 162 of SEQ ID NO: 5; and ee) R at the position corresponding to position 165 of SEQ ID NO: 5. 220. The carrier of embodiment 218, wherein the second deaminase comprises: a) N at the position corresponding to position 35 of SEQ ID NO: 5 and W at the position corresponding to position 162 of SEQ ID NO: 5; b) N at the position corresponding to position 35 of SEQ ID NO: 5 and Q at the position corresponding to position 46 of SEQ ID NO: 5; c) S at the position corresponding to position 81 of SEQ ID NO: 5 and R at the position corresponding to position 156 of SEQ ID NO: 5; d) Q at the position corresponding to position 46 of SEQ ID NO: 5 and R at the position corresponding to position 156 of SEQ ID NO: 5; e) R at the position corresponding to position 156 of SEQ ID NO: 5 and W at the position corresponding to position 162 of SEQ ID NO: 5; f) A at the position corresponding to position 68 of SEQ ID NO: 5 and S at the position corresponding to position 81 of SEQ ID NO: 5; g) N at the position corresponding to position 35 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position 162; h) N at the position corresponding to position 35 of SEQ ID NO: 5, Q at the position corresponding to position 46 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; i) W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; j) N at the position corresponding to position 35 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; k) N at the position corresponding to position 35 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and Q at the position corresponding to position 162 of SEQ ID NO: 5 NO: 5, R at the position corresponding to position 156, and W at the position corresponding to position 162 of SEQ ID NO: 5; l) M at the position corresponding to position 68 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; m) Q at the position corresponding to position 46 of SEQ ID NO: 5, M at the position corresponding to position 68 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; n) M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5 NO:5 position 108 corresponding to H, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; o) N corresponding to position 35, Q corresponding to position 46, SEQ ID NO:5 position 68 corresponding to M, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 155 corresponding to W, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; p) S corresponding to position 81, SEQ ID NO:5 position 155 corresponding to W; q) W corresponding to position 75, SEQ ID NO:5 position 76 corresponding to M, SEQ ID NO:5 position 87 corresponding to H, SEQ ID NO:5 position 88 corresponding to W, SEQ ID NO:5 position 89 corresponding to R, and SEQ ID NO:5 position 90 corresponding to W; NO:5 position corresponding to S; r) SEQ ID NO:5 position corresponding to S, and SEQ ID NO:5 position corresponding to D; s) SEQ ID NO:5 position corresponding to S, and SEQ ID NO:5 position corresponding to A; t) SEQ ID NO:5 position corresponding to W, and SEQ ID NO:5 position corresponding to W; u) SEQ ID NO:5 position corresponding to W, and SEQ ID NO:5 position corresponding to D; v) SEQ ID NO:5 position corresponding to A, and SEQ ID NO:5 position corresponding to W; w) SEQ ID NO:5 position corresponding to W, and SEQ ID NO:5 position corresponding to D; x) W at the position corresponding to position 75 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; y) A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; z) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; aa) S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; bb) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; cc) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; dd) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; ee) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ff) W at the position corresponding to position 75 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; gg) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5 NO:5 position 145 A, and SEQ ID NO:5 position 155 W; hh) SEQ ID NO:5 position 145 A, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; ii) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 145 A, and SEQ ID NO:5 position 160 D; jj) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 81 S, SEQ ID NO:5 position 155 W, and SEQ ID NO:5 position 160 D; kk) SEQ ID NO:5 position 75 W, SEQ ID NO:5 position 155 S, and SEQ ID NO:5 position 160 D; NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, and SEQ ID NO:5 position 155 corresponding to W; ll) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; mm) SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, and SEQ ID NO:5 position 160 corresponding to D; nn)  SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 155 corresponding to D, and SEQ ID NO:5 position 160 corresponding to D; NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; oo) SEQ ID NO: 5 position 75 corresponding to W, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; pp) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 105 corresponding to M; qq) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 121 corresponding to V; rr) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 145 corresponding to M; ss) L at the position corresponding to position 40 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; tt) L at the position corresponding to position 40 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; uu) M at the position corresponding to position 105 of SEQ ID NO: 5, and V at the position corresponding to position 121 of SEQ ID NO: 5; vv) M at the position corresponding to position 105 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; ww) M at the position corresponding to position 105 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; xx) M at the position corresponding to position 105 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; yy) NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 145 corresponding to M; zz) SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 159 corresponding to Q; aaa) SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 160 corresponding to W; bbb) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 159 corresponding to Q; ccc) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; ddd) SEQ ID NO:5 position 159 corresponding to Q, and SEQ ID NO:5 position 160 corresponding to W; eee) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; fff) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 159 corresponding to Q; ggg) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 81 corresponding to S; hhh) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; iii) SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; jjj) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 81 corresponding to S; NO:5 position 76 corresponding to G; kkk) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 117 corresponding to L; lll) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; mmm) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; nnn) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ooo) SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; NO:5 position corresponding to L at position 117; ppp) A at position corresponding to position 68 of SEQ ID NO:5, G at position corresponding to position 76 of SEQ ID NO:5, and L at position corresponding to position 117 of SEQ ID NO:5; qqq) A at position corresponding to position 68 of SEQ ID NO:5, G at position corresponding to position 76 of SEQ ID NO:5, S at position corresponding to position 81 of SEQ ID NO:5, and L at position corresponding to position 117 of SEQ ID NO:5; rrr) S at position corresponding to position 81 of SEQ ID NO:5, L at position corresponding to position 109 of SEQ ID NO:5, E at position corresponding to position 153 of SEQ ID NO:5, W at position corresponding to position 155 of SEQ ID NO:5, and D at position corresponding to position 160 of SEQ ID NO:5; sss) A at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, L at the position corresponding to position 117 of SEQ ID NO: 5, A at the position corresponding to position 121 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ttt) Q at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, I at the position corresponding to position 117 of SEQ ID NO: 5, Q at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; uuu) NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; vvv) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 160 corresponding to D; vvv) SEQ ID NO:5 position 22 corresponding to A, SEQ ID NO:5 position 68 corresponding to Y, SEQ ID NO:5 position 75 corresponding to G, SEQ ID NO:5 position 76 corresponding to S, SEQ ID NO:5 position 81 corresponding to H, SEQ ID NO:5 position 108 corresponding to L, SEQ ID NO:5 position 117 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; H at the position corresponding to position 122 of SEQ ID NO: 5, Y at the position corresponding to position 138 of SEQ ID NO: 5, L at the position corresponding to position 139 of SEQ ID NO: 5, A at the position corresponding to position 142 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, R at the position corresponding to position 153 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, D at the position corresponding to position 160 of SEQ ID NO: 5, and H at the position corresponding to position 162 of SEQ ID NO: 5; or www) S at the position corresponding to position 81 of SEQ ID NO: 5. 221. The carrier of embodiment 218 or 220, wherein the second deaminase comprises: a) N at the position corresponding to position 35 of SEQ ID NO: 5 and Q at the position corresponding to position 46 of SEQ ID NO: 5; b) S at the position corresponding to position 81 of SEQ ID NO: 5 and R at the position corresponding to position 156 of SEQ ID NO: 5; c) Q at the position corresponding to position 46 of SEQ ID NO: 5 and R at the position corresponding to position 156 of SEQ ID NO: 5; d) N at the position corresponding to position 35 of SEQ ID NO: 5, Q at the position corresponding to position 46 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; e) W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; f) N at the position corresponding to position 35 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; g) N at the position corresponding to position 35 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; h) M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; i) N at the position corresponding to position 35, Q at the position corresponding to position 46 of SEQ ID NO: 5, and Q at the position corresponding to position 47 of SEQ ID NO: 5. M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; j) S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; k) W at the position corresponding to position 75 of SEQ ID NO: 5, and S at the position corresponding to position 81 of SEQ ID NO: 5; l) S at the position corresponding to position 81 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; m) S at the position corresponding to position 81 of SEQ ID NO: 5, and R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; A at the position corresponding to position 145 of SEQ ID NO: 5; n) W at the position corresponding to position 75 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; o) W at the position corresponding to position 75 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; p) A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; q) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; r) S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; s) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; t) L at the position corresponding to position 40 of SEQ ID NO: 5, and M at the position corresponding to position 105 of SEQ ID NO: 5; u) L at the position corresponding to position 40 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; v) L at the position corresponding to position 40 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; w) L at the position corresponding to position 40 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; x) M at the position corresponding to position 105 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; y) M at the position corresponding to position 105 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; z) M at the position corresponding to position 145 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; aa) M at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; bb) Q at the position corresponding to position 159 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; cc) S at the position corresponding to position 81 of SEQ ID NO: 5, M at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; dd) A at the position corresponding to position 68 of SEQ ID NO: 5, and Q at the position corresponding to position 160 of SEQ ID NO: 5; NO:5 position 81 corresponding to S; ee) SEQ ID NO:5 position 76 corresponding to S, and SEQ ID NO:5 position 81 corresponding to S; ff) SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; gg) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 76 corresponding to G; hh) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 117 corresponding to L; ii) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; jj) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; ID NO:5 position 81 corresponding to S; kk) SEQ ID NO:5 position 68 corresponding to S, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ll) SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; mm) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; nn) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; NO:5 position 117 corresponding to L; oo) A corresponding to position 68 of SEQ ID NO:5 and S corresponding to position 81 of SEQ ID NO:5; pp) S corresponding to position 81 of SEQ ID NO:5, L corresponding to position 109 of SEQ ID NO:5, E corresponding to position 153 of SEQ ID NO:5, W corresponding to position 155 of SEQ ID NO:5, and D corresponding to position 160 of SEQ ID NO:5; qq) A corresponding to position 75 of SEQ ID NO:5, S corresponding to position 81 of SEQ ID NO:5, L corresponding to position 117 of SEQ ID NO:5, A corresponding to position 121 of SEQ ID NO:5, A corresponding to position 145 of SEQ ID NO:5, and D corresponding to position 160 of SEQ ID NO:5; NO: 5, W at the position corresponding to position 155, and D at the position corresponding to position 160 of SEQ ID NO: 5; rr) Q at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, I at the position corresponding to position 117 of SEQ ID NO: 5, Q at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ss) Y at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, L at the position corresponding to position 117 of SEQ ID NO: 5, G at the position corresponding to position 121 of SEQ ID NO: 5, L at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; tt) SEQ ID NO: 5 position 22 corresponding to W, SEQ ID NO: 5 position 68 corresponding to A, SEQ ID NO: 5 position 75 corresponding to Y, SEQ ID NO: 5 position 76 corresponding to G, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 108 corresponding to H, SEQ ID NO: 5 position 117 corresponding to L, SEQ ID NO: 5 position 122 corresponding to H, SEQ ID NO: 5 position 138 corresponding to Y, SEQ ID NO: 5 position 139 corresponding to L, SEQ ID NO: 5 position 142 corresponding to A, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 150 corresponding to L, SEQ ID NO: 5 position 151 corresponding to L, SEQ ID NO: 5 position 152 corresponding to L, SEQ ID NO: 5 position 153 corresponding to L, SEQ ID NO: 5 position 154 corresponding to L, SEQ ID NO: 5 position 156 corresponding to L, SEQ ID NO: 5 position 157 corresponding to L, SEQ ID NO: 5 position 158 corresponding to L, SEQ ID NO: 5 position 159 corresponding to L, SEQ ID NO: 5 position 160 corresponding to L, SEQ ID NO: 5 position 161 corresponding to L, SEQ ID NO: 5 position 162 corresponding to L, SEQ ID NO: 5 position 163 corresponding to L, SEQ ID NO: 5 position 164 corresponding to L, SEQ ID NO: 5 position 165 corresponding to L, SEQ ID NO: 5 position 166 corresponding to L, SEQ ID NO: 5 position 167 corresponding to L, SEQ ID NO: 5 position 168 corresponding to L R at the position corresponding to position 153 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, D at the position corresponding to position 160 of SEQ ID NO: 5, and H at the position corresponding to position 162 of SEQ ID NO: 5; uu) S at the position corresponding to position 81 of SEQ ID NO: 5; or vv) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. 222. The vector of any one of embodiments 218, 220 and 221, wherein the second deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5, S at a position corresponding to position 81 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; b) W at a position corresponding to position 75 of SEQ ID NO: 5, and W at a position corresponding to position 155 of SEQ ID NO: 5; c) S at a position corresponding to position 81 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; d) S at a position corresponding to position 81 of SEQ ID NO: 5, A at a position corresponding to position 145 of SEQ ID NO: 5, and D at a position corresponding to position 162 of SEQ ID NO: 5; NO:5 position 155 corresponding to W; e) S corresponding to position 81 of SEQ ID NO:5, M corresponding to position 145 of SEQ ID NO:5, and W corresponding to position 160 of SEQ ID NO:5; f) G corresponding to position 76 of SEQ ID NO:5, and S corresponding to position 81 of SEQ ID NO:5; g) S corresponding to position 81 of SEQ ID NO:5, and L corresponding to position 117 of SEQ ID NO:5; h) A corresponding to position 68 of SEQ ID NO:5, and S corresponding to position 81 of SEQ ID NO:5; i) S corresponding to position 81 of SEQ ID NO:5, L corresponding to position 109 of SEQ ID NO:5, E corresponding to position 153 of SEQ ID NO:5, and L corresponding to position 117 of SEQ ID NO:5; NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; j) SEQ ID NO: 5 position 75 corresponding to A, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 117 corresponding to L, SEQ ID NO: 5 position 121 corresponding to A, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; k) SEQ ID NO: 5 position 75 corresponding to Q, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 117 corresponding to I, SEQ ID NO: 5 position 145 corresponding to Q, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; NO:5 position 160 corresponding to D; l) SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; m) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 110 corresponding to H, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; m) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 121 corresponding to NO:5 position 117 corresponding to L, SEQ ID NO:5 position 122 corresponding to H, SEQ ID NO:5 position 138 corresponding to Y, SEQ ID NO:5 position 139 corresponding to L, SEQ ID NO:5 position 142 corresponding to A, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 153 corresponding to R, SEQ ID NO:5 position 155 corresponding to W, SEQ ID NO:5 position 156 corresponding to R, SEQ ID NO:5 position 160 corresponding to D, and SEQ ID NO:5 position 162 corresponding to H; n) SEQ ID NO:5 position 81 corresponding to S; or o) SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 163 corresponding to H; W at the position corresponding to position 155 of NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5. 223. The vector of any one of embodiments 218-222, wherein the second adenine deaminase has at least 90% sequence identity with SEQ ID NO: 5. 224. The vector of any one of embodiments 218-222, wherein the second adenine deaminase has at least 95% sequence identity with SEQ ID NO: 5. 225. A vector of any one of embodiments 218-222, wherein the second adenine deaminase has an amino acid sequence of any one of SEQ ID Nos: 300-414, 596-598, and 720-723. 226. A vector of any one of embodiments 218-225, wherein the first adenine deaminase has at least 85% sequence identity with SEQ ID NO: 5 and comprises at least one of the following amino acid residues: a) C at a position corresponding to position 2 of SEQ ID NO: 5; b) F or C at a position corresponding to position 22 of SEQ ID NO: 5; c) Q at a position corresponding to position 23 of SEQ ID NO: 5; d) N at a position corresponding to position 35 of SEQ ID NO: 5; e) L at a position corresponding to position 40 of SEQ ID NO: 5; f) Q at a position corresponding to position 46 of SEQ ID NO: 5; g) A or M at a position corresponding to position 68 of SEQ ID NO: 5; h) H at a position corresponding to position 72 of SEQ ID NO: 5; i) W, A, Q, Y, or D at the position corresponding to position 75 of SEQ ID NO: 5; j) G at the position corresponding to position 76 of SEQ ID NO: 5; k) S at the position corresponding to position 81 of SEQ ID NO: 5; l) M at the position corresponding to position 105 of SEQ ID NO: 5; m) H at the position corresponding to position 108 of SEQ ID NO: 5; n) L at the position corresponding to position 109 of SEQ ID NO: 5; o) I or L at the position corresponding to position 117 of SEQ ID NO: 5; p) F at the position corresponding to position 120 of SEQ ID NO: 5; q) E, T, A, G, or V at the position corresponding to position 121 of SEQ ID NO: 5; r) I or H at the position corresponding to position 122 of SEQ ID NO: 5; s) K at the position corresponding to position 125 of SEQ ID NO: 5; t) A at the position corresponding to position 126 of SEQ ID NO: 5; u) H at the position corresponding to position 135 of SEQ ID NO: 5; v) V at the position corresponding to position 137 of SEQ ID NO: 5; w) Y at the position corresponding to position 138 of SEQ ID NO: 5; x) L at the position corresponding to position 139 of SEQ ID NO: 5; y) K or A at the position corresponding to position 142 of SEQ ID NO: 5; z) A, Q, L, or M at the position corresponding to position 145 of SEQ ID NO: 5; aa) K at the position corresponding to position 148 of SEQ ID NO: 5; bb) Q at the position corresponding to position 151 of SEQ ID NO: 5; cc) E or R at the position corresponding to position 153 of SEQ ID NO: 5; dd) NO:5 corresponding to position 155 W; ee) SEQ ID NO:5 corresponding to position 156 R or V; ff) SEQ ID NO:5 corresponding to position 157 F; gg) SEQ ID NO:5 corresponding to position 158 R; hh) SEQ ID NO:5 corresponding to position 159 Q; ii) SEQ ID NO:5 corresponding to position 160 D or W; jj) SEQ ID NO:5 corresponding to position 162 W, H, V, or A; kk) SEQ ID NO:5 corresponding to position 165 R; and ll) SEQ ID NO:5 corresponding to position 166 H. 227. The carrier of embodiment 226, wherein the first deaminase comprises at least one of the following amino acid residues: a) C at the position corresponding to position 2 of SEQ ID NO: 5; b) F or C at the position corresponding to position 22 of SEQ ID NO: 5; c) Q at the position corresponding to position 23 of SEQ ID NO: 5; d) N at the position corresponding to position 35 of SEQ ID NO: 5; e) L at the position corresponding to position 40 of SEQ ID NO: 5; f) A at the position corresponding to position 68 of SEQ ID NO: 5; g) W, A, Q, or Y at the position corresponding to position 75 of SEQ ID NO: 5; h) G at the position corresponding to position 76 of SEQ ID NO: 5; i) S at the position corresponding to position 81 of SEQ ID NO: 5; j) M at the position corresponding to position 105 of SEQ ID NO: 5; k) H at the position corresponding to position 108 of SEQ ID NO: 5; l) L at the position corresponding to position 109 of SEQ ID NO: 5; m) I or L at the position corresponding to position 117 of SEQ ID NO: 5; n) A or G at the position corresponding to position 121 of SEQ ID NO: 5; o) H at the position corresponding to position 122 of SEQ ID NO: 5; p) A at the position corresponding to position 126 of SEQ ID NO: 5; q) H at the position corresponding to position 135 of SEQ ID NO: 5; r) V at the position corresponding to position 137 of SEQ ID NO: 5; s) Y at the position corresponding to position 138 of SEQ ID NO: 5; t) L at the position corresponding to position 139 of SEQ ID NO: 5; u) K or A at the position corresponding to position 142 of SEQ ID NO: 5; v) A, Q, L, or M at the position corresponding to position 145 of SEQ ID NO: 5; w) E or R at the position corresponding to position 153 of SEQ ID NO: 5; x) W at the position corresponding to position 155 of SEQ ID NO: 5; y) R at the position corresponding to position 156 of SEQ ID NO: 5; z) F at the position corresponding to position 157 of SEQ ID NO: 5; aa) R at the position corresponding to position 158 of SEQ ID NO: 5; bb) Q at the position corresponding to position 159 of SEQ ID NO: 5; cc) D or W at the position corresponding to position 160 of SEQ ID NO: 5; dd) A or W at the position corresponding to position 162 of SEQ ID NO: 5; and ee) R at the position corresponding to position 165 of SEQ ID NO: 5. 228. The carrier of embodiment 226, wherein the first deaminase comprises: a) N at the position corresponding to position 35 of SEQ ID NO: 5 and W at the position corresponding to position 162 of SEQ ID NO: 5; b) N at the position corresponding to position 35 of SEQ ID NO: 5 and Q at the position corresponding to position 46 of SEQ ID NO: 5; c) S at the position corresponding to position 81 of SEQ ID NO: 5 and R at the position corresponding to position 156 of SEQ ID NO: 5; d) Q at the position corresponding to position 46 of SEQ ID NO: 5 and R at the position corresponding to position 156 of SEQ ID NO: 5; e) R at the position corresponding to position 156 of SEQ ID NO: 5 and W at the position corresponding to position 162 of SEQ ID NO: 5; f) A at the position corresponding to position 68 of SEQ ID NO: 5 and S at the position corresponding to position 81 of SEQ ID NO: 5; g) N at the position corresponding to position 35 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position 162; h) N at the position corresponding to position 35 of SEQ ID NO: 5, Q at the position corresponding to position 46 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; i) W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; j) N at the position corresponding to position 35 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; k) N at the position corresponding to position 35 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and Q at the position corresponding to position 162 of SEQ ID NO: 5 NO: 5, R at the position corresponding to position 156, and W at the position corresponding to position 162 of SEQ ID NO: 5; l) M at the position corresponding to position 68 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; m) Q at the position corresponding to position 46 of SEQ ID NO: 5, M at the position corresponding to position 68 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; n) M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5 NO:5 position 108 corresponding to H, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; o) N corresponding to position 35, Q corresponding to position 46, SEQ ID NO:5 position 68 corresponding to M, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 155 corresponding to W, SEQ ID NO:5 position 156 corresponding to R, and SEQ ID NO:5 position 162 corresponding to W; p) S corresponding to position 81, SEQ ID NO:5 position 155 corresponding to W; q) W corresponding to position 75, SEQ ID NO:5 position 76 corresponding to M, SEQ ID NO:5 position 87 corresponding to H, SEQ ID NO:5 position 88 corresponding to W, SEQ ID NO:5 position 89 corresponding to R, and SEQ ID NO:5 position 90 corresponding to W; NO:5 position corresponding to S; r) SEQ ID NO:5 position corresponding to S, and SEQ ID NO:5 position corresponding to D; s) SEQ ID NO:5 position corresponding to S, and SEQ ID NO:5 position corresponding to A; t) SEQ ID NO:5 position corresponding to W, and SEQ ID NO:5 position corresponding to W; u) SEQ ID NO:5 position corresponding to W, and SEQ ID NO:5 position corresponding to D; v) SEQ ID NO:5 position corresponding to A, and SEQ ID NO:5 position corresponding to W; w) SEQ ID NO:5 position corresponding to W, and SEQ ID NO:5 position corresponding to D; x) W at the position corresponding to position 75 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; y) A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; z) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; aa) S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; bb) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; cc) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; dd) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; ee) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ff) W at the position corresponding to position 75 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; gg) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5 NO:5 position 145 corresponding to A, and SEQ ID NO:5 position 155 corresponding to W; hh) SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; ii) SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 145 corresponding to A, and SEQ ID NO:5 position 160 corresponding to D; jj) SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; kk)  SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 155 corresponding to S, and SEQ ID NO:5 position 160 corresponding to D; NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, and SEQ ID NO:5 position 155 corresponding to W; ll) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; mm) SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to A, and SEQ ID NO:5 position 160 corresponding to D; nn)  SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 155 corresponding to D, and SEQ ID NO:5 position 160 corresponding to D; NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; oo) SEQ ID NO: 5 position 75 corresponding to W, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; pp) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 105 corresponding to M; qq) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 121 corresponding to V; rr) SEQ ID NO: 5 position 40 corresponding to L, and SEQ ID NO: 5 position 145 corresponding to M; ss) L at the position corresponding to position 40 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; tt) L at the position corresponding to position 40 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; uu) M at the position corresponding to position 105 of SEQ ID NO: 5, and V at the position corresponding to position 121 of SEQ ID NO: 5; vv) M at the position corresponding to position 105 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; ww) M at the position corresponding to position 105 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; xx) M at the position corresponding to position 105 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; yy) NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 145 corresponding to M; zz) SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 159 corresponding to Q; aaa) SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 160 corresponding to W; bbb) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 159 corresponding to Q; ccc) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; ddd) SEQ ID NO:5 position 159 corresponding to Q, and SEQ ID NO:5 position 160 corresponding to W; eee) SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; NO:5 position 81 corresponding to S, SEQ ID NO:5 position 145 corresponding to M, and SEQ ID NO:5 position 160 corresponding to W; fff) SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 121 corresponding to V, and SEQ ID NO:5 position 159 corresponding to Q; ggg) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 81 corresponding to S; hhh) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; iii) SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; jjj) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 81 corresponding to S; NO:5 position 76 corresponding to G; kkk) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 117 corresponding to L; lll) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; mmm) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 81 corresponding to S; nnn) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ooo) SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; NO:5 position corresponding to L at position 117; ppp) A at position corresponding to position 68 of SEQ ID NO:5, G at position corresponding to position 76 of SEQ ID NO:5, and L at position corresponding to position 117 of SEQ ID NO:5; qqq) A at position corresponding to position 68 of SEQ ID NO:5, G at position corresponding to position 76 of SEQ ID NO:5, S at position corresponding to position 81 of SEQ ID NO:5, and L at position corresponding to position 117 of SEQ ID NO:5; rrr) S at position corresponding to position 81 of SEQ ID NO:5, L at position corresponding to position 109 of SEQ ID NO:5, E at position corresponding to position 153 of SEQ ID NO:5, W at position corresponding to position 155 of SEQ ID NO:5, and D at position corresponding to position 160 of SEQ ID NO:5; sss) A at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, L at the position corresponding to position 117 of SEQ ID NO: 5, A at the position corresponding to position 121 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ttt) Q at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, I at the position corresponding to position 117 of SEQ ID NO: 5, Q at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; uuu) NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; vvv) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 160 corresponding to D; vvv) SEQ ID NO:5 position 22 corresponding to A, SEQ ID NO:5 position 68 corresponding to Y, SEQ ID NO:5 position 75 corresponding to G, SEQ ID NO:5 position 76 corresponding to S, SEQ ID NO:5 position 81 corresponding to H, SEQ ID NO:5 position 108 corresponding to L, SEQ ID NO:5 position 117 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; H at the position corresponding to position 122 of SEQ ID NO: 5, Y at the position corresponding to position 138 of SEQ ID NO: 5, L at the position corresponding to position 139 of SEQ ID NO: 5, A at the position corresponding to position 142 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, R at the position corresponding to position 153 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, D at the position corresponding to position 160 of SEQ ID NO: 5, and H at the position corresponding to position 162 of SEQ ID NO: 5; or www) S at the position corresponding to position 81 of SEQ ID NO: 5. 229. The vector of embodiment 226 or 228, wherein the first deaminase comprises: a) N at the position corresponding to position 35 of SEQ ID NO: 5 and Q at the position corresponding to position 46 of SEQ ID NO: 5; b) S at the position corresponding to position 81 of SEQ ID NO: 5 and R at the position corresponding to position 156 of SEQ ID NO: 5; c) Q at the position corresponding to position 46 of SEQ ID NO: 5 and R at the position corresponding to position 156 of SEQ ID NO: 5; d) N at the position corresponding to position 35 of SEQ ID NO: 5, Q at the position corresponding to position 46 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; e) W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; f) N at the position corresponding to position 35 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; g) N at the position corresponding to position 35 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; h) M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; i) N at the position corresponding to position 35, Q at the position corresponding to position 46 of SEQ ID NO: 5, and Q at the position corresponding to position 47 of SEQ ID NO: 5. M at the position corresponding to position 68 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, H at the position corresponding to position 108 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; j) S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; k) W at the position corresponding to position 75 of SEQ ID NO: 5, and S at the position corresponding to position 81 of SEQ ID NO: 5; l) S at the position corresponding to position 81 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; m) S at the position corresponding to position 81 of SEQ ID NO: 5, and R at the position corresponding to position 156 of SEQ ID NO: 5, and W at the position corresponding to position 162 of SEQ ID NO: 5; A at the position corresponding to position 145 of SEQ ID NO: 5; n) W at the position corresponding to position 75 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; o) W at the position corresponding to position 75 of SEQ ID NO: 5, and A at the position corresponding to position 145 of SEQ ID NO: 5; p) A at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; q) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; r) S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; s) S at the position corresponding to position 81 of SEQ ID NO: 5, A at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 155 of SEQ ID NO: 5; t) L at the position corresponding to position 40 of SEQ ID NO: 5, and M at the position corresponding to position 105 of SEQ ID NO: 5; u) L at the position corresponding to position 40 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; v) L at the position corresponding to position 40 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; w) L at the position corresponding to position 40 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; x) M at the position corresponding to position 105 of SEQ ID NO: 5, and M at the position corresponding to position 145 of SEQ ID NO: 5; y) M at the position corresponding to position 105 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; z) M at the position corresponding to position 145 of SEQ ID NO: 5, and Q at the position corresponding to position 159 of SEQ ID NO: 5; aa) M at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; bb) Q at the position corresponding to position 159 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; cc) S at the position corresponding to position 81 of SEQ ID NO: 5, M at the position corresponding to position 145 of SEQ ID NO: 5, and W at the position corresponding to position 160 of SEQ ID NO: 5; dd) A at the position corresponding to position 68 of SEQ ID NO: 5, and Q at the position corresponding to position 160 of SEQ ID NO: 5; NO:5 position 81 corresponding to S; ee) SEQ ID NO:5 position 76 corresponding to S, and SEQ ID NO:5 position 81 corresponding to S; ff) SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; gg) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 76 corresponding to G; hh) SEQ ID NO:5 position 68 corresponding to A, and SEQ ID NO:5 position 117 corresponding to L; ii) SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; jj) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; ID NO:5 position 81 corresponding to S; kk) SEQ ID NO:5 position 68 corresponding to S, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; ll) SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; mm) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, and SEQ ID NO:5 position 117 corresponding to L; nn) SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, and SEQ ID NO:5 position 117 corresponding to L; NO:5 position 117 corresponding to L; oo) A corresponding to position 68 of SEQ ID NO:5 and S corresponding to position 81 of SEQ ID NO:5; pp) S corresponding to position 81 of SEQ ID NO:5, L corresponding to position 109 of SEQ ID NO:5, E corresponding to position 153 of SEQ ID NO:5, W corresponding to position 155 of SEQ ID NO:5, and D corresponding to position 160 of SEQ ID NO:5; qq) A corresponding to position 75 of SEQ ID NO:5, S corresponding to position 81 of SEQ ID NO:5, L corresponding to position 117 of SEQ ID NO:5, A corresponding to position 121 of SEQ ID NO:5, A corresponding to position 145 of SEQ ID NO:5, and D corresponding to position 160 of SEQ ID NO:5; NO: 5, W at the position corresponding to position 155, and D at the position corresponding to position 160 of SEQ ID NO: 5; rr) Q at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, I at the position corresponding to position 117 of SEQ ID NO: 5, Q at the position corresponding to position 145 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5; ss) Y at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, L at the position corresponding to position 117 of SEQ ID NO: 5, G at the position corresponding to position 121 of SEQ ID NO: 5, L at the position corresponding to position 145 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; tt) SEQ ID NO: 5 position 22 corresponding to W, SEQ ID NO: 5 position 68 corresponding to A, SEQ ID NO: 5 position 75 corresponding to Y, SEQ ID NO: 5 position 76 corresponding to G, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 108 corresponding to H, SEQ ID NO: 5 position 117 corresponding to L, SEQ ID NO: 5 position 122 corresponding to H, SEQ ID NO: 5 position 138 corresponding to Y, SEQ ID NO: 5 position 139 corresponding to L, SEQ ID NO: 5 position 142 corresponding to A, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 150 corresponding to L, SEQ ID NO: 5 position 151 corresponding to L, SEQ ID NO: 5 position 152 corresponding to L, SEQ ID NO: 5 position 153 corresponding to L, SEQ ID NO: 5 position 154 corresponding to L, SEQ ID NO: 5 position 156 corresponding to L, SEQ ID NO: 5 position 157 corresponding to L, SEQ ID NO: 5 position 158 corresponding to L, SEQ ID NO: 5 position 159 corresponding to L, SEQ ID NO: 5 position 160 corresponding to L, SEQ ID NO: 5 position 161 corresponding to L, SEQ ID NO: 5 position 162 corresponding to L, SEQ ID NO: 5 position 163 corresponding to L, SEQ ID NO: 5 position 164 corresponding to L, SEQ ID NO: 5 position 165 corresponding to L, SEQ ID NO: 5 position 166 corresponding to L, SEQ ID NO: 5 position 167 corresponding to L, SEQ ID NO: 5 position 168 corresponding to L R at the position corresponding to position 153 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, R at the position corresponding to position 156 of SEQ ID NO: 5, D at the position corresponding to position 160 of SEQ ID NO: 5, and H at the position corresponding to position 162 of SEQ ID NO: 5; uu) S at the position corresponding to position 81 of SEQ ID NO: 5; or vv) W at the position corresponding to position 75 of SEQ ID NO: 5, S at the position corresponding to position 81 of SEQ ID NO: 5, W at the position corresponding to position 155 of SEQ ID NO: 5, and D at the position corresponding to position 160 of SEQ ID NO: 5. 230. The vector of any one of embodiments 226, 228 and 229, wherein the first deaminase comprises: a) N at a position corresponding to position 35 of SEQ ID NO: 5, S at a position corresponding to position 81 of SEQ ID NO: 5, R at a position corresponding to position 156 of SEQ ID NO: 5, and W at a position corresponding to position 162 of SEQ ID NO: 5; b) W at a position corresponding to position 75 of SEQ ID NO: 5, and W at a position corresponding to position 155 of SEQ ID NO: 5; c) S at a position corresponding to position 81 of SEQ ID NO: 5, W at a position corresponding to position 155 of SEQ ID NO: 5, and D at a position corresponding to position 160 of SEQ ID NO: 5; d) S at a position corresponding to position 81 of SEQ ID NO: 5, A at a position corresponding to position 145 of SEQ ID NO: 5, and D at a position corresponding to position 162 of SEQ ID NO: 5; NO:5 position 155 corresponding to W; e) S corresponding to position 81 of SEQ ID NO:5, M corresponding to position 145 of SEQ ID NO:5, and W corresponding to position 160 of SEQ ID NO:5; f) G corresponding to position 76 of SEQ ID NO:5, and S corresponding to position 81 of SEQ ID NO:5; g) S corresponding to position 81 of SEQ ID NO:5, and L corresponding to position 117 of SEQ ID NO:5; h) A corresponding to position 68 of SEQ ID NO:5, and S corresponding to position 81 of SEQ ID NO:5; i) S corresponding to position 81 of SEQ ID NO:5, L corresponding to position 109 of SEQ ID NO:5, E corresponding to position 153 of SEQ ID NO:5, and L corresponding to position 117 of SEQ ID NO:5; NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; j) SEQ ID NO: 5 position 75 corresponding to A, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 117 corresponding to L, SEQ ID NO: 5 position 121 corresponding to A, SEQ ID NO: 5 position 145 corresponding to A, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; k) SEQ ID NO: 5 position 75 corresponding to Q, SEQ ID NO: 5 position 81 corresponding to S, SEQ ID NO: 5 position 117 corresponding to I, SEQ ID NO: 5 position 145 corresponding to Q, SEQ ID NO: 5 position 155 corresponding to W, and SEQ ID NO: 5 position 160 corresponding to D; NO:5 position 160 corresponding to D; l) SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 117 corresponding to L, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; m) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 110 corresponding to H, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 145 corresponding to L, SEQ ID NO:5 position 155 corresponding to W, and SEQ ID NO:5 position 160 corresponding to D; m) SEQ ID NO:5 position 22 corresponding to C, SEQ ID NO:5 position 68 corresponding to A, SEQ ID NO:5 position 75 corresponding to Y, SEQ ID NO:5 position 76 corresponding to G, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 108 corresponding to H, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 121 corresponding to G, SEQ ID NO:5 position 121 corresponding to NO:5 position 117 corresponding to L, SEQ ID NO:5 position 122 corresponding to H, SEQ ID NO:5 position 138 corresponding to Y, SEQ ID NO:5 position 139 corresponding to L, SEQ ID NO:5 position 142 corresponding to A, SEQ ID NO:5 position 145 corresponding to A, SEQ ID NO:5 position 153 corresponding to R, SEQ ID NO:5 position 155 corresponding to W, SEQ ID NO:5 position 156 corresponding to R, SEQ ID NO:5 position 160 corresponding to D, and SEQ ID NO:5 position 162 corresponding to H; n) SEQ ID NO:5 position 81 corresponding to S; or o) SEQ ID NO:5 position 75 corresponding to W, SEQ ID NO:5 position 81 corresponding to S, SEQ ID NO:5 position 163 corresponding to H; W at the position corresponding to position 155 of NO:5, and D at the position corresponding to position 160 of SEQ ID NO:5. 231. The vector of any of embodiments 226-230, wherein the first adenine deaminase has at least 90% sequence identity with SEQ ID NOs: 300-414, 596-598, and 720-723. 232. The vector of any of embodiments 226-230, wherein the first adenine deaminase has at least 95% sequence identity with SEQ ID NOs: 300-414, 596-598, and 720-723. 233. A vector of any one of embodiments 226-230, wherein the first adenine deaminase has an amino acid sequence of SEQ ID NO: 300-414, 596-598, and 720-723. 234. The vector of any of embodiments 218-233, wherein the DNA binding polypeptide is a meganuclease, a zinc finger fusion protein, or a TALEN. 235. A vector of any one of embodiments 218-233, wherein the DNA binding polypeptide is an RNA-guided DNA binding polypeptide. 236. The vector of embodiment 235, wherein the RNA-guided DNA-binding polypeptide is an RNA-guided nuclease (RGN) polypeptide. 237. The vector of embodiment 236, wherein the RGN is an RGN nickase. 238. A cell comprising a composition of any one of embodiments 186-205 or a vector of any one of embodiments 218-237. 239. A drug composition comprising a pharmaceutically acceptable carrier, and a composition of any one of embodiments 198-217, a carrier of any one of embodiments 218-237, or a cell of embodiment 238. 240. A method for treating an individual having a disease, disorder or symptom or at risk of developing a disease, disorder or symptom, the method comprising: administering to the individual a fusion protein of any of embodiments 27-50, an RNP complex of embodiment 51, a nucleic acid molecule of any of embodiments 52-77, a vector of any of embodiments 78-81 and 218-237, a cell of any of embodiments 88-92, 132-136, 190-194, and 238, a system of any of embodiments 104-129, a composition of any of embodiments 196-217, or a drug composition of any of embodiments 98, 142, 197, and 239. 241. The method of embodiment 240, wherein the disease is associated with a causal mutation and the treatment includes correcting the causal mutation. 242. A fusion protein of any one of embodiments 27-50, an RNP complex of embodiment 51, a nucleic acid molecule of any one of embodiments 52-77, a vector of any one of embodiments 78-81 and 218-237, a cell of any one of embodiments 88-92, 132-136, 190-194, and 238, a system of any one of embodiments 104-129, or a composition of any one of embodiments 196-217 for treating a disease, disorder or symptom in an individual having the disease, disorder or symptom or at risk of developing the disease, disorder or symptom. 243. The use of embodiment 242, wherein the disease is associated with a causal mutation and the treatment comprises correcting the causal mutation. 244. A fusion protein of any one of embodiments 27-50, an RNP complex of embodiment 51, a nucleic acid molecule of any one of embodiments 52-77, a vector of any one of embodiments 78-81 and 218-237, a cell of any one of embodiments 88-92, 132-136, 190-194, and 238, a system of any one of embodiments 104-129, or a composition of any one of embodiments 196-217 for use in the manufacture of a drug useful for treating a disease, disorder or symptom. 245. The use of embodiment 244, wherein the disease is associated with a causal mutation and the effective amount of the drug corrects the causal mutation.

The following examples are provided for illustration and not limitation. Experimental Example 1 : Inlaid Alkaline Editors Are Useful and Some Inlaid Alkaline Editors Are Displayed Shifted in the Edit Window

The parent adenine base editor (ABE; LPG50148-nAPG07433.1) was generated by an end-to-end fusion between LPG50148 (as shown in SEQ ID NO: 5 and originally disclosed in WO 2022/056254, which is incorporated herein by reference in its entirety) and a nickase version of APG07433.1 with a D11A mutation (as shown in SEQ ID NO: 49 and originally disclosed in WO 2019/236566, which is incorporated herein by reference in its entirety), with a linker (such as the L32 linker sequence shown in SEQ ID NO: 705) in between. The LPG50148 construct with nAPG07433.1 inserted is shown in FIG. 1A . The insertion position was chosen based on structural analysis to position the deaminase active site to a base outside the standard editing window.

LPG50148 (minus the starting methionine (as shown in SEQ ID NO: 5) and with a short GGS linker on the N-terminal flank and a SGG linker on the C-terminal flank) was inserted immediately after the following amino acid residues in nAPG07433.1 (numbered according to SEQ ID NO: 1): S772 (referred to as LPG20002, its sequence is shown in SEQ ID NO: 8), S775 (referred to as LPG20003, its sequence is shown in SEQ ID NO: 9), K778 (referred to as LPG20004, its sequence is shown in SEQ ID NO: 10), E900 (referred to as LPG20005, its sequence is shown in SEQ ID NO: 11), G910 (referred to as LPG20006, its sequence is shown in SEQ ID NO: 12), R30 (referred to as LPG20007, its sequence is shown in SEQ ID NO: 13), T642 (referred to as LPG20008, its sequence is shown in SEQ ID NO: 14), R670 (referred to as LPG20009, its sequence is shown in SEQ ID NO: 15), D737 (referred to as LPG20010, its sequence is shown in SEQ ID NO: 16) and A802 (referred to as LPG20011, its sequence is shown in SEQ ID NO: 17).

A domain replacement strategy was also performed in which the LPG50148 deaminase replaced the nAPG07433.1 HNH domain. This fusion protein is referred to herein as LPG20001 and is set forth as SEQ ID NO: 428. The base editors were fused to NLS sequences at the N- and C-termini.

For each inlaid base editor (IBE) and HNH replacement protein, the editing efficiency in human cells was measured. The IBE, HNH replacement protein and guide RNA were delivered into HEK293T cells as plasmids encoding the IBE, HNH replacement protein and guide RNA.

The results shown in Figure 2B show that for LPG20002-LPG20004, the editing efficiency between positions 19-22 of the editing window decreased significantly, while the editing efficiency between positions 6-9 increased. LPG20008-LPG20010 also showed a decrease in editing efficiency between positions 19-22 and an increase in editing efficiency between positions 6-9 (Figure 3). Therefore, these newly engineered base editors exhibit specific shifts in the editing window close to the PAM. For the domain replacement strategy, LPG20001 showed almost no editing (data not shown). Deaminases were also inserted into nAPG07433.1 proteins in which the HNH domain was deleted, and these proteins also showed very low editing (data not shown). In addition, deaminases were inserted into several positions in APG07433.1 that were nuclease-inactive. These IBEs (LPG20134-LPG20138) also showed little editing when tested in cells (data not shown).

Two constructs with altered editing windows and the highest editing efficiencies (LPG20002 and LPG20008) were selected for additional study. Positions A6-A9 of these constructs showed higher editing, less than end-to-end fusions, and overall editing efficiencies comparable to the parental ABE (Figure 4). Example 2 : Deletion of the linker within the inlay base editor

The inlaid base editors LPG20002 and LPG20008 exhibit wide editing windows (Figures 2B and 3), which is an important feature for gene knockouts targeting splice sites. However, a more focused window is needed to correct specific mutations. To reduce the width of the editing window, it was hypothesized that deleting the GGS linker between LPG50148 and nAPG07433.1 could reduce conformational flexibility and produce a more focused deamination effect. The linker from the N-terminus, C-terminus, or both of LPG20002 was deleted (Figure 5A). LPG20002 with the deleted amino terminal linker is shown in SEQ ID NO: 18 and is referred to herein as LPG20012. LPG20002 with the carboxyl terminal linker deleted is shown in SEQ ID NO: 19 and is referred to herein as LPG20013. In addition to deleting both linkers, LPG50148 was also truncated by a single amino acid at each end in the construct (LPG20014) shown in SEQ ID NO: 20. The IBE and guide RNA were delivered to HEK293T cells as plasmids encoding the IBE and guide RNA.

As expected, LPG20002 was still active after linker deletion (Fig. 5B), demonstrating that the GGS linker is dispensable. However, although linker deletions did not reduce the editing window width for LPG20002 (Fig. 5C), these deletions reduced protein size, which could facilitate AAV delivery. Example 3 : Therapeutic potential of inlaid base editors

The therapeutic potential of the inlaid base editor was demonstrated by editing the splice site of hereditary ATTR amyloidosis and deleting the β2-microglobulin (B2M) gene (Figure 6). Hereditary ATTR amyloidosis is caused by mutations within the transthyretin (TTR) gene, which results in an unstable and easily misfolded abnormal TTR protein, forming aggregates that deposit as amyloid in various organs and tissues in the body. ABE splice site targeting is a strategy to delete TTR production in the liver. In these studies, LPG20002 or parental ABE and guide RNA were delivered to HEK293T cells via nucleofection as plasmids encoding the LPG20002 or parental ABE and guide RNA. For editing the common splice donor sequence in exon 1 of the TTR gene, LPG20002 showed 23.3-fold higher editing than the parental ABE, demonstrating the therapeutic potential of this application (Figure 6A).

Allogeneic stem cells are an effective source for correcting cellular dysfunction. However, the risk of immune rejection limits the clinical use of these cells. B2M knockout is a strategy to circumvent this limitation. Therefore, the efficiency of IBE knockout of the B2M gene was evaluated. IBE and parental ABE were delivered to T cells as mRNA and guide RNA as RNA molecules via nuclear transfection. As shown in Figure 6B, LPG20002 showed an efficiency that was ~2.5 times higher than the parental ABE. In addition, a second version of LPG20002 (LPG20015 as shown in SEQ ID NO: 21) was produced by replacing the wild-type LPG50148 with the V81S variant (producing LPG50208 as shown in SEQ ID NO: 6). This LPG20015 showed a B2M knockout efficiency that was ~4 times higher than that of the parent (Figure 6B). Example 4 : nAPG05586 base editor

The parent adenine base editor (ABE; LPG50208-nAPG05586) was generated by an end-to-end fusion between LPG50208 (LPG50148 with a V81S mutation; as shown in SEQ ID NO: 6) and a nickase version of APG05586 with a D7A mutation (as shown in SEQ ID NO: 50 and originally disclosed in WO 2021/217002, which is incorporated herein by reference in its entirety), with a linker (L32 linker sequence as shown in SEQ ID NO: 705) in between. The insertion position for the IBE was selected based on structural analysis.

LPG50208 was inserted immediately after the following amino acid residues in nAPG05586 (numbered according to SEQ ID NO: 2): G342 (within the Rec-2 domain); D518 (marginal residue between RuvC-2 and L1); Q630 (HNH domain); R661 (HNH domain); F678 (L-2 linker); D736 (RuvC-3 domain); E778 (RuvC-3 domain); D788 (RuvC-3 domain); K922 (WED domain); and G1109 (PI domain). The sequences of nAPG05586 G342 IBE (referred to herein as LPG20016), D518 IBE (referred to herein as LPG20017), Q630 IBE (referred to herein as LPG20018), R661 IBE (referred to herein as LPG20019), F678 IBE (referred to herein as LPG20020), D736 IBE (referred to herein as LPG20021), E778 IBE (referred to herein as LPG20022), D788 IBE (referred to herein as LPG20023), K922 IBE (referred to herein as LPG20024), and G1109 IBE (referred to herein as LPG20025) are shown in SEQ ID NOs: 23-32, respectively. The base editors are fused to NLS sequences at the N- and C-termini.

For each nAPG05586 IBE, editing efficiency in human cells was measured using four guides known to contemplate APG05586 editing (3 targeting B2M and 1 targeting TRAC). The IBE and guide RNA were delivered into HEK293T cells as plasmids encoding the IBE and guide RNA.

The nAPG05586 IBE with insertions immediately after the F678, D736, E778, D788, and K922 residues had higher editing rates than the parental ABE, and the K922 IBE had the greatest activity (see FIG7A ). The remaining IBEs had lower activities than the parental ABE.

Figure 7B provides the editing rate for each adenine position within the editing window (5-24) for each nAPG05586 IBE, with positions 5-7, 9 (also highly edited by nAPG05586 E778 IBE) and position 24 being edited most by nAPG05586 F678 IBE, and position 23 being edited most by nAPG05586 F678 IBE. Positions 8 and 10 are edited most by nAPG05586 G736 IBE. Positions 21 and 22 are edited most by nAPG05586 D788 IBE, and the highest average editing activity at positions 18 and 23 is performed by nAPG05586 D788 IBE. Positions 12-16 were edited most by nAPG05586 K922 IBE, and the highest average editing rate at position 11 and the highest maximum activity at position 18 were performed by nAPG05586 K922 IBE. Example 5 : nAPG01604 Base Editor

The parent adenine base editor (ABE; LPG50208-nAPG01604) was generated by an end-to-end fusion between LPG50208 (LPG50148 with a V81S mutation; as shown in SEQ ID NO: 6) and a nickase version of APG01604 with a D10A mutation (as shown in SEQ ID NO: 51 and originally disclosed in WO 2021/217002, which is incorporated herein by reference in its entirety), with a linker (L32 linker sequence, as shown in SEQ ID NO: 705) in between. The insertion position of the IBE was selected based on structural analysis.

LPG50318 (as shown in SEQ ID NO: 598), which is similar to LPG50208 but has an additional A137V mutation, was inserted immediately after the following amino acid residues in nAPG01604 (with GSSG linkers at the N- and C-terminal flanks) (numbered according to SEQ ID NO: 3): G597 (referred to as LPG20027 or inlay 1.1), S631 (referred to as LPG20028 or inlay 2.1), K725 (referred to as LPG20029 or inlay 3.1), K739 (referred to as LPG20030 or inlay 4.1) and V744 (referred to as LPG20031 or inlay 5.1). The sequences of LPG20027, LPG20028, LPG20029, LPG20030 and LPG20031 are shown in SEQ ID NOs: 34-38, respectively. The base editor is fused to the NLS sequence at the N-terminus and the C-terminus.

For each nAPG01604 insertion, four guides known to be involved in APG01604 editing (3 targeting B2M and 1 targeting TRAC) were used to measure editing efficiency in human cells. IBEs and guide RNAs were delivered into HEK293T cells as plasmids encoding them.

LPG20029, LPG20030, and LPG20031 had greater editing activity than end-to-end ABE, while LPG20027 and LPG20028 exhibited lower editing activity than end-to-end ABE (see FIG8A ).

Figure 8B provides the editing rate of each nAPG01604 IBE at adenine positions 5-17 within the editing window, excluding position 9 which was not edited by any nAPG01604 IBE in these experiments. Position 8 was edited most by LPG20029 (inlay 3.1; K725). Positions 6, 7, and 12-14 were edited most by LPG20030 (inlay 4.1; K739), and the highest average activity at position 16 was by LPG20030 (inlay 4.1; K739). Positions 5, 10, 11, 15, and 17 were edited most by LPG20031 (inlay 5.1; V744), and the highest maximum activity at position 16 was by LPG20031 (inlay 5.1; V744). Example 6 : nLPG10145 embedded base editor

The parent adenine base editor (ABE; LPG50208-nLPG10145) was generated by an end-to-end fusion between LPG50208 (LPG50148 with a V81S mutation; as shown in SEQ ID NO: 6) and a nickase version of LPG10145 with a D16A mutation (as shown in SEQ ID NO: 52 and originally disclosed in WO 2023/139557, which is incorporated herein by reference in its entirety). The insertion position of the IBE was selected based on structural analysis.

LPG50208 (SEQ ID NO: 6, with a short SGG linker on the N-terminal flank and GGS on the C-terminal flank) was inserted immediately after the following amino acid residues in nLPG10145 (numbered according to SEQ ID NO: 4): G347 (within the Rec-2 domain), D524 (edge residue between RuvC-2 and L1), Q640 (HNH domain), R666 (HNH domain), D680 (L-2 linker), N740 (RuvC-3 domain), S785 (RuvC-3 domain), P910 (WED domain), and G1077 (PI domain). The sequences of LPG10145 G347 IBE (referred to herein as LPG20032), D524 IBE (referred to herein as LPG20033), Q640 IBE (referred to herein as LPG20034), R666 IBE (referred to herein as LPG20035), D680 IBE (referred to herein as LPG20036), N740 IBE (referred to herein as LPG20037), S785 IBE (referred to herein as LPG20038), P910 IBE (referred to herein as LPG20039), and G1077 IBE (referred to herein as LPG20040) are shown in SEQ ID NOs: 40-48, respectively.

For each nLPG10145 IBE, four guides known to confer LPG10145 editing (3 targeting B2M and 1 targeting TRAC) were used to measure editing efficiency in human cells. The IBE and guide RNA were delivered into HEK293T cells as plasmids encoding the IBE and guide RNA.

Most of the nLPG10145 IBEs had greater editing activity than the parent ABE, with P910 IBE demonstrating the highest level of ABE editing (see Figure 9A). Q640 IBE was the only LPG10145 IBE tested that had lower activity than the parent ABE.

Figure 9B provides the editing rate for each nLPG10145 IBE at each adenine position within the editing window (5-24), excluding positions 13, 16, 17, 19, and 23, which were not edited by any nLPG10145 IBE in these experiments. Position 4 was edited the most by nLPG10145 D680 IBE, and the highest maximum activity at position 18 and the highest average activity at position 21 were performed by nLPG10145 D680 IBE. Position 5 was edited the most by nLPG10145 R666 IBE, and the highest average activity at position 6 was performed by nLPG10145 R666 IBE. Positions 20 and 22 were most edited by nLPG10145 S785 IBE, and the highest average editing activity at position 18 was performed by nLPG10145 S785 IBE. Position 24 was most edited by nLPG10145 D524 IBE, and position 25 was most edited by nLPG10145 G347 IBE. The highest maximum activity at position 21 was performed by nLPG10145 G347 IBE. Positions 8-12, 14, and 15 were most edited by nLPG10145 P910 IBE, and the highest maximum activity at position 6 was performed by nLPG10145 P910 IBE. Example 7 : Directed evolution of adenosyl base editors (ABEs) to identify ABEs with improved editing efficiency

The parent ABE (LPG50148-dAPG07433.1) was generated by an end-to-end fusion between LPG50148 (as shown in SEQ ID NO: 5, without the starting methionine, originally disclosed in WO 2022/056254, which is incorporated herein by reference in its entirety) and a nuclease-inactive version of APG07433.1 (with D11A and H604A mutations to render both the RuvC and HNH nuclease domains inactive) (disclosed in WO 2019/236566, which is incorporated herein by reference in its entirety). The parent LPG50148-dAPG07433.1 ABE was used in bacterial assays, while the LPG50148-nAPG07433.1 ABE was used as the parent ABE in the human cell assay described below (LPG50148 fused to the D11A nickase version of APG07433.1).

In order to engineer the second generation ABE with improved activity, a conomycin selection system capable of iterative rounds of directed evolution was established in Escherichia coli (Figure 10A). This system is based on the introduction of a stop codon in the conomycin resistance gene to make it inactive and to make the Escherichia coli cell sensitive to conomycin treatment. The ABE variant library can be targeted to edit the A base in the stop codon, thereby converting it into a meaningful codon, wherein the conomycin resistance gene is reactivated to allow any Escherichia coli cell expressing active ABE to survive. These variants are then sequenced to identify beneficial mutations, which are promoted to be tested in human cells.

In order to understand the sequence-function relationship that can guide further directed evolution rounds, a deep mutation scan library was designed in which each residue of LPG50148 was mutated into all possible 20 amino acids. Using the conmycin selection system, different sequence contexts (TAT, CAC and TAG) and increased stringency were used to perform the selection step (Figure 10B). After the enrichment step, we confirmed that the variants measured by increased antibiotic resistance (MICkan) showed up to 8 times activity improvement. These variants were sequenced and mutations were identified. The variants selected from the single mutation variant library were then evaluated in human cells. Next, the lead mutation with the highest human cell editing activity was combined and re-evaluated in human cells.

When selection was performed in bacteria against the TAT sequence context, 32 single mutations were identified after the enrichment step (Table 2). The single mutations were incorporated into the human codon-optimized LPG50148-nAPG07433.1 fusion construct. The expression of these evolved deaminases in ABE was evaluated by editing HEK293T cells at eight endogenous genomic sites. Single mutations showing the highest average fold changes (Table 3) were combined and tested to identify the best hits: variants LPG50148.2.20 (variant 20), LPG50148.2.60 (variant 60), LPG50148.2.67 (variant 67), and LPG50148.2.68 (variant 68), which showed approximately 1.6-fold higher editing at typical positions (A5-A7) and approximately four-fold higher editing at atypical positions (A3-A4 and A8-A10) in the protospacer sequence compared to the parental ABE (Figure 11). Table 2 : TAT single mutations LPG50148 ABE variant SEQ ID NO Mutations related to SEQ ID NO : 5 (LPG50148) LPG50148.2.1 300 L35N LPG50148.2.2 301 R46Q LPG50148.2.3 302 V68M LPG50148.2.4 303 V81S LPG50148.2.5 304 S108H LPG50148.2.6 305 N121T LPG50148.2.7 306 F155W LPG50148.2.8 307 N156R LPG50148.2.9 308 L162W LPG50148.2.10 309 L162H LPG50148.2.25 324 M117I LPG50148.2.26 325 P138Y LPG50148.2.27 326 I75W LPG50148.2.28 327 A160D LPG50148.2.29 328 M125K LPG50148.2.30 329 N126A LPG50148.2.31 330 Q158R LPG50148.2.32 331 E139L LPG50148.2.33 332 C145A LPG50148.2.34 333 L162V LPG50148.2.35 334 N121E LPG50148.2.36 335 L120F LPG50148.2.37 336 P151Q LPG50148.2.38 337 Y148K LPG50148.2.39 338 G142K LPG50148.2.40 339 I165R LPG50148.2.41 340 N166H LPG50148.2.42 341 N2C LPG50148.2.43 342 D23Q LPG50148.2.44 343 G135H LPG50148.2.45 344 L137V LPG50148.2.46 345 L162A Table 3 : TAT binding mutations LPG50148 ABE variant SEQ ID NO Mutations related to SEQ ID NO : 5 (LPG50148) LPG50148.2.11 310 L35N, L162W LPG50148.2.12 311 L35N、R46Q LPG50148.2.13 312 V81S、N156R、 LPG50148.2.14 313 R46Q、N156R LPG50148.2.15 314 N156R、L162W LPG50148.2.16 315 L35N, V81S, L162W LPG50148.2.17 316 L35N, R46Q, L162W LPG50148.2.18 317 F155W, N156R, L162W LPG50148.2.19 318 L35N, N156R, L162W LPG50148.2.20 319 L35N, V81S, N156R, L162W LPG50148.2.21 320 V68M, S108H, N156R, L162W LPG50148.2.22 321 R46Q, V68M, S108H, N156R, L162W LPG50148.2.23 322 V68M, V81S, S108H, N156R, L162W LPG50148.2.24 323 L35N, R46Q, V68M, V81S, S108H, F155W, N156R, L162W LPG50148.2.56 355 V81S、F155W LPG50148.2.57 356 I75W、V81S LPG50148.2.58 357 V81S、A160D LPG50148.2.59 358 V81S、C145A LPG50148.2.60 359 I75W、F155W LPG50148.2.61 360 F155W、A60D LPG50148.2.62 361 C145A, F155W LPG50148.2.63 362 I75W、A160D LPG50148.2.64 363 I75W、C145A LPG50148.2.65 364 C145A, A160D LPG50148.2.66 365 I75W, V81S, F155W LPG50148.2.67 366 V81S, F155W, A160D LPG50148.2.68 367 V81S, C145A, F155W LPG50148.2.69 368 I75W, V81S, A160D LPG50148.2.70 369 I75W, V81S, C145A LPG50148.2.71 370 V81S, C145A, A160D LPG50148.2.72 371 I75W, F155W, A160D LPG50148.2.73 372 I75W, C145A, F155W LPG50148.2.74 373 C145A, F155W, A160D LPG50148.2.75 374 I75W, C145A, A160D LPG50148.2.76 375 I75W, V81S, F155W, A160D LPG50148.2.77 376 I75W, V81S, C145A, F155W LPG50148.2.78 377 V81S, C145A, F155W, A160D LPG50148.2.79 378 I75W, V81S, C145A, A160D LPG50148.2.80 379 I75W, C145A, F155W, A160D LPG50148.2.81 380 I75W, V81S, C145A, F155W, A160D

When the CAC sequence context was selected in bacteria, nine single mutations were identified after the enrichment step (Table 4). The single mutations were incorporated into the human codon-optimized LPG50148-nAPG07433.1 fusion construct. The performance of these evolved deaminases in ABE was evaluated by editing HEK293T cells at eight endogenous genomic sites. The single mutations showing the highest average fold change (Table 5) were combined and tested to identify the best alignment: variants LPG50148.2.106 (variant 106) and LPG50148.2.107 (variant 107) (Figure 11). Table 4 : CAC single mutations Table 5 : CAC binding mutations

When selection was performed in bacteria in the context of the TAG sequence, six single mutations were identified after the enrichment step (Table 6). The single mutations were incorporated into the human codon-optimized LPG50148-nAPG07433.1 fusion construct. The performance of these evolved deaminases in ABE was evaluated by editing HEK293T cells at three endogenous genomic sites. The single mutations showing the highest average fold change (Table 7) were combined and tested to identify the best alignment: variants LPG50148.2.88 (variant 88) and LPG50148.2.103 (variant 103) (Figure 11). Table 6 : TAG single mutations Table 7 : TAG binding mutations

Furthermore, when delivered as mRNA constructs, the evolved LPG50148 ABE variants LPG50148 numbers 20, 60, 67, 68 and 69 were able to be edited in human cells, showing up to ~80% editing and an average improvement of ~1.6-fold compared to the parental ABE ( FIG. 12 ).

Next, to identify the second generation ABEs with the most robust activity and highest specificity, the evolved LPG50148 ABE variants numbered 20, 60, 67, 68, 103, 106, and 107 were characterized by a comprehensive set of targets (Table 8). For all variants, robust improvements in base editing efficiency were observed (Figure 13A). For all variants tested, the average indel frequency and A to T/C transitions were only slightly above background (0-1%). ABEs including LPG50148 variants LPG50148.20, LPG50148.67, and LPG50148.103 significantly outperformed the parental ABE in editing efficiency across forty-eight genomic sites (Figure 13B). Variant 20 showed improvement (up to 5-fold) for 94% of the primers tested (Table 8). Table 8 : Total A to G substitutions (%) for all ABE constructs in HEK293T cells after plastid delivery across 48 genomic sites .

Compared to the parental ABE (10-21), ABE variants 20, 67, and 103 displayed a larger optimal window (8-22 nucleotides 5' to the PAM sequence on the non-target strand), broadening the targeting range for efficient A base editing (Figure 14).

Detailed analysis of this dataset provides details related to the preferred 5'-NA-3' and 5'-AN-3' editing contexts. For 5'NA, it is TA>CA>>AA>GA for variant 60 and TA>CA>>GA>AA for all other constructs. 5'-AN-3' shows the following preference AC>AT>AG>AA for all variants.

For the TAG context, variant 67 showed higher editing, while variant 20 performed better in all other sequence contexts (Figure 15).

Taken together, these results suggest that more potent ABEs have been developed by directed evolution of the deaminase of the parental ABE (LPG50148-nAPG07433.1). Example 8 : Demonstration of gene editing activity in plant cells

The base editing activity of the RGN deaminase fusion proteins of the present invention was demonstrated in plant cells using a protocol adapted from Li et al., 2013 ( Nat. Biotech. 31: 688-691 ). Briefly, an expression vector comprising an expression cassette capable of expressing an RGN deaminase fusion protein operably linked to an SV40 nuclear localization signal (SEQ ID NO: 430) in plant cells and a second expression cassette encoding a guide RNA targeting one or more sites in a plant PDS gene flanked by an appropriate PAM sequence was introduced into Nicotiana benthamiana mesophyll protoplasts using PEG-mediated transformation. Transformed protoplasts were cultured in the dark for up to 36 hours. Genomic DNA was isolated from protoplasts using the DNeasy Plant Mini Kit (Qiagen). Genome regions flanking the RGN target site were PCR amplified, the products purified, and the purified PCR products analyzed using next-generation sequencing on an Illumina MiSeq. Typically, each amplicon generated 100,000 paired-end reads of 250 bp (2 x 100,000 reads). Reads were analyzed using CRISPResso (Pinello, et al. 2016 Nature Biotech , 34:695-697) to calculate editing rates. Output alignments were analyzed for the introduction of specific adenine mutations or INDEL formation. Example 9 : Base-inlaid editors with improved editing performance by mRNA delivery to primary mouse hepatocytes

Example 9.1 : A vial of primary mouse hepatocytes was thawed in a 37 °C hot water bath and plated at a density of 10k cells per well in culture medium (Williams E medium + fetal bovine serum + cocktail A + dexamethasone; Thermo Fisher). After 4-6 hours in an incubator (37 °C, 5% CO2), cells were lipid-transfected with mRNA and sgRNA (1:3 ng ratio) using Lipofectamine MessengerMAX and 2% fetal bovine serum. A message RNA encoding LPG20046 (LPG50148.2.76 fused to the N-terminus of nAPG07433.1; as shown in SEQ ID NO: 577), LPG20047 (LPG50148.2.20 fused to the N-terminus of nAPG07433.1; as shown in SEQ ID NO: 578), LPG20123 (LPG50148.2.76 inserted after S772 of nAPG07433.1; as shown in SEQ ID NO: 580), or LPG20124 (LPG50148.2.20 inserted after S772 of nAPG07433.1; as shown in SEQ ID NO: 579) is delivered together with the guide RNA. On the second day, the medium was changed to maintenance medium (Williams E medium + cocktail B + dexamethasone Thermo Fisher), and the cells were cultured for another 3 days, after which the genomic DNA was extracted for next generation sequencing (NGS) analysis. The base editing rate at each position in the target HAO1 gene was calculated by obtaining the A to G conversion rate at each position of the entire target sequence. The results are shown in Tables 9-13. Table 9 : Base editing of LPG50148.2.20 N - terminal fusion with nAPG07433.1 (LPG20047 ; SEQ ID NO : 578) and shortened and full-length guide RNAs SGN Position in the target Average BE rate SGN001432 A10 41.1 SGN001432 A3 0.15 SGN001432 A1 0.05 SGN001433 A16 54.05 SGN001433 A9 51.25 SGN001433 A7 4.5 SGN001434 A18 36.35 SGN001434 A11 39 SGN001434 A9 24.85 SGN001434 A2 0 SGN001435 A22 30.95 SGN001435 A15 47.5 SGN001435 A13 44.45 SGN001435 A6 6 SGN008382 A10 43.35 SGN008382 A3 0.15 SGN008382 A1 0 SGN008383 A16 60 SGN008383 A9 65.6 SGN008383 A7 3.85 SGN008384 A18 28.05 SGN008384 A11 32.3 SGN008384 A9 22.1 SGN008384 A2 0 SGN008385 A22 32.95 SGN008385 A15 49.15 SGN008385 A13 43.95 SGN008385 A6 2.7

SGN001432, SGN001433, SGN001434, and SGN001435 contain the full-length backbone of the APG07433.1 nuclease (as set forth in SEQ ID NO: 693). SGN008382, SGN008383, SGN008384, and SGN008385 contain a shortened APG07433.1 backbone (as set forth in SEQ ID NO: 694). When using SGNs with shortened backbones, the base editor containing an N-terminal fusion of LPG50148.2.20 and nAPG07433.1 retained a high degree of editing at similar positions in several targets. Table 10 : N- terminal fusion of LPG50148.2.76 with nAPG07433.1 (LPG20046 ; SEQ ID NO : 577) and base editing of shortened and full-length guide RNAs SGN Location Average BE rate SGN001432 A10 59.6 SGN001432 A3 0.5 SGN001432 A1 0.05 SGN001433 A16 56.05 SGN001433 A9 53.9 SGN001433 A7 13.9 SGN001434 A18 35.05 SGN001434 A11 39.7 SGN001434 A9 37.05 SGN001434 A2 0 SGN001435 A22 36 SGN001435 A15 40.7 SGN001435 A13 41.85 SGN001435 A6 10.2 SGN008382 A10 67.35 SGN008382 A3 0.35 SGN008382 A1 0.1 SGN008383 A16 62.75 SGN008383 A9 61.85 SGN008383 A7 16.4 SGN008384 A18 38.6 SGN008384 A11 44.65 SGN008384 A9 42.8 SGN008384 A2 0 SGN008385 A22 42.2 SGN008385 A15 48.9 SGN008385 A13 49.4 SGN008385 A6 14

SGN001432, SGN001433, SGN001434, and SGN001435 contain the full-length backbone of the APG07433.1 nuclease (as set forth in SEQ ID NO: 693). SGN008382, SGN008383, SGN008384, and SGN008385 contain a shortened APG07433.1 backbone (as set forth in SEQ ID NO: 694). When using SGNs with shortened backbones, the base editor containing an N-terminal fusion of LPG50148.2.76 and nAPG07433.1 retained a high degree of editing at similar positions in several targets. Table 11 : Base editing of LPG50148.2.20 embedded fusion (LPG20124 ; SEQ ID NO : 579) with shortened and full-length guide RNAs in nAPG07433.1 SGN Location Average BE rate SGN001432 A10 33.8 SGN001432 A3 0.05 SGN001432 A1 0 SGN001433 A16 29.05 SGN001433 A9 42 SGN001433 A7 12 SGN001434 A18 16.25 SGN001434 A11 22.85 SGN001434 A9 16.1 SGN001434 A2 0 SGN001435 A22 12.1 SGN001435 A15 42.35 SGN001435 A13 36.75 SGN001435 A6 18.05 SGN008382 A10 38.55 SGN008382 A3 0 SGN008382 A1 0 SGN008383 A16 11.5 SGN008383 A9 18.3 SGN008383 A7 5.8 SGN008384 A18 16.1 SGN008384 A11 22.55 SGN008384 A9 14.2 SGN008384 A2 0 SGN008385 A22 8.85 SGN008385 A15 40.8 SGN008385 A13 34.25 SGN008385 A6 16.8 Table 12 : Base editing of LPG50148.2.76 inlaid fusion (LPG20123 ; SEQ ID NO : 580) with shortened and full-length guide RNAs in nAPG07433.1 SGN Location Average BE rate SGN001432 A10 31.1 SGN001432 A3 0.25 SGN001432 A1 0 SGN001433 A16 19.1 SGN001433 A9 21.95 SGN001433 A7 16.6 SGN001434 A18 19.95 SGN001434 A11 23.4 SGN001434 A9 18.25 SGN001434 A2 0 SGN001435 A22 38.1 SGN001435 A15 43.55 SGN001435 A13 46.2 SGN001435 A6 33 SGN008382 A10 46.55 SGN008382 A3 0.3 SGN008382 A1 0 SGN008383 A16 25.85 SGN008383 A9 28.9 SGN008383 A7 20.85 SGN008384 A18 28.1 SGN008384 A11 32.45 SGN008384 A9 26.55 SGN008384 A2 0 SGN008385 A22 44.35 SGN008385 A15 50.6 SGN008385 A13 52.7 SGN008385 A6 37.6

Efficient editing in mouse primary hepatocytes was observed by mRNA delivery of the base editor. Inlay, N-terminal and C-terminal fusions of the improved deaminase (data not shown) were effective. For some targets, N-terminal or C-terminal fusions of the deaminase had higher editing rates than the inlay base editor design. In addition, the editors tested worked with shortened (M) and full-length (F) guide RNA backbones. Example 9.2 : DNA templates for making mRNA were amplified by PCR reactions. An IVT (in vitro transcription) reaction was then performed, followed by DNase I and ProK treatment to remove the DNA template and enzymes. The mRNA was then purified by plate-based silica membrane. Dose response with mRNA delivery. Efficient dose-dependent editing was observed by lipofectamine delivery of ABE mRNA and synthetic guide RNA in mouse primary hepatocytes. 80 ng of guide RNA SGN008393 was co-transfected with varying amounts of mRNA. Figure 16 shows the results of base editing at position 11 with the base editor comprising the evolved deaminase LPG50148.2.20 (referred to as LPG20047 as shown in SEQ ID NO: 578) fused to the N-terminus of nAPG07433.1. The LPG20047 base editor was active at low mRNA doses in the base editor construct. Example 10 : Generation of deaminase LPG50319 and LPG50320 , and site saturation induction engineering to generate improved deaminase LPG50324

Deaminases LPG50319 (also referred to herein as LPG50148.2.107 and as shown in SEQ ID NO: 406) and LPG50320 (as shown in SEQ ID NO: 596) were generated by combining two frequently beneficial mutations observed in the E. coli screen previously described in Example 7. Both comprised a V81S mutation and a second mutation identified in a parallel selection in the CAC context in E. coli. Specifically, LPG50319 had M117L (along with V81S) and LPG50320 had V68A (along with V81S) relative to the parent LPG50148 deaminase.

During subsequent evolutionary rounds, LPG50265 (also referred to as LPG50148.2.67, as shown in SEQ ID NO: 366) was used as a new parent deaminase. A combinatorial library was generated above LPG50265 by site saturation induction (changing the four hotspot positions identified in the first round). This library was then screened in E. coli, resulting in the selection of deaminase LPG50324 (as shown in SEQ ID NO: 597) under highly stringent conditions. LPG50324 has seven mutations (I75Y, V81S, M117L, N121G, C145L, F155W, and A160D) relative to the parent LPG50148 deaminase as shown in SEQ ID NO: 5.

The directed evolution scheme can be found in Figure 17. Figure 18 shows LPG50324 with improved activity over parent LPG50148. The experiment in Figure 17C was performed in HEK293T cells (10K cells/reaction) transfected with a 4:1 ratio of base editor plasmids (160 ng) and guide plasmids (40 ng) using Lipofectamine P3000 transfection reagent. The sequences of LPG50148, LPG50265, LPG50321, LPG50322, LPG50323, and LPG50324 are shown in SEQ ID NOs: 5, 366, 720, 721, 722, and 597, respectively, and the base editor constructs are named LPG50148_nAPG07433.1, LPG20130, LPG20126, LPG20127, LPG20128, and LPG20129, respectively, which include a deaminase fused to the N-terminus of the nAPG07433.1 nickase. Cells were harvested 48 hours after transfection and subjected to genomic DNA extraction using QuickExtract DNA extraction solution. The genomic region targeted by the sgRNA was amplified by PCR, and the PCR amplicon was subsequently analyzed by NGS to assess editing efficiency. The experiment in FIG. 18 was performed in primary human hepatocytes described in Example 11.

Several nAPG07433.1-ABE variants in human primary T cells were analyzed for base editing efficiency using mRNA delivery. Briefly, six individual vials of T cells (donor-008) were thawed, activated, and cultured in three separate flasks by two different scientists. Three days after activation, 30K cells per condition were nucleofected using the EO-115 program with 2 µg mRNA + 4 µg sgRNA in P3 solution. A total of ten guide RNAs targeting five different genes were tested for each ABE variant. Triplicate per condition was performed to assess reproducibility. Four days after nucleofection, cells were harvested and genomic DNA was extracted using QuickExtract. On-target and predicted off-target edits were identified by PCR amplification of the relevant genomic loci and sequenced by Illumina short-read sequencing.

The maximum base editing rate (maximum BE rate) was calculated by taking the A to G conversion rate at each position in the entire guide and obtaining the maximum edit rate at a single position. The total adenine substitution rate (total A substitution rate) calculated the percentage of reads containing at least one adenine to guanine edit.

Note that LPG50148.2.4, LPG50148.2.20, LPG50148.2.24, LPG50148.2.27, LPG50148.2.60, LPG50148.2.67, LPG50148.2.68, LPG50148.2.76, LPG50148.2.103, LPG50148.2.106, and LPG50148.2.107 are referenced as alternative names in Tables 14-18 and in this example and Examples 11-14. The alternative names are listed in Table 13. Table 13 : Alternative names for various LPG50148 variants LPG5014.2.__ Nomenclature Alternative naming LPG50148.2.4 LPG50208 LPG50148.2.20 LPG50221 LPG50148.2.24 LPG50225 LPG50148.2.27 LPG50228 LPG50148.2.60 LPG50258 LPG50148.2.67 LPG50265 LPG50148.2.68 LPG50266 LPG50148.2.76 LPG50274 LPG50148.2.103 LPG50432 LPG50148.2.106 LPG50298 LPG50148.2.107 LPG50319 Table 14 : Performance of evolved deaminases and different fusion protein constructs on nAPG07433.1 Deaminase Nuclease Fusion Protein Fusion Type SGN Target gene The average of the maximum BE rate Average total A substitution rate LPG50148 nAPG07433.1 LPG20048 N-terminal SGN001256 B2M 41.53 58.85 LPG50148 nAPG07433.1 LPG20048 N-terminal SGN001947 B2M 6.77 13.51 LPG50148 nAPG07433.1 LPG20048 N-terminal SGN001960 B2M 68.56 84.98 LPG50148 nAPG07433.1 LPG20048 N-terminal SGN002259 Gene A 3.37 9.73 LPG50148 nAPG07433.1 LPG20048 N-terminal SGN002336 Gene B 7.96 12.88 LPG50148 nAPG07433.1 LPG20048 N-terminal SGN002352 Gene C 3.87 10.99 LPG50148 nAPG07433.1 LPG20048 N-terminal SGN002364 Gene C 8.08 20.16 LPG50148 nAPG07433.1 LPG20048 N-terminal SGN002372 Gene D 94.13 94.05 LPG50148 nAPG07433.1 LPG20048 N-terminal SGN003707 B2M 28.60 55.64 LPG50148 nAPG07433.1 LPG20048 N-terminal SGN004995 TRAC 37.61 54.65 LPG50432 nAPG07433.1 LPG20058 N-terminal SGN001256 B2M 65.06 78.95 LPG50432 nAPG07433.1 LPG20058 N-terminal SGN001947 B2M 12.13 17.59 LPG50432 nAPG07433.1 LPG20058 N-terminal SGN001960 B2M 54.25 85.90 LPG50432 nAPG07433.1 LPG20058 N-terminal SGN002259 Gene A 7.44 15.53 LPG50432 nAPG07433.1 LPG20058 N-terminal SGN002336 Gene B 20.23 26.37 LPG50432 nAPG07433.1 LPG20058 N-terminal SGN002352 Gene C 4.89 13.29 LPG50432 nAPG07433.1 LPG20058 N-terminal SGN002364 Gene C 8.85 21.56 LPG50432 nAPG07433.1 LPG20058 N-terminal SGN002372 Gene D 91.12 91.81 LPG50432 nAPG07433.1 LPG20058 N-terminal SGN003707 B2M 62.14 87.65 LPG50432 nAPG07433.1 LPG20058 N-terminal SGN004995 TRAC 45.02 59.64 LPG50298 nAPG07433.1 LPG20059 N-terminal SGN001256 B2M 65.94 80.93 LPG50298 nAPG07433.1 LPG20059 N-terminal SGN001947 B2M 19.13 31.00 LPG50298 nAPG07433.1 LPG20059 N-terminal SGN001960 B2M 80.61 91.38 LPG50298 nAPG07433.1 LPG20059 N-terminal SGN002259 Gene A 10.24 20.95 LPG50298 nAPG07433.1 LPG20059 N-terminal SGN002336 Gene B 26.98 36.55 LPG50298 nAPG07433.1 LPG20059 N-terminal SGN002352 Gene C 10.86 22.54 LPG50298 nAPG07433.1 LPG20059 N-terminal SGN002364 Gene C 19.37 30.34 LPG50298 nAPG07433.1 LPG20059 N-terminal SGN002372 Gene D 92.60 92.98 LPG50298 nAPG07433.1 LPG20059 N-terminal SGN003707 B2M 72.58 93.19 LPG50298 nAPG07433.1 LPG20059 N-terminal SGN004995 TRAC 69.22 83.82 LPG50319 nAPG07433.1 LPG20060 N-terminal SGN001256 B2M 72.94 82.63 LPG50319 nAPG07433.1 LPG20060 N-terminal SGN001947 B2M 23.38 37.24 LPG50319 nAPG07433.1 LPG20060 N-terminal SGN001960 B2M 85.69 93.36 LPG50319 nAPG07433.1 LPG20060 N-terminal SGN002259 Gene A 10.98 20.71 LPG50319 nAPG07433.1 LPG20060 N-terminal SGN002336 Gene B 32.18 41.65 LPG50319 nAPG07433.1 LPG20060 N-terminal SGN002352 Gene C 12.59 24.75 LPG50319 nAPG07433.1 LPG20060 N-terminal SGN002364 Gene C 27.38 40.40 LPG50319 nAPG07433.1 LPG20060 N-terminal SGN002372 Gene D 93.60 93.53 LPG50319 nAPG07433.1 LPG20060 N-terminal SGN003707 B2M 76.23 93.10 LPG50319 nAPG07433.1 LPG20060 N-terminal SGN004995 TRAC 73.46 88.29 LPG50221 nAPG07433.1 LPG20051 N-terminal SGN001256 B2M 46.76 63.20 LPG50221 nAPG07433.1 LPG20051 N-terminal SGN001947 B2M 13.37 23.72 LPG50221 nAPG07433.1 LPG20051 N-terminal SGN001960 B2M 63.89 81.81 LPG50221 nAPG07433.1 LPG20051 N-terminal SGN002259 Gene A 5.21 12.35 LPG50221 nAPG07433.1 LPG20051 N-terminal SGN002336 Gene B 10.64 18.70 LPG50221 nAPG07433.1 LPG20051 N-terminal SGN002352 Gene C 4.90 14.17 LPG50221 nAPG07433.1 LPG20051 N-terminal SGN002364 Gene C 8.34 22.25 LPG50221 nAPG07433.1 LPG20051 N-terminal SGN002372 Gene D 91.86 92.07 LPG50221 nAPG07433.1 LPG20051 N-terminal SGN003707 B2M 39.59 73.82 LPG50221 nAPG07433.1 LPG20051 N-terminal SGN004995 TRAC 36.09 51.74 LPG50225 nAPG07433.1 LPG20053 N-terminal SGN001256 B2M 35.71 54.14 LPG50225 nAPG07433.1 LPG20053 N-terminal SGN001947 B2M 9.06 15.49 LPG50225 nAPG07433.1 LPG20053 N-terminal SGN001960 B2M 74.18 85.35 LPG50225 nAPG07433.1 LPG20053 N-terminal SGN002259 Gene A 2.62 8.30 LPG50225 nAPG07433.1 LPG20053 N-terminal SGN002336 Gene B 6.13 11.70 LPG50225 nAPG07433.1 LPG20053 N-terminal SGN002352 Gene C 5.59 12.99 LPG50225 nAPG07433.1 LPG20053 N-terminal SGN002364 Gene C 10.09 19.22 LPG50225 nAPG07433.1 LPG20053 N-terminal SGN002372 Gene D 91.90 92.28 LPG50225 nAPG07433.1 LPG20053 N-terminal SGN003707 B2M 59.48 77.06 LPG50225 nAPG07433.1 LPG20053 N-terminal SGN004995 TRAC 41.49 58.96 LPG50228 nAPG07433.1 LPG20054 N-terminal SGN001256 B2M 52.81 68.30 LPG50228 nAPG07433.1 LPG20054 N-terminal SGN001947 B2M 17.71 27.18 LPG50228 nAPG07433.1 LPG20054 N-terminal SGN001960 B2M 73.23 88.86 LPG50228 nAPG07433.1 LPG20054 N-terminal SGN002259 Gene A 11.57 22.04 LPG50228 nAPG07433.1 LPG20054 N-terminal SGN002336 Gene B 20.69 29.16 LPG50228 nAPG07433.1 LPG20054 N-terminal SGN002352 Gene C 5.93 16.10 LPG50228 nAPG07433.1 LPG20054 N-terminal SGN002364 Gene C 11.30 22.60 LPG50228 nAPG07433.1 LPG20054 N-terminal SGN002372 Gene D 92.93 92.90 LPG50228 nAPG07433.1 LPG20054 N-terminal SGN003707 B2M 59.07 85.55 LPG50228 nAPG07433.1 LPG20054 N-terminal SGN004995 TRAC 54.77 69.97 LPG50208 nAPG07433.1 LPG20050 N-terminal SGN001256 B2M 63.43 76.31 LPG50208 nAPG07433.1 LPG20050 N-terminal SGN001947 B2M 17.82 29.15 LPG50208 nAPG07433.1 LPG20050 N-terminal SGN001960 B2M 82.36 91.53 LPG50208 nAPG07433.1 LPG20050 N-terminal SGN002259 Gene A 9.05 18.30 LPG50208 nAPG07433.1 LPG20050 N-terminal SGN002336 Gene B 20.69 29.30 LPG50208 nAPG07433.1 LPG20050 N-terminal SGN002352 Gene C 10.16 20.44 LPG50208 nAPG07433.1 LPG20050 N-terminal SGN002364 Gene C 17.88 30.49 LPG50208 nAPG07433.1 LPG20050 N-terminal SGN002372 Gene D 91.23 91.35 LPG50208 nAPG07433.1 LPG20050 N-terminal SGN003707 B2M 66.88 89.93 LPG50208 nAPG07433.1 LPG20050 N-terminal SGN004995 TRAC 63.01 79.26 LPG50320 nAPG07433.1 LPG20052 N-terminal SGN001256 B2M 68.24 77.48 LPG50320 nAPG07433.1 LPG20052 N-terminal SGN001947 B2M 25.92 41.71 LPG50320 nAPG07433.1 LPG20052 N-terminal SGN001960 B2M 80.60 89.41 LPG50320 nAPG07433.1 LPG20052 N-terminal SGN002259 Gene A 10.87 21.96 LPG50320 nAPG07433.1 LPG20052 N-terminal SGN002336 Gene B 25.74 35.68 LPG50320 nAPG07433.1 LPG20052 N-terminal SGN002352 Gene C 14.94 29.13 LPG50320 nAPG07433.1 LPG20052 N-terminal SGN002364 Gene C 30.27 45.68 LPG50320 nAPG07433.1 LPG20052 N-terminal SGN002372 Gene D 92.44 92.48 LPG50320 nAPG07433.1 LPG20052 N-terminal SGN003707 B2M 66.50 87.30 LPG50320 nAPG07433.1 LPG20052 N-terminal SGN004995 TRAC 71.76 87.15 LPG50208 nAPG07433.1 LPG20044 Inlay 642 SGN001256 B2M 30.63 41.77 LPG50208 nAPG07433.1 LPG20044 Inlay 642 SGN001947 B2M 8.61 14.77 LPG50208 nAPG07433.1 LPG20044 Inlay 642 SGN001960 B2M 47.26 56.96 LPG50208 nAPG07433.1 LPG20044 Inlay 642 SGN002259 Gene A 2.17 5.66 LPG50208 nAPG07433.1 LPG20044 Inlay 642 SGN002336 Gene B 13.70 15.70 LPG50208 nAPG07433.1 LPG20044 Inlay 642 SGN002352 Gene C 1.92 7.26 LPG50208 nAPG07433.1 LPG20044 Inlay 642 SGN002364 Gene C 6.74 10.08 LPG50208 nAPG07433.1 LPG20044 Inlay 642 SGN002372 Gene D 65.57 68.73 LPG50208 nAPG07433.1 LPG20044 Inlay 642 SGN003707 B2M 65.74 77.06 LPG50208 nAPG07433.1 LPG20044 Inlay 642 SGN004995 TRAC 35.32 42.38 LPG50208 nAPG07433.1 LPG20045 Inlay 772 SGN001256 B2M 51.13 67.01 LPG50208 nAPG07433.1 LPG20045 Inlay 772 SGN001947 B2M 26.41 38.61 LPG50208 nAPG07433.1 LPG20045 Inlay 772 SGN001960 B2M 62.45 76.35 LPG50208 nAPG07433.1 LPG20045 Inlay 772 SGN002259 Gene A 8.83 13.31 LPG50208 nAPG07433.1 LPG20045 Inlay 772 SGN002336 Gene B 41.31 42.73 LPG50208 nAPG07433.1 LPG20045 Inlay 772 SGN002352 Gene C 10.55 20.54 LPG50208 nAPG07433.1 LPG20045 Inlay 772 SGN002364 Gene C 13.06 19.86 LPG50208 nAPG07433.1 LPG20045 Inlay 772 SGN002372 Gene D 59.43 69.72 LPG50208 nAPG07433.1 LPG20045 Inlay 772 SGN003707 B2M 54.69 78.24 LPG50208 nAPG07433.1 LPG20045 Inlay 772 SGN004995 TRAC 23.91 36.30 LPG50258 nAPG07433.1 LPG20055 N-terminal SGN001256 B2M 49.72 69.98 LPG50258 nAPG07433.1 LPG20055 N-terminal SGN001947 B2M 16.43 27.75 LPG50258 nAPG07433.1 LPG20055 N-terminal SGN001960 B2M 79.19 90.04 LPG50258 nAPG07433.1 LPG20055 N-terminal SGN002259 Gene A 8.02 16.08 LPG50258 nAPG07433.1 LPG20055 N-terminal SGN002336 Gene B 17.98 24.01 LPG50258 nAPG07433.1 LPG20055 N-terminal SGN002352 Gene C 8.59 17.19 LPG50258 nAPG07433.1 LPG20055 N-terminal SGN002364 Gene C 12.70 21.45 LPG50258 nAPG07433.1 LPG20055 N-terminal SGN002372 Gene D 93.64 94.06 LPG50258 nAPG07433.1 LPG20055 N-terminal SGN003707 B2M 72.08 87.28 LPG50258 nAPG07433.1 LPG20055 N-terminal SGN004995 TRAC 58.38 73.39 LPG50265 nAPG07433.1 LPG20056 N-terminal SGN001256 B2M 57.15 75.17 LPG50265 nAPG07433.1 LPG20056 N-terminal SGN001947 B2M 18.53 26.03 LPG50265 nAPG07433.1 LPG20056 N-terminal SGN001960 B2M 84.92 91.62 LPG50265 nAPG07433.1 LPG20056 N-terminal SGN002259 Gene A 4.78 11.81 LPG50265 nAPG07433.1 LPG20056 N-terminal SGN002336 Gene B 17.47 23.35 LPG50265 nAPG07433.1 LPG20056 N-terminal SGN002352 Gene C 12.52 20.04 LPG50265 nAPG07433.1 LPG20056 N-terminal SGN002364 Gene C 20.84 30.75 LPG50265 nAPG07433.1 LPG20056 N-terminal SGN002372 Gene D 93.50 93.87 LPG50265 nAPG07433.1 LPG20056 N-terminal SGN003707 B2M 78.08 88.84 LPG50265 nAPG07433.1 LPG20056 N-terminal SGN004995 TRAC 60.61 74.03 LPG50266 nAPG07433.1 LPG20057 N-terminal SGN001256 B2M 60.11 76.46 LPG50266 nAPG07433.1 LPG20057 N-terminal SGN001947 B2M 21.46 30.74 LPG50266 nAPG07433.1 LPG20057 N-terminal SGN001960 B2M 85.45 91.38 LPG50266 nAPG07433.1 LPG20057 N-terminal SGN002259 Gene A 6.64 14.43 LPG50266 nAPG07433.1 LPG20057 N-terminal SGN002336 Gene B 16.18 24.13 LPG50266 nAPG07433.1 LPG20057 N-terminal SGN002352 Gene C 13.47 21.35 LPG50266 nAPG07433.1 LPG20057 N-terminal SGN002364 Gene C 19.03 27.85 LPG50266 nAPG07433.1 LPG20057 N-terminal SGN002372 Gene D 92.69 92.98 LPG50266 nAPG07433.1 LPG20057 N-terminal SGN003707 B2M 76.91 89.70 LPG50266 nAPG07433.1 LPG20057 N-terminal SGN004995 TRAC 63.19 77.50 LPG50274 nAPG07433.1 LPG20049 N-terminal SGN001256 B2M 79.31 85.78 LPG50274 nAPG07433.1 LPG20049 N-terminal SGN001947 B2M 45.61 64.55 LPG50274 nAPG07433.1 LPG20049 N-terminal SGN001960 B2M 84.21 87.08 LPG50274 nAPG07433.1 LPG20049 N-terminal SGN002259 Gene A 20.63 32.57 LPG50274 nAPG07433.1 LPG20049 N-terminal SGN002336 Gene B 41.81 49.88 LPG50274 nAPG07433.1 LPG20049 N-terminal SGN002352 Gene C 26.46 38.98 LPG50274 nAPG07433.1 LPG20049 N-terminal SGN002364 Gene C 35.49 42.45 LPG50274 nAPG07433.1 LPG20049 N-terminal SGN002372 Gene D 88.66 89.07 LPG50274 nAPG07433.1 LPG20049 N-terminal SGN003707 B2M 86.65 89.38 LPG50274 nAPG07433.1 LPG20049 N-terminal SGN004995 TRAC 76.68 82.52

Evolved variants demonstrated an average increase in activity of up to 50% by mRNA delivery in primary T cells. Some constructs have lead specific efficacy, indicating that relationships between specific target sequences and base editor structures exist and were not apparent prior to experimental testing. The results in Table 14 demonstrate an increase in A to G editing activity of up to 50% by mRNA delivery in T cells for evolved ABE variants having an LPG20049 fusion protein comprising LPG50274/LPG50148.2.76 (highest ranked on average) fused to the N-terminus of nAPG07433.1. Example 11 : Evolution of mRNA delivery to primary human hepatocytes :

Using previously tested inlay and end-fusion architectures, the evolved deaminases were combined with RNA-guided nucleases to generate different adenine base editors. DNA templates for mRNA production were amplified by PCR reactions. IVT (in vitro transcription) reactions were then performed, followed by DNase I and ProK treatment to remove the DNA template and enzyme. mRNA was then purified by plate-based silica membranes. Primary human hepatocytes were transfected with ABE mRNA and guide RNA (ABE mRNA: 112 ng; sgRNA: 38 ng) using Lipofectamine MessengerMax transfection reagent. Cells were harvested 96 hours after transfection and subjected to genomic DNA extraction using QuickExtract DNA extraction solution. The genomic region targeted by the sgRNA was amplified by PCR, and the PCR amplicon was subsequently analyzed by NGS to assess editing efficiency. The maximum base editing rate (MaxEdit) was calculated by taking the adenine to guanine conversion rate at each position in the entire guide and obtaining the maximum editing rate at a single position. Table 15 : Base editing rates of evolved deaminases in multiple RNA- guided nucleases with different fusion structures in primary human hepatocytes Deaminase Nuclease Fusion Construct Fusion SEQ ID NO Fusion Type Gene SGN Max Edit LPG50221 nAPG07433.1 LPG20047 578 N-terminal B2M SGN003707 twenty one LPG50221 nAPG07433.1 LPG20073 612 Inlay 772 B2M SGN003707 26.3 LPG50221 nLPG10145 LPG20068 607 N-terminal B2M SGN003018 21.9 LPG50221 nLPG10145 LPG20064 603 Inlay 910 B2M SGN003018 24.5 LPG50221 nAPG05586 LPG20072 611 N-terminal B2M SGN003540 16.1 LPG50221 nAPG05586 LPG20076 615 Inlay 678 B2M SGN003540 13.7 LPG50221 nAPG05586 LPG20063 640 Inlay 922 B2M SGN003540 19.8 LPG50274 nAPG07433.1 LPG20046 638 N-terminal B2M SGN003707 20.8 LPG50274 nAPG07433.1 LPG20067 606 Inlay 772 B2M SGN003707 19.6 LPG50274 nLPG10145 LPG20074 613 N-terminal B2M SGN003018 19.2 LPG50274 nLPG10145 LPG20062 600 Inlay 910 B2M SGN003018 22.7 LPG50274 nAPG05586 LPG20069 608 N-terminal B2M SGN003540 16.2 LPG50274 nAPG05586 LPG20071 610 Inlay 678 B2M SGN003540 11.3 LPG50274 nAPG05586 LPG20061 642 Inlay 922 B2M SGN003540 16.4 LPG50319 nAPG07433.1 LPG20077 616 N-terminal B2M SGN003707 28.3 LPG50319 nAPG07433.1 LPG20096 630 Inlay 772 B2M SGN003707 25.5 LPG50319 nLPG10145 LPG20094 628 N-terminal B2M SGN003018 26.6 LPG50319 nLPG10145 LPG20087 621 Inlay 910 B2M SGN003018 42.8 LPG50319 nAPG05586 LPG20091 625 N-terminal B2M SGN003540 21.6 LPG50319 nAPG05586 LPG20083 617 Inlay 678 B2M SGN003540 12.6 LPG50319 nAPG05586 LPG20089 623 Inlay 922 B2M SGN003540 19 LPG50320 nAPG07433.1 LPG20065 636 N-terminal B2M SGN003707 18.3 LPG50320 nAPG07433.1 LPG20097 631 Inlay 772 B2M SGN003707 22.4 LPG50320 nLPG10145 LPG20084 618 N-terminal B2M SGN003018 31.9 LPG50320 nLPG10145 LPG20090 624 Inlay 910 B2M SGN003018 34.9 LPG50320 nAPG05586 LPG20093 627 N-terminal B2M SGN003540 21.7 LPG50320 nAPG05586 LPG20086 620 Inlay 678 B2M SGN003540 13.8 LPG50320 nAPG05586 LPG20092 626 Inlay 922 B2M SGN003540 21.6 LPG50324 nAPG07433.1 LPG20066 637 N-terminal B2M SGN003707 22.1 LPG50324 nAPG07433.1 LPG20098 632 Inlay 772 B2M SGN003707 19.5 LPG50324 nLPG10145 LPG20095 629 N-terminal B2M SGN003018 20.3 LPG50324 nLPG10145 LPG20088 622 Inlay 910 B2M SGN003018 38.9 LPG50324 nAPG05586 LPG20070 609 N-terminal B2M SGN003540 16.9 LPG50324 nAPG05586 LPG20085 619 Inlay 678 B2M SGN003540 17.4 LPG50324 nAPG05586 LPG20075 614 Inlay 922 B2M SGN003540 28

Efficient editing in human primary hepatocytes was observed by mRNA delivery of base editors. Improved inlay and N-terminal fusion of deaminase was effective for three unique nucleases (nAPG07433.1, nAPG05586, and nLPG10145). Example 12 : Editing in HepG2 cells

HepG2 cells were transfected with ABE mRNA and guide RNA (ABE mRNA: 150 ng and sgRNA: 50 ng) at a 3:1 ratio using Lipofectamine MessengerMax transfection reagent. Cells were harvested 48 hours after transfection and subjected to genomic DNA extraction using QuickExtract DNA Extraction Solution. The genomic region targeted by the sgRNA was amplified by PCR, and the PCR amplicon was subsequently analyzed by NGS to assess editing efficiency. The maximum base editing rate (maximum edit) was calculated by taking the adenine to guanine conversion rate at each position in the entire guide and obtaining the maximum editing rate at a single position. Table 16 : Base editing rates of evolved deaminases fused to the amino terminus of nAPG07433.1 in HepG2 cells Deaminase Fusion Construct Fusion Type SGN Target gene Average maximum BE rate LPG50148 LPG20048 N-terminal SGN003707 B2M 36.625 LPG50148 LPG20048 N-terminal SGN00AAAA Gene E 46.4125 LPG50148 LPG20048 N-terminal SGN008971 TRAC 15.975 LPG50221 LPG20051 N-terminal SGN003707 B2M 40.9 LPG50221 LPG20051 N-terminal SGN00AAAA Gene E 32.925 LPG50221 LPG20051 N-terminal SGN008971 TRAC 9.65 LPG50208 LPG20050 N-terminal SGN003707 B2M 54.65 LPG50208 LPG20050 N-terminal SGN00AAAA Gene E 53.675 LPG50208 LPG20050 N-terminal SGN008971 TRAC 18.05 LPG50320 LPG20065 N-terminal SGN003707 B2M 57.9 LPG50320 LPG20065 N-terminal SGN00AAAA Gene E 59 LPG50320 LPG20065 N-terminal SGN008971 TRAC 17.55 LPG50324 LPG20066 N-terminal SGN003707 B2M 59.9 LPG50324 LPG20066 N-terminal SGN00AAAA Gene E 54.775 LPG50324 LPG20066 N-terminal SGN008971 TRAC 11.45 LPG50274 LPG20046 N-terminal SGN003707 B2M 73.3 LPG50274 LPG20046 N-terminal SGN00AAAA Gene E 56.85 LPG50274 LPG20046 N-terminal SGN008971 TRAC 16.95 Table 17 : Base editing rates of evolved deaminases in nAPG05586 with different fusion structures in HepG2 cells Deaminase Fusion Protein Fusion Type SGN Target gene Average BE maximum LPG50221 LPG20076 Inlay 678 SGN003486 TRAC 17.6 LPG50221 LPG20076 Inlay 678 SGN003540 B2M 20.65 LPG50274 LPG20063 Inlay 922 SGN003486 TRAC 37.3666667 LPG50274 LPG20063 Inlay 922 SGN003540 B2M 44.2 LPG50221 LPG20071 Inlay 678 SGN003486 TRAC 30.25 LPG50221 LPG20071 Inlay 678 SGN003540 B2M 31.15 LPG50274 LPG20061 Inlay 922 SGN003486 TRAC 54.0333333 LPG50274 LPG20061 Inlay 922 SGN003540 B2M 67.6

The inlay configurations used for nAPG05586 and nAPG07433.1 with the lead deaminase enable editing in HepG2 cells by mRNA delivery. Example 13 : N-terminal fusion of nLPG10196 and the inlay base editor function with the evolved deaminase

Based on sequence and structure analysis, four inlay constructs of nLPG10196 were prepared in addition to the N-terminal fusion. Messenger RNA was expressed and purified for LPG10196 base editor constructs. Briefly, DNA templates for mRNA production were amplified by PCR reactions. IVT (in vitro transcription) reactions were then performed, followed by DNase I and ProK treatments to remove the DNA template and enzymes. mRNA was then purified by plate-based silica gel membranes. For base editing, 150 ng of mRNA and 50 ng of sgRNA (synthetic guide) were lipid-transfected into HEK293T cells seeded at 10,000 cells/well using MessengerMax. Cells were cultured for three days and then genomic DNA was extracted. PCR amplification was used to amplify the edited region of interest and sent to NGS sequencing. The maximum base editing rate (Max BE Rate) was calculated by taking the adenine to guanine conversion rate at each position in the entire guide and obtaining the maximum editing rate for a single position. Table 18 : nLPG10196 base editor function in HEK293T cells delivered by mRNA Deaminase Fusion Location Fusion Protein SGN Target gene Average maximum BE rate LPG50221 N-terminal LPG20099 SGN005326 TRAC 5.750% LPG50221 N-terminal LPG20099 SGN005329 B2M 0.000% LPG50274 N-terminal LPG20100 SGN005326 TRAC 3.034% LPG50274 N-terminal LPG20100 SGN005329 B2M 0.124% LPG50324 N-terminal LPG20101 SGN005326 TRAC 8.132% LPG50324 N-terminal LPG20101 SGN005329 B2M 0.080% LPG50319 N-terminal LPG20102 SGN005326 TRAC 5.996% LPG50319 N-terminal LPG20102 SGN005329 B2M 0.208% LPG50274 Inlay T806 LPG20111 SGN005326 TRAC 3.018% LPG50274 Inlay T806 LPG20111 SGN005329 B2M 0.000% LPG50274 Inlay D700 LPG20120 SGN005326 TRAC 0.000% LPG50274 Inlay D700 LPG20120 SGN005329 B2M 0.000% LPG50274 Inlay I797 LPG20121 SGN005326 TRAC 0.057% LPG50274 Inlay I797 LPG20121 SGN005329 B2M 0.000% LPG50274 Inlay G766 LPG20122 SGN005326 TRAC 4.263%

Several deaminases were tested as fusions to the N-terminus of nLPG10196. Several inlay positions were tested, but only two showed editing against the above background (LPG20122 and LPG20111), indicating that LPG10196 has a site-specific requirement for inlaying the base editor construct. The N-terminal fusion at SGN005329 showed higher editing compared to SGN005326 with all deaminases tested. LPG10196 is able to exploit evolved deaminases for base editing activity, but there are target-specific and deaminases-specific factors that influence the rate of base editing. Example 14 : Discovery and Evaluation of LPG50310 Variants

38 beneficial mutations distributed at 28 positions were identified from the first round of selection. These mutations were combined to form a library with 1-28 mutations per variant (average 19 mutations). This library was then subjected to more stringent selection conditions, using 256-512µg/ml of conamycin concentration and two stop codons to identify the most promising variants. Among them, a particularly enriched variant, LPG50310 (as shown in SEQ ID NO: 723), was found and then evaluated in mammalian cells. Evaluation was performed in HEK293T cells (10K cells/reaction) transfected with the base editor plasmid (160 ng) and guide plasmid (40 ng) at a 4:1 ratio using Lipofectamine P3000 transfection reagent. The base editor sequence is shown in SEQ ID NO:727 and is named LPG20125, which contains the LPG50310 deaminase fused to the N-terminus of the nAPG07433.1 nickase. Cells were harvested 48 hours after transfection and genomic DNA was extracted using QuickExtract DNA Extraction Solution. The genomic region targeted by the sgRNA was amplified by PCR, and the PCR amplicon was subsequently analyzed by NGS to evaluate editing efficiency. The results are shown in Figure 19, which compares the base editors LPG20130 (comprising LPG50265 deaminase fused to the N-terminus of nAPG07433.1) and LPG20125 (comprising LPG50310 fused to the N-terminus of nAPG07433.1) edited using sgRNAs SGN00CCCC, SGN005430 and SGN005420 (each targeting a different gene at positions A6, A9 and A10, respectively). Table 19. Other mutations in the currently disclosed evolved deaminases relative to the parental LPG50148 deaminase (SEQ ID NO: 5) R22C I75A I75Q I7 K109L N121A N121G Y122H G142A C145Q C145L Q153E Q153R Table 20. Application sequence Sequence Name SEQ ID NO APG07433.1 1 APG05586 2 APG01604 3 LPG10145 4 LPG50148 (minus the starting methionine) 5 LPG50148 V81S (minus starting methionine) 6 LPG50148_nAPG07433.1_parent 7 nAPG07433.1_Inlay S772_LPG50148 (LPG20002) 8 nAPG07433.1_Inlay S775_LPG50148 (LPG20003) 9 nAPG07433.1_Inlay K778_LPG50148 (LPG20004) 10 nAPG07433.1_Inlay E900_LPG50148 (LPG20005) 11 nAPG07433.1_Inlay G910_LPG50148 (LPG20006) 12 nAPG07433.1_Inlay R30_LPG50148 (LPG20007) 13 nAPG07433.1_Inlay T642_LPG50148 (LPG20008) 14 nAPG07433.1_Inlay R670_LPG50148 (LPG20009) 15 nAPG07433.1_Inlay D737_LPG50148 (LPG20010) 16 nAPG07433.1_Inlay A802_LPG50148 (LPG20011) 17 nAPG07433.1 inlay S772_LPG50148 (delNterlinker/ LPG20012) 18 nAPG07433.1_Inlay S772LPG50148 (delCterlinker/LPG20013) 19 nAPG07433.1 embedded S772LPG50148_del1aaNandC (nolinker/1aaNandC/LPG20014) 20 nAPG07433.1_Inlaid S772_LPG50148+V81S mutant (LPG20015) twenty one LPG50148+V81S _nAPG05586_parent twenty two nAPG05586_Inlay G342_LPG50148+V81S (LPG20016) twenty three nAPG05586_Inlay D518_LPG50148+V81S (LPG20017) twenty four nAPG05586_Inlay Q630_LPG50148+V81S (LPG20018) 25 nAPG05586_Inlay R661_LPG50148+V81S (LPG20019) 26 nAPG05586_Inlay F678_LPG50148+V81S (LPG20020) 27 nAPG05586_Inlay D736_LPG50148+V81S (LPG20021) 28 nAPG05586_Inlay E778_LPG50148+V81S (LPG20022) 29 nAPG05586_Inlay D788_LPG50148+V81S (LPG20023) 30 nAPG05586_Inlay K922_LPG50148+V81S (LPG20024) 31 nAPG05586_Inlay G1109_LPG50148+V81S (LPG20025) 32 LPG50148+V81S _nAPG01604_parent 33 nAPG01604_Inlay G597_LPG50148+V81S+A137V (LPG20027) 34 nAPG01604_Inlay S631_LPG50148+V81S+A137V (LPG20028) 35 nAPG01604_Inlay K725_LPG50148+V81S+A137V (LPG20029) 36 nAPG01604_Inlay K739_LPG50148+V81S+A137V (LPG20030) 37 nAPG01604_Inlay V744_LPG50148+V81S+A137V (LPG20031) 38 LPG50148+V81S_nLPG10145_parent 39 nLPG10145_Inlay G347_LPG50148+V81S (LPG20032) 40 nLPG10145_Inlay D524_LPG50148+V81S (LPG20033) 41 nLPG10145_Inlay Q640_LPG50148+V81S (LPG20034) 42 nLPG10145_Inlay R666_LPG50148+V81S (LPG20035) 43 nLPG10145_Inlay D680_LPG50148+V81S (LPG20036) 44 nLPG10145_Inlay N740_LPG50148+V81S (LPG20037) 45 nLPG10145_Inlay S785_LPG50148+V81S (LPG20038) 46 nLPG10145_Inlay P910_LPG50148+V81S (LPG20039) 47 nLPG10145_Inlay G1077_LPG50148+V81S (LPG20040) 48 nAPG07433.1 (D11A) 49 nAPG05586 (D11A) 50 nAPG01604 (D11A) 51 nLPG10145 (D11A) 52 nAPG05586 (H840A) 53 nAPG01604 (H840A) 54 nLPG10145 (H840A) 55 nAPG07433.1 (H840A) 56 APG08290.1 57 APG05459.1 58 APG007513.1 59 APG05083.1 60 APG04583.1 61 APG01688.1 62 APG00969 63 APG03128 64 APG00771 65 APG05733 66 APG06207 67 APG01647 68 APG08032 69 APG05712 70 APG01658 71 APG06498 72 APG09882 73 APG02675 74 APG01405 75 APG06250 76 APG06877 77 APG09053 78 APG04293 79 APG01308 80 APG06646 81 APG06622 82 APG02787 83 APG06248 84 APG06007 85 APG02874 86 APG03850 87 APG07553 88 APG03031 89 APG09208 90 APG08770 91 APG08167 92 APG03021 93 APG06015 94 APG09344 95 APG07991 96 APG01868 97 APG02998 98 APG09298 99 APG06251 100 APG03066 101 APG01560 102 APG02777 103 APG05761 104 APG02479 105 APG08385 106 APG09217 107 APG06657 108 LPG10134 109 LPG10136 110 LPG10138 111 LPG10139 112 LPG10141 113 LPG10146 114 LPG10147 115 LPG10150 116 LPG10155 117 LPG10159 118 LPG10160 119 LPG10165 120 LPG10166 121 LPG10167 122 LPG10168 123 LPG10169 124 LPG10171 125 LPG10186 126 LPG10190 127 LPG10191 128 LPG10194 129 LPG10195 130 LPG10196 131 LPG10197 132 LPG10198 133 LPG10200 134 LPG10203 135 LPG10204 136 LPG10205 137 LPG10207 138 LPG10208 139 APG09748 140 APG02789 141 APG09106 142 APG07339 143 APG09624 144 APG03003 145 APG05405 146 APG09777 147 APG05680 148 APG02119 149 APG03285 150 APG04998 151 APG07078 152 APG06369 153 APG03847 154 APG05625 155 APG03759 156 APG05123 157 APG03524 158 APG07446 159 APG07641 160 APG01250 161 APG02261 162 LPG10134 crRNA repeat 163 LPG10136 crRNA repeat 164 LPG10138 crRNA repeat 165 LPG10139 crRNA repeat 166 LPG10141 crRNA repeat 167 LPG10145 crRNA repeat 168 LPG10146 crRNA repeat 169 LPG10147 crRNA repeat 170 LPG10150 crRNA repeat 171 LPG10155 crRNA repeat 172 LPG10159 crRNA repeat 173 LPG10160 crRNA repeat 174 LPG10134 tracrRNA 175 LPG10136 tracrRNA 176 LPG10138 tracrRNA 177 LPG10139 tracrRNA 178 LPG10141 tracrRNA 179 LPG10145 tracrRNA 180 LPG10146 tracrRNA 181 LPG10147 tracrRNA 182 LPG10150 tracrRNA 183 LPG10155 tracrRNA 184 LPG10159 tracrRNA 185 LPG10160 tracrRNA 186 LPG10165 crRNA repeat 187 LPG10166 crRNA repeat 188 LPG10167 crRNA repeat 189 LPG10168 crRNA repeat 190 LPG10169 crRNA repeat 191 LPG10171 crRNA repeat 192 LPG10186 crRNA repeat 193 LPG10190 crRNA repeat 194 LPG10191 crRNA repeat 195 LPG10194 crRNA repeat 196 LPG10195 crRNA repeat 197 LPG10196 crRNA repeat 198 LPG10197 crRNA repeat 199 LPG10198 crRNA repeat 200 LPG10200 crRNA repeat 201 LPG10203 crRNA repeat 202 LPG10204 crRNA repeat 203 LPG10205 crRNA repeat 204 LPG10205 crRNA repeat 2 205 LPG10207 crRNA repeat 206 LPG10208 crRNA repeat 207 LPG10165 tracrRNA 208 LPG10166 tracrRNA 209 LPG10167 tracrRNA 210 LPG10168 tracrRNA 211 LPG10169 tracrRNA 212 LPG10171 tracrRNA 213 LPG10186 tracrRNA 214 LPG10190 tracrRNA 215 LPG10191 tracrRNA 216 LPG10194 tracrRNA 217 LPG10195 tracrRNA 218 LPG10196 tracrRNA 219 LPG10197 tracrRNA 220 LPG10198 tracrRNA 221 LPG10200 tracrRNA 222 LPG10203 tracrRNA 223 LPG10204 tracrRNA 224 LPG10205 tracrRNA 225 LPG10205 tracrRNA2 226 LPG10207 tracrRNA 227 LPG10208 tracrRNA 228 APG05241 229 APG07280 230 APG09260 231 APG08360 232 APG09980 233 APG07386 234 APG09688 235 APG05840 236 APG02316 237 APG00868 238 APG30125 239 APG30126 240 APG30127 241 APG30128 242 APG30129 243 APG30130 244 APG09980.1 245 APG05840.1 246 APG00868.1 247 APG09982 248 APG03724 249 APG09949 250 APG08196 251 APG06333 252 APG06489 253 APG08449 254 APG05174 255 APG09102 256 APG05723 257 LPG50140 258 LPG50141 259 LPG50142 260 LPG50143 261 LPG50144 262 LPG50145 263 LPG50146 264 LPG50147 265 LPG50149 266 LPG50150 267 LPG50151 268 LPG50152 269 LPG50153 270 LPG50154 271 LPG50155 272 LPG50156 273 LPG50157 274 LPG50158 275 LPG50159 276 LPG50160 277 LPG50161 278 LPG50162 279 LPG50163 280 LPG50164 281 LPG50165 282 LPG50166 283 LPG50167 284 LPG50168 285 LPG50169 286 LPG50170 287 LPG50171 288 LPG50172 289 LPG50173 290 LPG50174 291 LPG50175 292 LPG50176 293 LPG50177 294 LPG50178 295 LPG50179 296 LPG50180 297 LPG50181 298 LPG50182 299 LPG50148.2.1 300 LPG50148.2.2 301 LPG50148.2.3 302 LPG50148.2.4 303 LPG50148.2.5 304 LPG50148.2.6 305 LPG50148.2.7 306 LPG50148.2.8 307 LPG50148.2.9 308 LPG50148.2.10 309 LPG50148.2.11 310 LPG50148.2.12 311 LPG50148.2.13 312 LPG50148.2.14 313 LPG50148.2.15 314 LPG50148.2.16 315 LPG50148.2.17 316 LPG50148.2.18 317 LPG50148.2.19 318 LPG50148.2.20 319 LPG50148.2.21 320 LPG50148.2.22 321 LPG50148.2.23 322 LPG50148.2.24 323 LPG50148.2.25 324 LPG50148.2.26 325 LPG50148.2.27 326 LPG50148.2.28 327 LPG50148.2.29 328 LPG50148.2.30 329 LPG50148.2.31 330 LPG50148.2.32 331 LPG50148.2.33 332 LPG50148.2.34 333 LPG50148.2.35 334 LPG50148.2.36 335 LPG50148.2.37 336 LPG50148.2.38 337 LPG50148.2.39 338 LPG50148.2.40 339 LPG50148.2.41 340 LPG50148.2.42 341 LPG50148.2.43 342 LPG50148.2.44 343 LPG50148.2.45 344 LPG50148.2.46 345 LPG50148.2.47 346 LPG50148.2.48 347 LPG50148.2.49 348 LPG50148.2.50 349 LPG50148.2.51 350 LPG50148.2.52 351 LPG50148.2.53 352 LPG50148.2.54 353 LPG50148.2.55 354 LPG50148.2.56 355 LPG50148.2.57 356 LPG50148.2.58 357 LPG50148.2.59 358 LPG50148.2.60 359 LPG50148.2.61 360 LPG50148.2.62 361 LPG50148.2.63 362 LPG50148.2.64 363 LPG50148.2.65 364 LPG50148.2.66 365 LPG50148.2.67 366 LPG50148.2.68 367 LPG50148.2.69 368 LPG50148.2.70 369 LPG50148.2.71 370 LPG50148.2.72 371 LPG50148.2.73 372 LPG50148.2.74 373 LPG50148.2.75 374 LPG50148.2.76 375 LPG50148.2.77 376 LPG50148.2.78 377 LPG50148.2.79 378 LPG50148.2.80 379 LPG50148.2.81 380 LPG50148.2.82 381 LPG50148.2.83 382 LPG50148.2.84 383 LPG50148.2.85 384 LPG50148.2.86 385 LPG50148.2.87 386 LPG50148.2.88 387 LPG50148.2.89 388 LPG50148.2.90 389 LPG50148.2.91 390 LPG50148.2.92 391 LPG50148.2.93 392 LPG50148.2.94 393 LPG50148.2.95 394 LPG50148.2.96 395 LPG50148.2.97 396 LPG50148.2.98 397 LPG50148.2.99 398 LPG50148.2.100 399 LPG50148.2.101 400 LPG50148.2.102 401 LPG50148.2.103 402 LPG50148.2.104 403 LPG50148.2.105 404 LPG50148.2.106 405 LPG50148.2.107 (also known as LPG50319) 406 LPG50148.2.108 407 LPG50148.2.109 408 LPG50148.2.110 409 LPG50148.2.111 410 LPG50148.2.112 411 LPG50148.2.113 412 LPG50148.2.114 413 LPG50148.2.115 414 Streptococcus pyogenes Cas9 415 APG07433.1 crRNA repeat 416 APG07433.1 tracrRNA 417 APG07433.1 PAM 418 APG05586 crRNA repeat 419 APG05586 tracrRNA 420 APG05586 PAM 421 APG01604 crRNA repeat 422 APG01604 tracrRNA 423 APG01604 PAM 424 LPG10145 crRNA repeat 425 LPG10145 tracrRNA 426 LPG10145 PAM 427 nAPG07433.1_HNH replaces_LPG50148 (LPG20001) 428 nAPG07433.1_Inlay S772LPG50148 (Nolinker/ LPG20041) 429 SV40 NLS 430 Nucleoplasmin NLS 431 APG05083.1 crRNA repeat 432 APG05083.1 tracrRNA 433 APG05083.1 PAM 434 APG07513.1 435 APG07513.1 crRNA repeat 436 APG07513.1 tracrRNA 437 APG07513.1 PAM 438 APG08290.1 crRNA repeat 439 APG08290.1 tracrRNA 440 APG08290.1 PAM 441 APG05459.1 crRNA repeat 442 APG05459.1 tracrRNA 443 APG05459.1 PAM 444 APG04583.1 crRNA repeat 445 APG04583.1 tracrRNA 446 APG04583.1 PAM 447 APG01688.1 crRNA repeat 448 APG01688.1 tracrRNA 449 APG01688.1 PAM 450 APG00969 crRNA repeat 451 APG00969 tracrRNA 452 APG00969 PAM 453 APG03128 crRNA repeat 454 APG03128 tracrRNA 455 APG03128 PAM 456 APG09748 crRNA repeat 457 APG09748 tracrRNA 458 APG09748 PAM 459 APG00771 crRNA repeat 460 APG00771 tracrRNA 461 APG00771 PAM 462 APG02789 crRNA repeat 463 APG02789 tracrRNA 464 APG02789 PAM 465 APG09106 crRNA repeat 466 APG09106 tracrRNA 467 APG09106 PAM 468 APG05733.1 crRNA repeat 469 APG05733.1 tracrRNA 470 APG05733.1 PAM 471 APG06207.1 crRNA repeat 472 APG06207.1 tracrRNA 473 APG06207.1 PAM 474 APG01647.1 crRNA repeat 475 APG01647.1 tracrRNA 476 APG01647.1 PAM 477 APG08032.1 crRNA repeat 478 APG08032.1 tracrRNA 479 APG08032.1 PAM 480 APG05712.1 crRNA repeat 481 APG05712.1 tracrRNA 482 APG05712.1 PAM 483 APG01658.1 crRNA repeat 484 APG01658.1 tracrRNA 485 APG01658.1 PAM 486 APG06498.1 crRNA repeat 487 APG06498.1 tracrRNA 488 APG06498.1 PAM 489 APG09106.1 crRNA repeat 490 APG09106.1 tracrRNA 491 APG09106.1 PAM 492 APG09882.1 crRNA repeat 493 APG09882.1 tracrRNA 494 APG09882.1 PAM 495 APG02675.1 crRNA repeat 496 APG02675.1 tracrRNA 497 APG02675.1 PAM 498 APG01405.1 crRNA repeat 499 APG01405.1 tracrRNA 500 APG01405.1 PAM 501 APG06250.1 crRNA repeat 502 APG06250.1 tracrRNA 503 APG06250.1 PAM 504 APG06877.1 crRNA repeat 505 APG06877.1 tracrRNA 506 APG06877.1 PAM 507 APG09053.1 crRNA repeat 508 APG09053.1 tracrRNA 509 APG09053.1 PAM 510 APG04293.1 crRNA repeat 511 APG04293.1 tracrRNA 512 APG04293.1 PAM 513 APG01308.1 crRNA repeat 514 APG01308.1 tracrRNA 515 APG01308.1 PAM 516 APG06646.1 crRNA repeat 517 APG06646.1 tracrRNA 518 APG06646.1 PAM 519 APG09624 crRNA repeat 520 APG09624 tracrRNA 521 APG05405 crRNA repeat 522 APG05405 tracrRNA 523 APG06622 crRNA repeat 524 APG06622 tracrRNA 525 APG06622 PAM 526 APG02787 crRNA repeat 527 APG02787 tracrRNA 528 APG02787 PAM 529 APG06248 crRNA repeat 530 APG06248 tracrRNA 531 APG06248 PAM 532 APG06007 crRNA repeat 533 APG06007 tracrRNA 534 APG06007 PAM 535 APG02874 crRNA repeat 536 APG02874 tracrRNA 537 APG02874 PAM 538 APG03850 crRNA repeat 539 APG03850 tracrRNA 540 APG03850 PAM 541 APG07553 crRNA repeat 542 APG07553 tracrRNA 543 APG07553 PAM 544 APG03031 crRNA repeat 545 APG03031 tracrRNA 546 APG03031 PAM 547 APG09208 crRNA repeat 548 APG09208 tracrRNA 549 APG09208 PAM 550 APG08770 crRNA repeat 551 APG08770 tracrRNA 552 APG08770 PAM 553 APG08167 crRNA repeat 554 APG08167 tracrRNA 555 APG08167 PAM 556 APG03021 crRNA repeat 557 APG03021 tracrRNA 558 APG03021 PAM 559 APG06015 crRNA repeat 560 APG06015 tracrRNA 561 APG06015 PAM 562 APG09344 crRNA repeat 563 APG09344 tracrRNA 564 APG09344 PAM 565 APG07991 crRNA repeat 566 APG07991 tracrRNA 567 APG07991 PAM 568 APG01868 crRNA repeat 569 APG01868 tracrRNA 570 APG01868 PAM 571 APG02998 crRNA repeat 572 APG02998 tracrRNA 573 APG02998 PAM 574 APG07433.1 deletion variant 575 APG08290.1 deletion variant 576 LPG20046 577 LPG20047 578 LPG20124 579 LPG20123 580 LPG20048 581 LPG20051 582 LPG20055 583 LPG20056 584 LPG20057 585 LPG20058 586 LPG20059 587 LPG20060 588 LPG20050 589 LPG20053 590 LPG20054 591 LPG20044 592 LPG20052 593 LPG20049 594 LPG20045 595 LPG50320 596 LPG50324 597 LPG50318 598 LPG20061 599 LPG20062 600 SGN008971 Target sequence 601 LPG20063 602 LPG20064 603 LPG20065 604 LPG20066 605 LPG20067 606 LPG20068 607 LPG20069 608 LPG20070 609 LPG20071 610 LPG20072 611 LPG20073 612 LPG20074 613 LPG20075 614 LPG20076 615 LPG20077 616 LPG20083 617 LPG20084 618 LPG20085 619 LPG20086 620 LPG20087 621 LPG20088 622 LPG20089 623 LPG20090 624 LPG20091 625 LPG20092 626 LPG20093 627 LPG20094 628 LPG20095 629 LPG20096 630 LPG20097 631 LPG20098 632 LPG50318 633 Inactive APG07433.1_Inlaid S772_LPG50148 (LPG20134) 634 Inactive APG07433.1_Inlaid S775_LPG50148 (LPG20135) 635 Inactive APG07433.1_Inlaid K778_LPG50148 (LPG20136) 636 Inactive APG07433.1_Inlay E900_LPG50148 (LPG20137) 637 Inactive APG07433.1_Inlay G910_LPG50148 (LPG20138) 638 LPG20130 639 SGN002336 640 SGN002364 641 Peptide Linker 642 LPG20099 643 LPG20100 644 LPG20101 645 LPG20102 646 LPG20111 647 LPG20120 648 LPG20121 649 LPG20122 650 SGN001432 651 SGN001433 652 SGN001434 653 SGN001435 654 SGN008382 655 SGN008383 656 SGN008384 657 SGN008385 658 SGN008393 659 SGN001432 Target sequence 660 SGN001433 Target Sequence 661 SGN001434 Target Sequence 662 SGN001435 target sequence 663 SGN008382 Target Sequence 664 SGN008383 Target Sequence 665 SGN008384 Target Sequence 666 SGN008385 target sequence 667 SGN008393 Target Sequence 668 SGN001256 669 SGN001947 670 SGN001960 671 SGN003707 672 SGN004995 673 SGN001256 target sequence 674 SGN001947 Target Sequence 675 SGN001960 Target Sequence 676 SGN003707 target sequence 677 SGN004995 target sequence 678 SGN003018 679 SGN003540 680 SGN003018 target sequence 681 SGN003540 Target Sequence 682 SGN003486 683 SGN002352 684 SGN001881 685 SGN003486 target sequence 686 SGN005430 687 SGN005420 688 SGN005326 689 SGN005329 690 SGN005326 target sequence 691 SGN005329 target sequence 692 Full length APG07433.1 frame (F) 693 Shortened APG07433.1 frame (M) 694 APG05586 skeleton 695 Shortened LPG10145 frame 696 Shortened LPG10196 skeleton 697 nLPG10196 (D11A) 698 nLPG10196 (H840A) 699 LAGLIDADG 700 Streptococcus thermophilus Cas9 701 Staphylococcus aureus Cas9 702 Francisella novicida Cas12a 703 L16 Linker Sequence 704 L32 Linker Sequence 705 NLS connector 706 P(AP)3 Connector 707 (EAAAK)2 Connector 708 24A Connector 709 24B Connector 710 GS16 Connector 711 18x Connectors 712 POLD1 NLS 713 ADAR2 NLS 714 Iwr1 NLS 715 OpT NLS 716 SV40 Bipartite NLS 717 c-Myc NLS 718 NLS connector 719 LPG50321 720 LPG50322 721 LPG50323 722 LPG50310 723 LPG20126 724 LPG20127 725 LPG20128 726 LPG20125 727 NLS connector 728 LPG20129 729 SGN008971 730

ABE: parental adenine base editor TTR: transthyretin protein

Figure 1 describes a rational design approach to improve the editing efficiency of bases outside the standard editing window of the parental adenine base editor LPG50148-nAPG07433.1. Figure 1A provides a schematic diagram of a linear base editor showing the parental adenine base editor (ABE) as an end-to-end fusion between LPG50148 and nAPG07433.1, and an internal base editor in which LPG50148 is inserted into nAPG07433.1. Figure 1B shows a structural model of APG07433.1 with insertion points (blue spheres). LPG50148 (green) is inserted after the position shown. The G910, V872, and E900 insertion sites are within the wedge domain; the T642 and R670 insertion sites are within the HNH domain; and the D737, A802, S775, S772, K778, and R30 insertion sites are within the RuvCIII domain. Figure 2 shows the editing efficiency and editing window of nAPG07433.1 inlay base editors (IBEs) LPG20002-LPG20006 and HNH substitution LPG20001. Figure 2A provides the total editing efficiency of the top 5 designed nAPG07433.1 IBEs, which were tested using the genomic target and the total percentage of A to G substitutions. Figure 2B shows the edit window for LPG20001-LPG20006. The heat map provides the percentage of edits for each position. The columns represent five individual guides (from top to bottom: SGN001681, SGN001062, SGN000968, SGN000754, and SGN001064). Positions 1-25 represent the positions of the 1st to 25th targeted adenines within the protospacer, where position 1 is the first adenine 5' to the PAM. Figure 3 shows the edit efficiency and edit window for nAPG07433.1 IBE (LPG20007-LPG20011). The heat map provides the percentage of edits for each position. The columns represent four individual guides (from top to bottom: SGN001062, SGN000968, SGN000754, and SGN001064). Figure 4 depicts nAPG07433.1 IBE 2 and 8. Figure 4A provides a structural representation of the insertion sites of nAPG07433.1 IBE 2 (S772) and 8 (T642). Figure 4B depicts the schematic domain organization of LPG20002 and LPG20008 compared to the parental ABE. Figure 4C shows the average editing efficiency of LPG20002 and LPG20008 for three target sites (SGN001947, SGN001064, and SGN000909) compared to the parental ABE. Figure 5 shows the evaluation of nAPG07433.1 IBE2 with deleted linkers. Figure 5A depicts the insertion of truncated LPG50148 into nAPG07433.1 and the deletion of the N-terminal linker, the C-terminal linker, or both linkers to create nAPG07433.1 IBE2 variants. Figure 5B shows the total editing efficiency (percentage of A to G substitutions) for all LPG20002 variants tested using four genomic targets. Figure 5C provides a heat map showing the percentage of editing at each position. The columns represent four individual target sites (from top to bottom: SGN001062, SGN001064, SGN000754, and SGN000968). Figure 6 shows the therapeutic potential of the engineered IBEs. Figure 6A provides the results of disruption of the splice donor in exon 1 in the transthyretin (TTR) gene as a gene knockout strategy. Plasmids were delivered to HEK cells by nucleofection. Figure 6B shows the use of LPG20002 variants to reduce surface presentation of β2-microglobulin (B2M). mRNA was delivered to T cells by nucleofection. Figure 7 shows the editing activity of nAPG05586 IBE. Figure 7A provides the average editing rate of nAPG05586 IBE with four guide RNAs across the editing window (adenine 5-24) after delivery of plasmids encoding IBE and guide RNAs to HEK293T cells by nucleofection. Figure 7B provides the editing rate at each adenine position within the editing window of each nAPG05586 IBE. Figure 8 shows the editing activity of nAPG01604 IBE. Figure 8A provides the average editing rate across the editing window (adenine 5-19) of nAPG01604 IBE with four guide RNAs after delivery of plasmids encoding IBEs and guide RNAs to HEK293T cells by nucleofection. Figure 8B provides the editing rate at each adenine position within the editing window of each nAPG01604 IBE. Figure 9 shows the editing activity of nLPG10145 IBE. Figure 9A provides the average editing rate across the editing window (adenine 4-25) of LPG10145 IBE with four guide RNAs after delivery of plasmids encoding IBE and guide RNAs to HEK293T cells by nucleofection. Figure 9B provides the editing rate at each adenine position within the editing window for each nLPG10145 IBE. Figures 10A and 10B depict the first step of a directed evolution strategy to identify adenine base editor variants with greater activity than the parental ABE (LPG50148 fused to dAPG07433.1). Figure 10A shows an end-to-end fusion protein of the LPG50148 adenosine deaminase variant and a nuclease-inactive version of the APG07433.1 RNA-guided nuclease, which is expressed in E. coli and converts the stop codon in the kanmycin resistance gene to a sense codon to confer resistance. Figure 10B shows how the evolved ABEs are enriched for those with stronger editing activity than the parental ABE. E. coli containing the target plasmid were transformed with a pool of mutant LPG50148 fused to dAPG07433.1. In order to grow in high concentrations of kanmycin, cells need to repair the antibiotic resistance gene (KanR*) with a higher editing efficiency than the parental ABE. The selections were performed individually for three sequence contexts: TAT, CAC or TAG. After the enrichment step, variants with up to eightfold improvements were identified. Figure 11 shows the complete directed evolution strategy for identifying adenine base editor variants with higher activity than the parent ABE. ABE variants with single point mutations that were up to eightfold more active than the parent ABE were selected in bacteria and then evaluated in a first round of human cell screening in human HEK293T cells. Single point mutants identified in selections in the TAT or CAC sequence context were evaluated at eight endogenous genomic sites, whereas single point mutants identified in selections in the TAG sequence context were evaluated at four endogenous genomic sites. Single mutations showing the highest average fold change were combined to generate the top hits: for TAT, 20 (LPG50148 with L35N, V81S, N156R, and L162W mutations, as shown in SEQ ID NO: 319), 60 (LPG50148 with I75W and F155W mutations, as shown in SEQ ID NO: 359), 67 (LPG50148 with V81S, F155W and A160D mutations, as shown in SEQ ID NO: 366), and 68 (LPG50148 with V81S, C145A and F155W mutations, as shown in SEQ ID NO: 367); for CAC, 106 (LPG50148 with D76G and V81S mutations, as shown in SEQ ID NO: 405) and 107 (LPG50148 with V81S and M117L mutations, as shown in SEQ ID NO: 406); and, for TAG, 88 (LPG50148 with I40L and V105M mutations, as shown in SEQ ID NO: 387) and 103 (LPG50148 with V81S, C145M and A160W mutations, as shown in SEQ ID NO: 402). Figure 12 shows the higher editing efficiency of the evolved ABE variants LPG50148.2.20, LPG50148.2.60, LPG50148.2.67, LPG50148.2.68, and LPG50148.2.69 compared to the parental ABE when the ABE was delivered as mRNA. Figure 13 provides the results of the robustness testing of the evolved ABE variants LPG50148.2.20, LPG50148.2.60, LPG50148.2.67, LPG50148.2.68, LPG50148.2.103, LPG50148.2.106, and LPG20107. Figure 13A shows the percentage of guides (from 48 genomic sites) with more than 20% edits in total A-T substitutions. Figure 13B shows the average A to G substitutions for all genomic sites. There were three significant effects: variants LPG50148.2.20 (p≤0.001), LPG50148.2.103 (p＜0.001), and LPG50148.2.67 (p=0.01). Figure 14 shows the changes in the optimal editing window for three of the evolved ABE variants. This figure shows the A-T substitutions showing the editor activity window by position for the parental ABE and the three evolved ABE variants LPG50148.2.20, LPG50148.2.67, and LPG50148.2.103. Numbers indicate positions within the protospacer upstream of the PAM sequence. The optimal window is ≥30% of the maximum edit. Figure 15 shows A to G edits within different sequence contexts for multiple evolved ABE variants (LPG50148.2.20, LPG50148.2.60, LPG50148.2.67, LPG50148.2.68, LPG50148.2.103, LPG50148.2.106, and LPG50148.2.107) and the parental ABE. The edit percentages reflect the median value for each context across 48 genomic sites. Figure 16 provides the percentage of A to G conversions at position 11 in the target sequence of SGN008393 using LPG20047 in primary mouse hepatocytes. Figure 17 shows the engineering of a third generation deaminase based on a second generation deaminase that provides higher levels of A to G editing against multiple targets when fused to the N-terminus of nAPG07433.1. Figure 18 shows the improved performance of the third generation base editor LPG50324 fused to nAPG07433.1. Figure 19 shows improved editing using the LPG50310 deaminase relative to the LPG50265 deaminase in HEK293T cells with plastid delivery when fused to nAPG07433.1.

TW202434726A_112142724_SEQL.xml

Claims (245)

A fusion protein comprising an RNA-guided nuclease (RGN) and at least one heterologous polypeptide inserted therein, wherein the RGN comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699. The fusion protein of claim 1, wherein the RGN comprises the amino acid sequence of any one of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699. The fusion protein of claim 1 or claim 2, wherein the heterologous polypeptide is inserted into a linker domain 2, a wedge domain, a RuvC domain, a HNH domain, a Rec-2 domain or a PAM interaction domain of the RGN. A fusion protein as described in any one of claims 1 to 3, wherein: a) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 1 and the at least one heterologous polypeptide is inserted in the RGN immediately after the amino acid position selected from the group consisting of: i) an amino acid position corresponding to position 30 of SEQ ID NO: 1; ii) an amino acid position corresponding to position 642 of SEQ ID NO: 1; iii) an amino acid position corresponding to position 670 of SEQ ID NO: 1; iv) an amino acid position corresponding to position 737 of SEQ ID NO: 1; v) an amino acid position corresponding to position 772 of SEQ ID NO: 1; vi) an amino acid position corresponding to position 775 of SEQ ID NO: 1; vii) an amino acid position corresponding to position 778 of SEQ ID NO: 1; and viii) an amino acid position corresponding to position 802 of SEQ ID NO: 1; b) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 2 and the at least one heterologous polypeptide is inserted into the RGN immediately after the amino acid position selected from the group consisting of: i) an amino acid position corresponding to position 678 of SEQ ID NO: 2; ii) an amino acid position corresponding to position 736 of SEQ ID NO: 2; iii) an amino acid position corresponding to position 778 of SEQ ID NO: 2; iv) an amino acid position corresponding to position 788 of SEQ ID NO: 2; and v) an amino acid position corresponding to position 922 of SEQ ID NO: 2; c) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 2 and the at least one heterologous polypeptide is inserted into the RGN immediately after the amino acid position selected from the group consisting of: i) an amino acid position corresponding to position 678 of SEQ ID NO: 2; ii) an amino acid position corresponding to position 736 of SEQ ID NO: 2; iii) an amino acid position corresponding to position 778 of SEQ ID NO: 2; iv) an amino acid position corresponding to position 788 of SEQ ID NO: 2; and v) an amino acid position corresponding to position 922 of SEQ ID NO: 2; NO:3 has an amino acid sequence with at least 90% sequence identity and the at least one heterologous polypeptide is inserted into the RGN immediately after the amino acid position selected from the group consisting of: i) the amino acid position corresponding to position 725 of SEQ ID NO:3; ii) the amino acid position corresponding to position 739 of SEQ ID NO:3; and iii) the amino acid position corresponding to position 744 of SEQ ID NO:3; d) the RGN includes an amino acid sequence with at least 90% sequence identity to SEQ ID NO:4 and the at least one heterologous polypeptide is inserted into the RGN immediately after the amino acid position selected from the group consisting of: i) the amino acid position corresponding to position 347 of SEQ ID NO:4; ii) the amino acid position corresponding to position 524 of SEQ ID NO:4; iii) the amino acid position corresponding to position 744 of SEQ ID NO:3 NO:4; iv) an amino acid position corresponding to position 666 of SEQ ID NO:4; v) an amino acid position corresponding to position 680 of SEQ ID NO:4; vi) an amino acid position corresponding to position 740 of SEQ ID NO:4; vii) an amino acid position corresponding to position 785 of SEQ ID NO:4; vii) an amino acid position corresponding to position 910 of SEQ ID NO:4; and viii) an amino acid position corresponding to position 1077 of SEQ ID NO:4; or e) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:131 and the at least one heterologous polypeptide is inserted into the RGN immediately after the amino acid position selected from the group consisting of: i)    an amino acid position corresponding to position 766 of SEQ ID NO:131; and ii)   an amino acid position corresponding to position 1077 of SEQ ID NO:4 NO: The amino acid position corresponding to position 806 of 131. A fusion protein as described in any one of claims 1 to 4, wherein the heterologous polypeptide comprises a base editing polypeptide or a lead editing polypeptide. The fusion protein of claim 5, wherein the base-editing polypeptide comprises a deaminase. A fusion protein as described in claim 6, wherein the fusion protein is a base editor fusion protein, and wherein the base editor fusion protein has improved editing activity compared to a parent base editor comprising the deaminase fused to the amino terminus of the RGN. A fusion protein as described in claim 6 or claim 7, wherein the at least one heterologous polypeptide is inserted in an RGN immediately after the amino acid position selected from the group consisting of: a) an amino acid position corresponding to position 642 of SEQ ID NO: 1; b)      an amino acid position corresponding to position 670 of SEQ ID NO: 1; c) an amino acid position corresponding to position 737 of SEQ ID NO: 1; d)      an amino acid position corresponding to position 772 of SEQ ID NO: 1; e) an amino acid position corresponding to position 775 of SEQ ID NO: 1; and f) an amino acid position corresponding to position 778 of SEQ ID NO: 1; and Wherein the fusion protein is a base editor fusion protein, and wherein the base editor fusion protein has an editing window that is shifted compared to a parent base editor comprising the deaminase fused to the amino terminus of the RGN. A fusion protein as described in any one of claims 6 to 8, wherein the deaminase lacks the first and last amino acid residues compared to a parent deaminase from which the deaminase is derived. The fusion protein of any one of claims 6 to 9, wherein the deaminase comprises an adenine deaminase and the fusion protein is an adenine base editor (ABE) fusion protein. The fusion protein of claim 10, wherein the adenine deaminase comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 5, 6, 248-414, 596, 597, and 720-723. The fusion protein of claim 10, wherein the adenine deaminase comprises the amino acid sequence of any one of SEQ ID NOs: 5, 6, 248-414, 596, 597, and 720-723. A fusion protein as described in claim 10, wherein the ABE fusion protein comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 8-10, 13-21, 27-31, 36-38, 40-41, 43-48, 647, and 650. A fusion protein as described in claim 10, wherein the ABE fusion protein comprises the amino acid sequence shown in any one of SEQ ID NOs: 8-10, 13-21, 27-31, 36-38, 40-41, 43-48, 647, and 650. A fusion protein as described in claim 10, wherein the ABE fusion protein comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 8-10 and 14-16, and wherein the ABE fusion protein has an editing window that is shifted compared to a parent ABE base editor, the parent ABE base editor comprising the adenine deaminase fused to the amino terminus of the RGN. The fusion protein of any one of claims 1 to 15, wherein the RGN is a notchase or a nuclease inactive RGN. The fusion protein of claim 16, wherein the RGN nickase comprises an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 49-56, 698 and 699 and retains nickase activity. The fusion protein of claim 16, wherein the RGN nickase comprises the amino acid sequence of any one of SEQ ID NOs: 49-56, 698 and 699. A ribonucleoprotein (RNP) complex comprising a fusion protein as described in any one of claims 1 to 18, 110 and 111, and a guide RNA bound to the fusion protein. A nucleic acid molecule comprising a polynucleotide encoding a fusion protein, wherein the fusion protein comprises an RNA-guided nuclease (RGN) and at least one heterologous polypeptide inserted therein, wherein the RGN comprises an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699. The nucleic acid molecule of claim 20, wherein the RGN comprises the amino acid sequence of any one of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699. A nucleic acid molecule as described in claim 20 or claim 21, wherein the heterologous polypeptide is inserted into a linker domain 2, a wedge domain, a RuvC domain, a HNH domain, a Rec-2 domain or a PAM interaction domain of the RGN. A nucleic acid molecule as described in any one of claim 20 to claim 22, wherein: a) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 1 and the at least one heterologous polypeptide is inserted in the RGN immediately after the amino acid position selected from the group consisting of: i) the amino acid position corresponding to position 30 of SEQ ID NO: 1; ii) the amino acid position corresponding to position 642 of SEQ ID NO: 1; iii) the amino acid position corresponding to position 670 of SEQ ID NO: 1; iv) the amino acid position corresponding to position 737 of SEQ ID NO: 1; v) the amino acid position corresponding to position 772 of SEQ ID NO: 1; vi) the amino acid position corresponding to position 775 of SEQ ID NO: 1; vii) the amino acid position corresponding to position 776 of SEQ ID NO: 1; NO:1; and viii) an amino acid position corresponding to position 802 of SEQ ID NO:1; b) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:2 and the at least one heterologous polypeptide is inserted into the RGN immediately after the amino acid position selected from the group consisting of: i) an amino acid position corresponding to position 678 of SEQ ID NO:2; ii) an amino acid position corresponding to position 736 of SEQ ID NO:2; iii) an amino acid position corresponding to position 778 of SEQ ID NO:2; iv) an amino acid position corresponding to position 788 of SEQ ID NO:2; and v) an amino acid position corresponding to position 922 of SEQ ID NO:2; c) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:2 and the at least one heterologous polypeptide is inserted into the RGN immediately after the amino acid position selected from the group consisting of: i) an amino acid position corresponding to position 678 of SEQ ID NO:2; ii) an amino acid position corresponding to position 736 of SEQ ID NO:2; iii) an amino acid position corresponding to position 778 of SEQ ID NO:2; iv) an amino acid position corresponding to position 788 of SEQ ID NO:2; and v) an amino acid position corresponding to position 922 of SEQ ID NO:2; NO:3 has an amino acid sequence with at least 90% sequence identity and the at least one heterologous polypeptide is inserted into the RGN immediately after the amino acid position selected from the group consisting of: i)    The amino acid position corresponding to position 725 of SEQ ID NO:3; ii) The amino acid position corresponding to position 739 of SEQ ID NO:3; and iii) The amino acid position corresponding to position 744 of SEQ ID NO:3; d) The RGN includes an amino acid sequence with at least 90% sequence identity to SEQ ID NO:4 and the at least one heterologous polypeptide is inserted into the RGN immediately after the amino acid position selected from the group consisting of: i)    The amino acid position corresponding to position 347 of SEQ ID NO:4; ii) The amino acid position corresponding to position 524 of SEQ ID NO:4; iii) The amino acid position corresponding to position 744 of SEQ ID NO:3 NO:4; iv) an amino acid position corresponding to position 666 of SEQ ID NO:4; v) an amino acid position corresponding to position 680 of SEQ ID NO:4; vi) an amino acid position corresponding to position 740 of SEQ ID NO:4; vii) an amino acid position corresponding to position 785 of SEQ ID NO:4; vii) an amino acid position corresponding to position 910 of SEQ ID NO:4; and viii) an amino acid position corresponding to position 1077 of SEQ ID NO:4; or e) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:131 and the at least one heterologous polypeptide is inserted into the RGN immediately after the amino acid position selected from the group consisting of: i)    an amino acid position corresponding to position 766 of SEQ ID NO:131; and ii)   an amino acid position corresponding to position 1077 of SEQ ID NO:4 NO: The amino acid position corresponding to position 806 of 131. A nucleic acid molecule as described in any one of claims 20 to 23, wherein the heterologous polypeptide comprises a base editing polypeptide or a lead editing polypeptide. A nucleic acid molecule as described in claim 24, wherein the base editing polypeptide comprises a deaminase. A nucleic acid molecule as described in claim 25, wherein the fusion protein is a base editor fusion protein, and wherein the base editor fusion protein has improved editing activity compared to a parent base editor comprising the deaminase fused to the amino terminus of the RGN. A nucleic acid molecule as described in claim 25 or claim 26, wherein the at least one heterologous polypeptide is inserted into the RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 1 immediately after the amino acid position selected from the group consisting of: a) an amino acid position corresponding to position 642 of SEQ ID NO: 1; b)       an amino acid position corresponding to position 670 of SEQ ID NO: 1; c) an amino acid position corresponding to position 737 of SEQ ID NO: 1; d)       an amino acid position corresponding to position 772 of SEQ ID NO: 1; e) an amino acid position corresponding to position 775 of SEQ ID NO: 1; and f) an amino acid position corresponding to position 778 of SEQ ID NO: 1; and Wherein the fusion protein is an alkaline editor fusion protein, and wherein the alkaline editor fusion protein has an editing window that is shifted compared to a parent alkaline editor, the parent alkaline editor comprising the deaminase fused to the amino terminus of the RGN. A nucleic acid molecule as described in any one of claims 25 to 27, wherein the deaminase lacks the first and last amino acid residues compared to a parent deaminase from which the deaminase is derived. A nucleic acid molecule as described in any one of claims 25 to 28, wherein the deaminase comprises an adenine deaminase and is an adenosine base editor (ABE) fusion protein. The nucleic acid molecule of claim 29, wherein the adenine deaminase comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 5, 6, 248-414, 596, 597, and 720-723. The nucleic acid molecule of claim 29, wherein the adenine deaminase comprises the amino acid sequence of any one of SEQ ID NOs: 5, 6, 248-414, 596, 597, and 720-723. A nucleic acid molecule as described in claim 29, wherein the fusion protein comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 8-10, 13-21, 27-31, 36-38, 40-41, 43-48, 647, and 650. A nucleic acid molecule as described in claim 29, wherein the ABE fusion protein comprises the amino acid sequence shown in any one of SEQ ID NOs: 8-10, 13-21, 27-31, 36-38, 40-41, 43-48, 647, and 650. A nucleic acid molecule as described in claim 29, wherein the ABE fusion protein comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 8-10 and 14-16, and wherein the ABE fusion protein has an editing window that is shifted compared to a parent ABE base editor, the parent ABE base editor comprising the adenine deaminase fused to the amino terminus of the RGN. The nucleic acid molecule of any one of claims 20 to 34, wherein the RGN is a notchase or a nuclease inactive RGN. The nucleic acid molecule of claim 35, wherein the RGN nickase comprises an amino acid sequence having at least 95% sequence identity to any one of SEQ ID NOs: 49-56, 698 and 699 and retains nickase activity. The nucleic acid molecule of claim 35, wherein the RGN nickase comprises the amino acid sequence of any one of SEQ ID NOs: 49-56, 698 and 699. A vector comprising the nucleic acid molecule as described in any one of claims 20 to 37 and 120 to 126. The vector of claim 38, further comprising at least one nucleotide sequence encoding a guide RNA capable of hybridizing with a non-target strand of a target sequence of the RGN. A cell comprising the fusion protein as described in any one of claims 1 to 18 and 113 to 119 or the RNP complex as described in claim 19. A cell comprising the fusion protein of any one of claims 1 to 18 and 113 to 119, wherein the cell further comprises a guide RNA. A cell comprising the nucleic acid molecule of any one of claims 20 to 37 and 120 to 126 or the vector of claim 38 or 39. A cell as described in any one of claims 40 to 42, wherein the cell is a mammalian cell. A cell as described in any one of claims 40 to 42, wherein the cell is a plant cell. A plant or seed comprising the cell of claim 44. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a fusion protein as described in any one of claims 1 to 18 and 113 to 119, an RNP complex as described in claim 19, a nucleic acid molecule as described in any one of claims 20 to 37 and 120 to 126, a vector as described in claim 38 or 39, or a cell as described in claim 38. A method for preparing an RGN fusion ribonucleoprotein complex, comprising introducing a nucleic acid molecule as described in any one of claims 20 to 37 and 120 to 126 and a nucleic acid molecule comprising an expression box encoding a guide RNA, or a vector as described in claim 38 or 39 into a cell, and culturing the cell under conditions in which the fusion protein and the gRNA are expressed and form an RGN fusion ribonucleoprotein complex. A system for localizing a heterologous polypeptide to a target DNA molecule including a target DNA sequence, the system comprising: a) a fusion protein, or a nucleotide sequence encoding the fusion protein, wherein the fusion protein comprises an RNA-guided nuclease (RGN) and at least one heterologous polypeptide inserted therein; wherein the RGN comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699; and b) one or more guide RNAs capable of hybridizing with a non-target strand of the target DNA sequence or encoding the one or more guide RNAs wherein the one or more guide RNAs are capable of forming a complex with the fusion protein to guide the fusion protein to bind to the target DNA sequence. The system of claim 48, wherein the RGN comprises the amino acid sequence of any one of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699. The system of claim 48 or claim 49, wherein the heterologous polypeptide is inserted into a linker domain 2, a wedge domain, a RuvC domain, a HNH domain, a Rec-2 domain, or a PAM interaction domain of the RGN. A system as described in any of claims 48 to 50, wherein: i) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 1 and the at least one heterologous polypeptide is inserted into the RGN immediately after the amino acid position selected from the group consisting of: A. an amino acid position corresponding to position 30 of SEQ ID NO: 1; B. an amino acid position corresponding to position 642 of SEQ ID NO: 1; C. an amino acid position corresponding to position 670 of SEQ ID NO: 1; D. an amino acid position corresponding to position 737 of SEQ ID NO: 1; E. an amino acid position corresponding to position 772 of SEQ ID NO: 1; F. an amino acid position corresponding to position 775 of SEQ ID NO: 1; G. an amino acid position corresponding to position 778 of SEQ ID NO: 1; and H. an amino acid position corresponding to position 779 of SEQ ID NO: 1; ID NO:1; ii) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:2 and the at least one heterologous polypeptide is inserted into the RGN immediately after the amino acid position selected from the group consisting of: A. the amino acid position corresponding to position 678 of SEQ ID NO:2; B. the amino acid position corresponding to position 736 of SEQ ID NO:2; C. the amino acid position corresponding to position 778 of SEQ ID NO:2; D. the amino acid position corresponding to position 788 of SEQ ID NO:2; and E. the amino acid position corresponding to position 922 of SEQ ID NO:2; iii) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:2 and the at least one heterologous polypeptide is inserted into the RGN immediately after the amino acid position selected from the group consisting of: A. the amino acid position corresponding to position 678 of SEQ ID NO:2; B. the amino acid position corresponding to position 736 of SEQ ID NO:2; C. the amino acid position corresponding to position 778 of SEQ ID NO:2; D. the amino acid position corresponding to position 788 of SEQ ID NO:2; and E. the amino acid position corresponding to position 922 of SEQ ID NO:2; NO:3 has an amino acid sequence with at least 90% sequence identity and the at least one heterologous polypeptide is inserted into the RGN immediately after the amino acid position selected from the group consisting of: A. The amino acid position corresponding to position 725 of SEQ ID NO:3; B. The amino acid position corresponding to position 739 of SEQ ID NO:3; and C. The amino acid position corresponding to position 744 of SEQ ID NO:3; iv) The RGN includes an amino acid sequence with at least 90% sequence identity to SEQ ID NO:4 and the at least one heterologous polypeptide is inserted into the RGN immediately after the amino acid position selected from the group consisting of: A. The amino acid position corresponding to position 347 of SEQ ID NO:4; B. The amino acid position corresponding to position 524 of SEQ ID NO:4; and C. The amino acid position corresponding to position 744 of SEQ ID NO:3. NO:4; D. the amino acid position corresponding to position 666 of SEQ ID NO:4; E. the amino acid position corresponding to position 740 of SEQ ID NO:4; F. the amino acid position corresponding to position 785 of SEQ ID NO:4; G. the amino acid position corresponding to position 910 of SEQ ID NO:4; and H. the amino acid position corresponding to position 1077 of SEQ ID NO:4; or v) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:131 and the at least one heterologous polypeptide is inserted into the RGN immediately after the amino acid position selected from the group consisting of: A. the amino acid position corresponding to position 766 of SEQ ID NO:131; and B. the amino acid position corresponding to position 806 of SEQ ID NO:131. The system of any one of claims 48 to 51, wherein the heterologous polypeptide comprises a base editing polypeptide or a lead editing polypeptide. The system of claim 52, wherein the base-editing polypeptide comprises a deaminase. The system of claim 53, wherein the fusion protein is a base editor fusion protein, and wherein the base editor fusion protein has improved editing activity compared to a parent base editor comprising the deaminase fused to the amino terminus of the RGN. A system as described in claim 53 or claim 54, wherein the at least one heterologous polypeptide is inserted into the RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 1 immediately after the amino acid position selected from the group consisting of: a) an amino acid position corresponding to position 642 of SEQ ID NO: 1; b)      an amino acid position corresponding to position 670 of SEQ ID NO: 1; c) an amino acid position corresponding to position 737 of SEQ ID NO: 1; d)      an amino acid position corresponding to position 772 of SEQ ID NO: 1; e) an amino acid position corresponding to position 775 of SEQ ID NO: 1; and f) an amino acid position corresponding to position 778 of SEQ ID NO: 1; and Wherein the fusion protein is a base editor fusion protein, and wherein the base editor fusion protein has an editing window that is shifted compared to a parent base editor comprising the deaminase fused to the amino terminus of the RGN. A system as described in any of claims 53 to 55, wherein the deaminase lacks the first and last amino acid residues compared to a parent deaminase from which the deaminase is derived. A system as described in any of claims 53 to 56, wherein the deaminase comprises an adenine deaminase and the fusion protein is an adenosine base editor (ABE) fusion protein. The system of claim 57, wherein the adenine deaminase comprises an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 5, 6, 248-414, 596, 597, and 720-723. The system of claim 57, wherein the adenine deaminase comprises the amino acid sequence of any one of SEQ ID NOs: 5, 6, 248-414, 596, 597, and 720-723. The system of claim 57, wherein the ABE fusion protein comprises an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 8-10, 13-21, 27-31, 36-38, 40-41, 43-48, 647, and 650. The system of claim 57, wherein the ABE fusion protein comprises the amino acid sequence shown in any one of SEQ ID NOs: 8-10, 13-21, 27-31, 36-38, 40-41, 43-48, 647, and 650. The system of claim 57, wherein the ABE fusion protein comprises an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 8-10 and 14-16, and wherein the ABE fusion protein has an editing window that is shifted compared to a parent ABE base editor, the parent ABE base editor comprising the adenine deaminase fused to the amino terminus of the RGN. The system of any one of claim 48 to claim 62, wherein the RGN is a notchase or a nuclease inactive RGN. The system of claim 63, wherein the RGN nickase comprises an amino acid sequence having at least 95% sequence identity to any one of SEQ ID NOs: 49-56, 698 and 699 and retains nickase activity. The system of claim 63, wherein the RGN nickase comprises the amino acid sequence of any one of SEQ ID NOs: 49-56, 698, and 699. The system of any one of claims 48 to 65, wherein at least one of the nucleotide sequence encoding the one or more guide RNAs and the nucleotide sequence encoding the fusion protein is operably linked to a promoter heterologous to the nucleotide sequence. A system as described in any of claim 48 to claim 66, wherein the target DNA sequence is a eukaryotic target DNA sequence. The system of any one of claims 48 to 67, wherein the target DNA sequence is positioned adjacent to a protospacer adjacent motif (PAM) recognized by the RGN. A system as described in any one of claims 48 to 68, wherein the nucleotide sequence encoding the one or more guide RNAs and the nucleotide sequence encoding a fusion protein are located on a vector. A cell comprising a system as described in any of claims 48 to 69, 117, and 118. The cell of claim 70, wherein the cell is a mammalian cell. A cell as described in claim 70, wherein the cell is a plant cell. A plant or seed comprising the cell of claim 72. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the system as described in any one of claims 48 to 69 and 127 to 133, or the cell as described in claim 71. A method for localizing a heterologous polypeptide to a target DNA molecule comprising a target DNA sequence, the method comprising delivering a system as described in any one of claims 48 to 69 and 127 to 133 to the target DNA molecule or a cell comprising the target DNA molecule. A method for modifying a target DNA molecule comprising a target DNA sequence, the method comprising delivering a system as described in any one of claims 48 to 69 and 127 to 133 to the target DNA molecule or a cell comprising the target DNA molecule. A method for localizing a heterologous polypeptide to a target DNA molecule comprising a target DNA sequence, comprising: a) assembling the ribonucleotide complex in vitro under conditions suitable for forming a ribonucleotide complex by combining: i) one or more guide RNAs capable of hybridizing with a non-target strand of the target DNA sequence; and ii) a fusion protein comprising an RNA-guided nuclease (RGN) and at least one heterologous polypeptide inserted therein, wherein the RGN comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699; and b) contacting the target DNA molecule or a cell comprising the target DNA molecule with the in vitro assembled ribonucleotide complex; The one or more guide RNAs hybridize with a non-target strand of the target DNA sequence, thereby guiding the fusion protein to bind to the target DNA sequence. The method of claim 77, wherein the RGN comprises an amino acid sequence having the amino acid sequence of any one of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699. The method of claim 77 or claim 78, wherein the heterologous polypeptide is inserted into a linker domain 2, a wedge domain, a RuvC domain, a HNH domain, a Rec-2 domain or a PAM interaction domain of the RGN. A method as described in any of claims 77 to 79, wherein: a) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 1 and the at least one heterologous polypeptide is inserted into the RGN immediately after the amino acid position selected from the group consisting of: I) the amino acid position corresponding to position 30 of SEQ ID NO: 1; II) the amino acid position corresponding to position 642 of SEQ ID NO: 1; III) the amino acid position corresponding to position 670 of SEQ ID NO: 1; IV) the amino acid position corresponding to position 737 of SEQ ID NO: 1; V) the amino acid position corresponding to position 772 of SEQ ID NO: 1; VI) the amino acid position corresponding to position 775 of SEQ ID NO: 1; VII) the amino acid position corresponding to position 778 of SEQ ID NO: 1; and VIII) an amino acid position corresponding to position 802 of SEQ ID NO: 1; b) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 2 and the at least one heterologous polypeptide is inserted into the RGN immediately after the amino acid position selected from the group consisting of: I) an amino acid position corresponding to position 678 of SEQ ID NO: 2; II) an amino acid position corresponding to position 736 of SEQ ID NO: 2; III) an amino acid position corresponding to position 778 of SEQ ID NO: 2; IV) an amino acid position corresponding to position 788 of SEQ ID NO: 2; and V) an amino acid position corresponding to position 922 of SEQ ID NO: 2; c) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 2 and the at least one heterologous polypeptide is inserted into the RGN immediately after the amino acid position selected from the group consisting of: I) an amino acid position corresponding to position 678 of SEQ ID NO: 2; II) an amino acid position corresponding to position 736 of SEQ ID NO: 2; III) an amino acid position corresponding to position 778 of SEQ ID NO: 2; IV) an amino acid position corresponding to position 788 of SEQ ID NO: 2; and V) an amino acid position corresponding to position 922 of SEQ ID NO: 2; NO:3 has an amino acid sequence with at least 90% sequence identity and the at least one heterologous polypeptide is inserted in the RGN immediately after the amino acid position selected from the group consisting of: I) the amino acid position corresponding to position 725 of SEQ ID NO:3; II) the amino acid position corresponding to position 739 of SEQ ID NO:3; III) the amino acid position corresponding to position 744 of SEQ ID NO:3; d) the RGN includes an amino acid sequence with at least 90% sequence identity to SEQ ID NO:4 and the at least one heterologous polypeptide is inserted in the RGN immediately after the amino acid position selected from the group consisting of: I) the amino acid position corresponding to position 347 of SEQ ID NO:4; II) the amino acid position corresponding to position 524 of SEQ ID NO:4; III) the amino acid position corresponding to position 744 of SEQ ID NO:3 NO:4; IV) an amino acid position corresponding to position 666 of SEQ ID NO:4; V) an amino acid position corresponding to position 680 of SEQ ID NO:4; V) an amino acid position corresponding to position 740 of SEQ ID NO:4; VI) an amino acid position corresponding to position 785 of SEQ ID NO:4; VII) an amino acid position corresponding to position 910 of SEQ ID NO:4; and VIII) an amino acid position corresponding to position 1077 of SEQ ID NO:4; or e) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:131 and the at least one heterologous polypeptide is inserted into the RGN immediately after the amino acid position selected from the group consisting of: I) an amino acid position corresponding to position 766 of SEQ ID NO:131; and II) an amino acid position corresponding to position 910 of SEQ ID NO:4; and VIII) an amino acid position corresponding to position 1077 of SEQ ID NO:4; or e) the RGN comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO:131 and the at least one heterologous polypeptide is inserted into the RGN immediately after the amino acid position selected from the group consisting of: I) an amino acid position corresponding to position 766 of SEQ ID NO:131; and NO: The amino acid position corresponding to position 806 of 131. A method as described in any one of claims 77 to 80, wherein the heterologous polypeptide comprises a base editing polypeptide or a lead editing polypeptide and wherein the method further comprises modifying the target DNA molecule to produce a modified target DNA molecule. A method as described in claim 81, wherein the target DNA molecule comprises a causal mutation for a disease or condition and wherein modification of the target DNA molecule corrects the causal mutation. A method as described in claim 82, wherein the correction of the causal mutation includes correcting a meaningless mutation. A method as described in any one of claims 81 to 83, wherein the base editing polypeptide comprises a deaminase. A method as described in claim 84, wherein the fusion protein is a base editor fusion protein, and wherein the base editor fusion protein has improved editing activity compared to a parent base editor comprising the deaminase fused to the amino terminus of the RGN. A method as described in claim 84 or claim 85, wherein the at least one heterologous polypeptide is inserted into the RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 1 immediately after the amino acid position selected from the group consisting of: a) an amino acid position corresponding to position 642 of SEQ ID NO: 1; b)      an amino acid position corresponding to position 670 of SEQ ID NO: 1; c) an amino acid position corresponding to position 737 of SEQ ID NO: 1; d)      an amino acid position corresponding to position 772 of SEQ ID NO: 1; e) an amino acid position corresponding to position 775 of SEQ ID NO: 1; and f) an amino acid position corresponding to position 778 of SEQ ID NO: 1; and Wherein the fusion protein is a base editor fusion protein, and wherein the base editor fusion protein has an editing window that is shifted compared to a parent base editor comprising the deaminase fused to the amino terminus of the RGN. A method as described in any of claims 84 to 86, wherein the deaminase lacks the first and last amino acid residues compared to a parent deaminase from which the deaminase is derived. A method as described in any one of claims 84 to 87, wherein the deaminase comprises an adenine deaminase and the fusion protein is an adenosine base editor (ABE) fusion protein. The method of claim 88, wherein the adenine deaminase comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 5, 6, 248-414, 596, 597, and 720-723. The method of claim 88, wherein the adenine deaminase comprises the amino acid sequence of any one of SEQ ID NOs: 5, 6, 248-414, 596, 597, and 720-723. The method of claim 88, wherein the ABE fusion protein comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 8-10, 13-21, 27-31, 36-38, 40-41, 43-48, 647, and 650. A method as described in claim 88, wherein the ABE fusion protein comprises the amino acid sequence shown in any one of SEQ ID NOs: 8-10, 13-21, 27-31, 36-38, 40-41, 43-48, 647, and 650. A method as described in claim 88, wherein the ABE fusion protein comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 8-10 and 14-16, and wherein the ABE fusion protein has an editing window that is shifted compared to a parent ABE base editor, the parent ABE base editor comprising the adenine deaminase fused to the amino terminus of the RGN. The method of any one of claims 77 to 93, wherein the RGN is a notchase or a nuclease inactive RGN. The method of claim 94, wherein the RGN nickase comprises an amino acid sequence having at least 95% sequence identity to any one of SEQ ID NOs: 49-56, 698 and 699 and retains nickase activity. The method of claim 94, wherein the RGN nickase comprises the amino acid sequence of any one of SEQ ID NOs: 49-56, 698 and 699. A method as described in any one of claims 77 to 96, wherein at least one of the nucleotide sequence encoding the one or more guide RNAs and the nucleotide sequence encoding the fusion protein is operably linked to a promoter heterologous to the nucleotide sequence. A method as described in any one of claim 77 to claim 97, wherein the target DNA sequence is a eukaryotic target DNA sequence. A method as described in any of claims 77 to 98, wherein the target DNA sequence is positioned adjacent to a protospacer adjacent motif (PAM) recognized by the RGN. A method as described in any one of claims 77 to 99, wherein the target DNA molecule is within a cell. The method of claim 100 further comprises selecting a cell comprising the modified target DNA molecule. A cell comprising a modified target DNA molecule according to the method of claim 101. The cell of claim 102, wherein the cell is a mammalian cell. The cell of claim 102, wherein the cell is a plant cell. A plant or a seed comprising the cell of claim 104. A pharmaceutical composition comprising the cell as described in claim 103 and a pharmaceutically acceptable carrier. A method for treating an individual suffering from or at risk of developing a disease, disorder or symptom, the method comprising: administering to the individual a fusion protein as described in any one of claims 1 to 18 and 113 to 119, an RNP complex as described in claim 19, a nucleic acid molecule as described in any one of claims 20 to 37 and 120 to 126, a vector as described in claim 38 or 39, a cell as described in any one of claims 43, 71, and 103, a system as described in any one of claims 48 to 69 and 127 to 133, or a pharmaceutical composition as described in any one of claims 46, 74, and 106. The method of claim 107, wherein the disease is associated with a causal mutation and the treatment comprises correcting the causal mutation. A fusion protein as described in any one of claims 1 to 18 and 113 to 119, an RNP complex as described in claim 19, a nucleic acid molecule as described in any one of claims 20 to 37 and 120 to 126, a vector as described in claim 38 or 39, a cell as described in any one of claim 43, claim 71, and claim 103, or a system as described in any one of claims 48 to 69 and 127 to 133 for treating a disease, disorder or symptom in an individual suffering from or at risk of developing the disease, disorder or symptom. The use of claim 109, wherein the disease is associated with a causal mutation and the treatment comprises correcting the causal mutation. A fusion protein as described in any one of claims 1 to 18 and 113 to 119, an RNP complex as described in claim 19, a nucleic acid molecule as described in any one of claims 20 to 37 and 120 to 126, a vector as described in claim 38 or 39, a cell as described in any one of claim 43, claim 71, and 103, or a system as described in any one of claims 48 to 69 and 127 to 133 for the manufacture of a medicament useful for treating a disease, disorder or symptom. The use of claim 111, wherein the disease is associated with a causal mutation and an effective amount of the drug corrects the causal mutation. A fusion protein as described in claim 10, wherein the adenine deaminase comprises an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 5, and at least one of the following amino acid residues: a) a C at a position corresponding to position 2 of SEQ ID NO: 5; b) an F or C at a position corresponding to position 22 of SEQ ID NO: 5; c) a Q at a position corresponding to position 23 of SEQ ID NO: 5; d) an N at a position corresponding to position 35 of SEQ ID NO: 5; e) an L at a position corresponding to position 40 of SEQ ID NO: 5; f) a Q at a position corresponding to position 46 of SEQ ID NO: 5; g) an A or M at a position corresponding to position 68 of SEQ ID NO: 5; h) an H at a position corresponding to position 72 of SEQ ID NO: 5; i) an N at a position corresponding to position 35 of SEQ ID NO: 5; e) an L at a position corresponding to position 40 of SEQ ID NO: 5; f) a Q at a position corresponding to position 46 of SEQ ID NO: 5; g) an A or M at a position corresponding to position 68 of SEQ ID NO: 5; h) an H at a position corresponding to position 72 of SEQ ID NO: 5; i) an N at a position corresponding to position 35 of SEQ ID NO: 5; NO:5 position 75 corresponding to a W, A, Q, Y, or D; j) a G at a position corresponding to a position 76 corresponding to a position 81 corresponding to a position 81 of SEQ ID NO:5; l) an M at a position corresponding to a position 105 of SEQ ID NO:5; m) an H at a position corresponding to a position 108 of SEQ ID NO:5; n) an L at a position corresponding to a position 109 of SEQ ID NO:5; o) an I or L at a position corresponding to a position 117 of SEQ ID NO:5; p) an F at a position corresponding to a position 120 of SEQ ID NO:5; q) an E, T, A, G, or V at a position corresponding to a position 121 of SEQ ID NO:5; r) an I or H at a position corresponding to a position 122 of SEQ ID NO:5; s) an L at a position corresponding to a position 117 of SEQ ID NO:5; NO:5 position 125 corresponding to a K; t) an A at a position corresponding to a position 126 corresponding to a SEQ ID NO:5; u) an H at a position corresponding to a position 135 corresponding to a SEQ ID NO:5; v) a V at a position corresponding to a position 137 corresponding to a SEQ ID NO:5; w) a Y at a position corresponding to a position 138 corresponding to a SEQ ID NO:5; x) an L at a position corresponding to a position 139 corresponding to a SEQ ID NO:5; y) a K or A at a position corresponding to a position 142 corresponding to a SEQ ID NO:5; z) an A, Q, L, or M at a position corresponding to a position 145 corresponding to a SEQ ID NO:5; aa) a K at a position corresponding to a position 148 corresponding to a SEQ ID NO:5; bb) a Q at a position corresponding to a position 151 corresponding to a SEQ ID NO:5; cc) a K at a position corresponding to a position 152 corresponding to a SEQ ID NO:5. NO:5 position 153 corresponding to an E or R; dd) a W at a position corresponding to a position 155 corresponding to a SEQ ID NO:5; ee) an R or V at a position corresponding to a position 156 corresponding to a SEQ ID NO:5; ff) an F at a position corresponding to a position 157 corresponding to a SEQ ID NO:5; gg) an R at a position corresponding to a position 158 corresponding to a SEQ ID NO:5; hh) a Q at a position corresponding to a position 159 corresponding to a SEQ ID NO:5; ii) a D or W at a position corresponding to a position 160 corresponding to a SEQ ID NO:5; jj) a W, H, V, or A at a position corresponding to a position 162 corresponding to a SEQ ID NO:5; kk) an R at a position corresponding to a position 165 corresponding to a SEQ ID NO:5; and ll) an H at a position corresponding to a position 166 corresponding to a SEQ ID NO:5. A fusion protein as described in claim 113, wherein the adenine deaminase comprises: a) an N at a position corresponding to position 35 of SEQ ID NO: 5 and a W at a position corresponding to position 162 of SEQ ID NO: 5; b) an N at a position corresponding to position 35 of SEQ ID NO: 5 and a Q at a position corresponding to position 46 of SEQ ID NO: 5; c) an S at a position corresponding to position 81 of SEQ ID NO: 5 and an R at a position corresponding to position 156 of SEQ ID NO: 5; d) a Q at a position corresponding to position 46 of SEQ ID NO: 5 and an R at a position corresponding to position 156 of SEQ ID NO: 5; e) an R at a position corresponding to position 156 of SEQ ID NO: 5 and a W at a position corresponding to position 162 of SEQ ID NO: 5; f) an A at a position corresponding to position 68 of SEQ ID NO: 5 and a 162 of SEQ ID NO:5; i) a W at a position corresponding to position 155 of SEQ ID NO:5, a R at a position corresponding to position 156 of SEQ ID NO:5, and a W at a position corresponding to position 162 of SEQ ID NO:5; j) a N at a position corresponding to position 35 of SEQ ID NO:5, a Q at a position corresponding to position 46 of SEQ ID NO:5, and a W at a position corresponding to position 162 of SEQ ID NO:5; NO:5 position 162 corresponding to a W; k) a N at a position corresponding to a position 35 of SEQ ID NO:5, a S at a position corresponding to a position 81 of SEQ ID NO:5, a R at a position corresponding to a position 156 of SEQ ID NO:5, and a W at a position corresponding to a position 162 of SEQ ID NO:5; l) a M at a position corresponding to a position 68 of SEQ ID NO:5, a H at a position corresponding to a position 108 of SEQ ID NO:5, a R at a position corresponding to a position 156 of SEQ ID NO:5, and a W at a position corresponding to a position 162 of SEQ ID NO:5; m) a Q at a position corresponding to a position 46 of SEQ ID NO:5, a M at a position corresponding to a position 68 of SEQ ID NO:5, a H at a position corresponding to a position 108 of SEQ ID NO:5, a NO:5 position 156 corresponding to an R, and a position corresponding to position 162 corresponding to SEQ ID NO:5; n) a M at a position corresponding to position 68 of SEQ ID NO:5, a S at a position corresponding to position 81 of SEQ ID NO:5, a H at a position corresponding to position 108 of SEQ ID NO:5, a R at a position corresponding to position 156 of SEQ ID NO:5, and a W at a position corresponding to position 162 of SEQ ID NO:5; o) a Q at a position corresponding to position 46 of SEQ ID NO:5, a N at a position corresponding to position 35, a M at a position corresponding to position 68 of SEQ ID NO:5, a S at a position corresponding to position 81 of SEQ ID NO:5, a H at a position corresponding to position 108 of SEQ ID NO:5, a W at a position corresponding to position 155 of SEQ ID NO:5, and a W at a position corresponding to position 162 of SEQ ID NO:5; NO: 5 position 156 corresponding to an R, and a position corresponding to a W corresponding to a position 162 of SEQ ID NO: 5; p) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and a W at a position corresponding to a position 155 of SEQ ID NO: 5; q) a W at a position corresponding to a position 75 of SEQ ID NO: 5, and an S at a position corresponding to a position 81 of SEQ ID NO: 5; r) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and a D at a position corresponding to a position 160 of SEQ ID NO: 5; s) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and an A at a position corresponding to a position 145 of SEQ ID NO: 5; t) a W at a position corresponding to a position 75 of SEQ ID NO: 5, and a W at a position corresponding to a position 155 of SEQ ID NO: 5; u) a W at a position corresponding to position 155 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; v) an A at a position corresponding to position 145 of SEQ ID NO: 5, and a W at a position corresponding to position 155 of SEQ ID NO: 5; w) a W at a position corresponding to position 75 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; x) a W at a position corresponding to position 75 of SEQ ID NO: 5, and an A at a position corresponding to position 145 of SEQ ID NO: 5; y) an A at a position corresponding to position 145 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; z) a W at a position corresponding to position 75 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5 NO:5 position 81 corresponding to an S, and a position corresponding to a W corresponding to a position 155 of SEQ ID NO:5; aa) an S at a position corresponding to a S, a W at a position corresponding to a W, and a D at a position corresponding to a position 160 of SEQ ID NO:5; bb) an S at a position corresponding to a S, a A at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 155 of SEQ ID NO:5; cc) a W at a position corresponding to a W, a S at a position corresponding to a S, and a D at a position corresponding to a position 160 of SEQ ID NO:5; dd) a W at a position corresponding to a W, a A at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 155 of SEQ ID NO:5; NO:5 position 81 corresponding to an S, and a position corresponding to a position 145 corresponding to SEQ ID NO:5; ee) an S at a position corresponding to a position 81 corresponding to SEQ ID NO:5, an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5; ff) a W at a position corresponding to a position 75 corresponding to SEQ ID NO:5, a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5; gg) a W at a position corresponding to a position 75 corresponding to SEQ ID NO:5, an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, and a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5; hh) an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5. NO:5 position 155 corresponding to a W, and a D corresponding to a position 160 corresponding to a SEQ ID NO:5; ii) a W at a position corresponding to a SEQ ID NO:5 position 75 corresponding to a W, an A at a position corresponding to a SEQ ID NO:5 position 145 corresponding to a SEQ ID NO:5 position 160 corresponding to a D; jj) a W at a position corresponding to a SEQ ID NO:5 position 75 corresponding to a W, an S at a position corresponding to a SEQ ID NO:5 position 81 corresponding to a W, a W at a position corresponding to a SEQ ID NO:5 position 155 corresponding to a D, and a D at a position corresponding to a SEQ ID NO:5 position 160 corresponding to a SEQ ID NO:5; kk) a W at a position corresponding to a SEQ ID NO:5 position 75 corresponding to a SEQ ID NO:5 position 81 corresponding to a S, an A at a position corresponding to a SEQ ID NO:5 position 145 corresponding to a SEQ ID NO:5 position 160 corresponding to a SEQ ID NO:5 position NO:5 position 155 corresponding to a W; ll) a S at a position corresponding to the 81st position of SEQ ID NO:5, an A at a position corresponding to the 145th position of SEQ ID NO:5, a W at a position corresponding to the 155th position of SEQ ID NO:5, and a D at a position corresponding to the 160th position of SEQ ID NO:5; mm) a W at a position corresponding to the 75th position of SEQ ID NO:5, an S at a position corresponding to the 81st position of SEQ ID NO:5, an A at a position corresponding to the 145th position of SEQ ID NO:5, and a D at a position corresponding to the 160th position of SEQ ID NO:5; nn) a W at a position corresponding to the 75th position of SEQ ID NO:5, an A at a position corresponding to the 145th position of SEQ ID NO:5, a W at a position corresponding to the 155th position of SEQ ID NO:5, and a D at a position corresponding to the 160th position of SEQ ID NO:5. NO:5 position 160 corresponding to a D; oo) a W at a position corresponding to a W at a position corresponding to a S ... an L at a position corresponding to position 40 of SEQ ID NO: 5, and a Q at a position corresponding to position 159 of SEQ ID NO: 5; tt) an L at a position corresponding to position 40 of SEQ ID NO: 5, and a W at a position corresponding to position 160 of SEQ ID NO: 5; uu) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a V at a position corresponding to position 121 of SEQ ID NO: 5; vv) an M at a position corresponding to position 105 of SEQ ID NO: 5, and an M at a position corresponding to position 145 of SEQ ID NO: 5; ww) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a Q at a position corresponding to position 159 of SEQ ID NO: 5; xx) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a V at a position corresponding to position 121 of SEQ ID NO: 5; NO:5, a W at a position corresponding to position 160; yy) a V at a position corresponding to position 121 of SEQ ID NO:5, and an M at a position corresponding to position 145 of SEQ ID NO:5; zz) a V at a position corresponding to position 121 of SEQ ID NO:5, and a Q at a position corresponding to position 159 of SEQ ID NO:5; aaa) a V at a position corresponding to position 121 of SEQ ID NO:5, and a W at a position corresponding to position 160 of SEQ ID NO:5; bbb) an M at a position corresponding to position 145 of SEQ ID NO:5, and a Q at a position corresponding to position 159 of SEQ ID NO:5; ccc) an M at a position corresponding to position 145 of SEQ ID NO:5, and a W at a position corresponding to position 160 of SEQ ID NO:5; ddd) a NO:5 position 159 corresponding to a Q, and a W corresponding to a position 160 corresponding to a W; eee) a S at a position corresponding to a position 81 of SEQ ID NO:5, a M at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 160 of SEQ ID NO:5; fff) a S at a position corresponding to a position 81 of SEQ ID NO:5, a V at a position corresponding to a position 121 of SEQ ID NO:5, and a Q at a position corresponding to a position 159 of SEQ ID NO:5; ggg) an A at a position corresponding to a position 68 of SEQ ID NO:5, and a S at a position corresponding to a position 81 of SEQ ID NO:5; hhh) a G at a position corresponding to a position 76 of SEQ ID NO:5, and a S at a position corresponding to a position 81 of SEQ ID NO:5; iii) an S at a position corresponding to position 81 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; jjj) an A at a position corresponding to position 68 of SEQ ID NO: 5, and a G at a position corresponding to position 76 of SEQ ID NO: 5; kkk) an A at a position corresponding to position 68 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; lll) a G at a position corresponding to position 76 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; mmm) an A at a position corresponding to position 68 of SEQ ID NO: 5, a G at a position corresponding to position 76 of SEQ ID NO: 5, and an S at a position corresponding to position 81 of SEQ ID NO: 5; nnn) an A at a position corresponding to position 68 of SEQ ID NO: 5, a G at a position corresponding to position 76 of SEQ ID NO: 5, and an S at a position corresponding to position 81 of SEQ ID NO: 5 NO:5 position 68 corresponding to an A, a position corresponding to an S, and a position corresponding to an L in a position corresponding to a position 117 of SEQ ID NO:5; ooo) a G at a position corresponding to a position 76 of SEQ ID NO:5, a S at a position corresponding to a S, and a L in a position corresponding to a position 117 of SEQ ID NO:5; ppp) an A at a position corresponding to a position 68 of SEQ ID NO:5, a G at a position corresponding to a position 76 of SEQ ID NO:5, and a L in a position corresponding to a position 117 of SEQ ID NO:5; qqq) an A at a position corresponding to a position 68 of SEQ ID NO:5, a G at a position corresponding to a position 76 of SEQ ID NO:5, a S at a position corresponding to a position 81 of SEQ ID NO:5, and a L in a position corresponding to a position 117 of SEQ ID NO:5; NO:5 position 117 - L; rrr) SEQ ID NO:5 position 81 - S, SEQ ID NO:5 position 109 - L, SEQ ID NO:5 position 153 - E, SEQ ID NO:5 position 155 - W, and SEQ ID NO:5 position 160 - D; sss) SEQ ID NO:5 position 75 - A, SEQ ID NO:5 position 81 - S, SEQ ID NO:5 position 117 - L, SEQ ID NO:5 position 121 - A, SEQ ID NO:5 position 145 - A, SEQ ID NO:5 position 155 - W, and SEQ ID NO:5 position 160 - D; NO:5 position 160 corresponding to a D; ttt) a Q at a position corresponding to ... NO:5 position 155 corresponding to a W, and a D corresponding to a position 160 corresponding to a D of SEQ ID NO:5; vvv) a C corresponding to a position 22 corresponding to a position 68 corresponding to a position 75 corresponding to a Y of SEQ ID NO:5, a G corresponding to a position 76 corresponding to a position 81 corresponding to a S of SEQ ID NO:5, a H corresponding to a position 108 corresponding to a position 117 corresponding to a L of SEQ ID NO:5, a H corresponding to a position 122 corresponding to a position 138 corresponding to a Y of SEQ ID NO:5, a L corresponding to a position 139 corresponding to a L of SEQ ID NO:5, a H corresponding to a position 140 corresponding to a position 141 corresponding to a position 142 corresponding to a position 143 corresponding to a position 147 corresponding to a position 149 corresponding to a position 150 corresponding to a position 151 corresponding to a position 152 corresponding to a position 153 corresponding to a position 154 corresponding to a position 156 corresponding to a position 157 corresponding to a position 158 corresponding to a position 15 ... NO:5 position 142 corresponding to an A, SEQ ID NO:5 position 145 corresponding to an A, SEQ ID NO:5 position 153 corresponding to an R, SEQ ID NO:5 position 155 corresponding to a W, SEQ ID NO:5 position 156 corresponding to an R, SEQ ID NO:5 position 160 corresponding to a D, and SEQ ID NO:5 position 162 corresponding to an H; or www) SEQ ID NO:5 position 81 corresponding to an S. The fusion protein of claim 113 or claim 114, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 300-414, 596-598, and 720-723. The fusion protein of claim 113 or claim 114, wherein the deaminase has the amino acid sequence shown in any one of SEQ ID NOs: 300-414, 596-598, and 720-723. A fusion protein as described in claim 113 or claim 114, wherein the fusion protein is selected from the group consisting of: a) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 375 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; b) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 375 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 52; c) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 319 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: ID NO: 50 having an amino acid sequence with at least 90% sequence identity after an amino acid position corresponding to position 922 of SEQ ID NO: 2; d) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 319 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 52; e) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 375 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 49; f) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 319 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 52; NO:375 has an amino acid sequence with at least 90% sequence identity and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; g) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:319 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; h) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:597 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; i) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 319 and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; j) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 406 and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; k) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; NO: 2 after an amino acid position corresponding to position 678; l) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 596 and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; m) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 406 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 52; n) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: NO:52 has an amino acid sequence with at least 90% sequence identity after the amino acid position corresponding to position 910 of SEQ ID NO:4; o) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; p) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:596 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:52; q) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; NO:596 has an amino acid sequence with at least 90% sequence identity and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; r) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:406 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; s) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:596 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; and t) A fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49. A fusion protein as described in claim 113 or claim 114, wherein the fusion protein is selected from the group consisting of: a) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 375 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having the amino acid sequence shown in SEQ ID NO: 50; b) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 375 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having the amino acid sequence shown in SEQ ID NO: 52; c) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 319 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having the amino acid sequence shown in SEQ ID NO: 50; NO: 2 after an amino acid position corresponding to position 922; d) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 319 and is inserted in the RGN having the amino acid sequence shown in SEQ ID NO: 52 after an amino acid position corresponding to position 910 of SEQ ID NO: 4; e) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 375 and is inserted in the RGN having the amino acid sequence shown in SEQ ID NO: 49 after an amino acid position corresponding to position 772 of SEQ ID NO: 1; f) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 375 and is inserted in the RGN having the amino acid sequence shown in SEQ ID NO: 50 after an amino acid position corresponding to position 678 of SEQ ID NO: 2; g) a fusion protein, wherein the deaminase has the amino acid sequence as shown in SEQ ID NO: 319 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having the amino acid sequence as shown in SEQ ID NO: 49; h) a fusion protein, wherein the deaminase has the amino acid sequence as shown in SEQ ID NO: 597 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having the amino acid sequence as shown in SEQ ID NO: 50; i) a fusion protein, wherein the deaminase has the amino acid sequence as shown in SEQ ID NO: 319 and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having the amino acid sequence as shown in SEQ ID NO: 50; j) a fusion protein, wherein the deaminase has the amino acid sequence as shown in SEQ ID NO: NO:406 and inserted after an amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having the amino acid sequence as shown in SEQ ID NO:50; k) a fusion protein, wherein the deaminase has the amino acid sequence as shown in SEQ ID NO:597 and inserted after an amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having the amino acid sequence as shown in SEQ ID NO:50; l) a fusion protein, wherein the deaminase has the amino acid sequence as shown in SEQ ID NO:596 and inserted after an amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having the amino acid sequence as shown in SEQ ID NO:50; m) a fusion protein, wherein the deaminase has the amino acid sequence as shown in SEQ ID NO:406 and inserted after an amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having the amino acid sequence as shown in SEQ ID NO:50; NO:52 after an amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having the amino acid sequence shown in SEQ ID NO:597; n) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:597 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having the amino acid sequence shown in SEQ ID NO:52; o) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:406 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:50; p) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:596 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:52; NO:4 after an amino acid position corresponding to position 910; q) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:596 and is inserted in the RGN having the amino acid sequence shown in SEQ ID NO:50 after an amino acid position corresponding to position 922 of SEQ ID NO:2; r) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:406 and is inserted in the RGN having the amino acid sequence shown in SEQ ID NO:49 after an amino acid position corresponding to position 772 of SEQ ID NO:1; s) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:596 and is inserted in the RGN having the amino acid sequence shown in SEQ ID NO:49 after an amino acid position corresponding to position 772 of SEQ ID NO:1; and t) A fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 597 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having the amino acid sequence shown in SEQ ID NO: 49. The fusion protein of claim 118, wherein the fusion protein has the sequence shown in any one of SEQ ID NOs: 599, 600, 602, 603, 606, 610, 612, 614, 615, 617, 619-624, 626, and 630-632. A nucleic acid molecule as described in claim 29, wherein the adenine deaminase comprises an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 5, and at least one of the following amino acid residues: a) a C at a position corresponding to position 2 of SEQ ID NO: 5; b) an F or C at a position corresponding to position 22 of SEQ ID NO: 5; c) a Q at a position corresponding to position 23 of SEQ ID NO: 5; d) an N at a position corresponding to position 35 of SEQ ID NO: 5; e) an L at a position corresponding to position 40 of SEQ ID NO: 5; f) a Q at a position corresponding to position 46 of SEQ ID NO: 5; g) an A or M at a position corresponding to position 68 of SEQ ID NO: 5; h) an H at a position corresponding to position 72 of SEQ ID NO: 5; i) an N at a position corresponding to position 35 of SEQ ID NO: 5; e) an L at a position corresponding to position 40 of SEQ ID NO: 5; f) a Q at a position corresponding to position 46 of SEQ ID NO: 5; g) an A or M at a position corresponding to position 68 of SEQ ID NO: 5; h) an H at a position corresponding to position 72 of SEQ ID NO: 5; i) an N at a position corresponding to position 35 of SEQ ID NO: 5; NO:5 position 75 corresponding to a W, A, Q, Y, or D; j) a G at a position corresponding to a position 76 corresponding to a position 81 corresponding to a position 81 of SEQ ID NO:5; l) an M at a position corresponding to a position 105 of SEQ ID NO:5; m) an H at a position corresponding to a position 108 of SEQ ID NO:5; n) an L at a position corresponding to a position 109 of SEQ ID NO:5; o) an I or L at a position corresponding to a position 117 of SEQ ID NO:5; p) an F at a position corresponding to a position 120 of SEQ ID NO:5; q) an E, T, A, G, or V at a position corresponding to a position 121 of SEQ ID NO:5; r) an I or H at a position corresponding to a position 122 of SEQ ID NO:5; s) an L at a position corresponding to a position 117 of SEQ ID NO:5; NO:5 position 125 corresponding to a K; t) an A at a position corresponding to a position 126 corresponding to a SEQ ID NO:5; u) an H at a position corresponding to a position 135 corresponding to a SEQ ID NO:5; v) a V at a position corresponding to a position 137 corresponding to a SEQ ID NO:5; w) a Y at a position corresponding to a position 138 corresponding to a SEQ ID NO:5; x) an L at a position corresponding to a position 139 corresponding to a SEQ ID NO:5; y) a K or A at a position corresponding to a position 142 corresponding to a SEQ ID NO:5; z) an A, Q, L, or M at a position corresponding to a position 145 corresponding to a SEQ ID NO:5; aa) a K at a position corresponding to a position 148 corresponding to a SEQ ID NO:5; bb) a Q at a position corresponding to a position 151 corresponding to a SEQ ID NO:5; cc) a K at a position corresponding to a position 152 corresponding to a SEQ ID NO:5. NO:5 position 153 corresponding to an E or R; dd) a W at a position corresponding to a position 155 corresponding to a SEQ ID NO:5; ee) an R or V at a position corresponding to a position 156 corresponding to a SEQ ID NO:5; ff) an F at a position corresponding to a position 157 corresponding to a SEQ ID NO:5; gg) an R at a position corresponding to a position 158 corresponding to a SEQ ID NO:5; hh) a Q at a position corresponding to a position 159 corresponding to a SEQ ID NO:5; ii) a D or W at a position corresponding to a position 160 corresponding to a SEQ ID NO:5; jj) a W, H, V, or A at a position corresponding to a position 162 corresponding to a SEQ ID NO:5; kk) an R at a position corresponding to a position 165 corresponding to a SEQ ID NO:5; and ll) an H at a position corresponding to a position 166 corresponding to a SEQ ID NO:5. A nucleic acid molecule as described in claim 120, wherein the adenine deaminase comprises: a) an N at a position corresponding to position 35 of SEQ ID NO: 5 and a W at a position corresponding to position 162 of SEQ ID NO: 5; b) an N at a position corresponding to position 35 of SEQ ID NO: 5 and a Q at a position corresponding to position 46 of SEQ ID NO: 5; c) an S at a position corresponding to position 81 of SEQ ID NO: 5 and an R at a position corresponding to position 156 of SEQ ID NO: 5; d) a Q at a position corresponding to position 46 of SEQ ID NO: 5 and an R at a position corresponding to position 156 of SEQ ID NO: 5; e) an R at a position corresponding to position 156 of SEQ ID NO: 5 and a W at a position corresponding to position 162 of SEQ ID NO: 5; f) an A at a position corresponding to position 68 of SEQ ID NO: 5 and a 162 of SEQ ID NO:5; i) a W at a position corresponding to position 155 of SEQ ID NO:5, a R at a position corresponding to position 156 of SEQ ID NO:5, and a W at a position corresponding to position 162 of SEQ ID NO:5; j) a N at a position corresponding to position 35 of SEQ ID NO:5, a Q at a position corresponding to position 46 of SEQ ID NO:5, and a W at a position corresponding to position 162 of SEQ ID NO:5; NO:5 position 162 corresponding to a W; k) a N at a position corresponding to a position 35 of SEQ ID NO:5, a S at a position corresponding to a position 81 of SEQ ID NO:5, a R at a position corresponding to a position 156 of SEQ ID NO:5, and a W at a position corresponding to a position 162 of SEQ ID NO:5; l) a M at a position corresponding to a position 68 of SEQ ID NO:5, a H at a position corresponding to a position 108 of SEQ ID NO:5, a R at a position corresponding to a position 156 of SEQ ID NO:5, and a W at a position corresponding to a position 162 of SEQ ID NO:5; m) a Q at a position corresponding to a position 46 of SEQ ID NO:5, a M at a position corresponding to a position 68 of SEQ ID NO:5, a H at a position corresponding to a position 108 of SEQ ID NO:5, a NO:5 position 156 corresponding to an R, and a position corresponding to position 162 corresponding to SEQ ID NO:5; n) a M at a position corresponding to position 68 of SEQ ID NO:5, a S at a position corresponding to position 81 of SEQ ID NO:5, a H at a position corresponding to position 108 of SEQ ID NO:5, a R at a position corresponding to position 156 of SEQ ID NO:5, and a W at a position corresponding to position 162 of SEQ ID NO:5; o) a Q at a position corresponding to position 46 of SEQ ID NO:5, a N at a position corresponding to position 35, a M at a position corresponding to position 68 of SEQ ID NO:5, a S at a position corresponding to position 81 of SEQ ID NO:5, a H at a position corresponding to position 108 of SEQ ID NO:5, a W at a position corresponding to position 155 of SEQ ID NO:5, and a W at a position corresponding to position 162 of SEQ ID NO:5; NO: 5 position 156 corresponding to an R, and a position corresponding to a W corresponding to a position 162 of SEQ ID NO: 5; p) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and a W at a position corresponding to a position 155 of SEQ ID NO: 5; q) a W at a position corresponding to a position 75 of SEQ ID NO: 5, and an S at a position corresponding to a position 81 of SEQ ID NO: 5; r) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and a D at a position corresponding to a position 160 of SEQ ID NO: 5; s) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and an A at a position corresponding to a position 145 of SEQ ID NO: 5; t) a W at a position corresponding to a position 75 of SEQ ID NO: 5, and a W at a position corresponding to a position 155 of SEQ ID NO: 5; u) a W at a position corresponding to position 155 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; v) an A at a position corresponding to position 145 of SEQ ID NO: 5, and a W at a position corresponding to position 155 of SEQ ID NO: 5; w) a W at a position corresponding to position 75 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; x) a W at a position corresponding to position 75 of SEQ ID NO: 5, and an A at a position corresponding to position 145 of SEQ ID NO: 5; y) an A at a position corresponding to position 145 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; z) a W at a position corresponding to position 75 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5 NO:5 position 81 corresponding to an S, and a position corresponding to a W corresponding to a position 155 of SEQ ID NO:5; aa) an S at a position corresponding to a S, a W at a position corresponding to a W, and a D at a position corresponding to a position 160 of SEQ ID NO:5; bb) an S at a position corresponding to a S, a A at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 155 of SEQ ID NO:5; cc) a W at a position corresponding to a W, a S at a position corresponding to a S, and a D at a position corresponding to a position 160 of SEQ ID NO:5; dd) a W at a position corresponding to a W, a A at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 155 of SEQ ID NO:5; NO:5 position 81 corresponding to an S, and a position corresponding to a position 145 corresponding to SEQ ID NO:5; ee) an S at a position corresponding to a position 81 corresponding to SEQ ID NO:5, an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5; ff) a W at a position corresponding to a position 75 corresponding to SEQ ID NO:5, a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5; gg) a W at a position corresponding to a position 75 corresponding to SEQ ID NO:5, an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, and a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5; hh) an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5. NO:5 position 155 corresponding to a W, and a position corresponding to a D at a position corresponding to a position 160 of SEQ ID NO:5; ii) a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a NO:5 position 155 corresponding to a W; ll) a S at a position corresponding to the 81st position of SEQ ID NO:5, an A at a position corresponding to the 145th position of SEQ ID NO:5, a W at a position corresponding to the 155th position of SEQ ID NO:5, and a D at a position corresponding to the 160th position of SEQ ID NO:5; mm) a W at a position corresponding to the 75th position of SEQ ID NO:5, an S at a position corresponding to the 81st position of SEQ ID NO:5, an A at a position corresponding to the 145th position of SEQ ID NO:5, and a D at a position corresponding to the 160th position of SEQ ID NO:5; nn) a W at a position corresponding to the 75th position of SEQ ID NO:5, an A at a position corresponding to the 145th position of SEQ ID NO:5, a W at a position corresponding to the 155th position of SEQ ID NO:5, and a D at a position corresponding to the 160th position of SEQ ID NO:5. NO:5 position 160 corresponding to a D; oo) a W at a position corresponding to a W at a position corresponding to a S ... an L at a position corresponding to position 40 of SEQ ID NO: 5, and a Q at a position corresponding to position 159 of SEQ ID NO: 5; tt) an L at a position corresponding to position 40 of SEQ ID NO: 5, and a W at a position corresponding to position 160 of SEQ ID NO: 5; uu) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a V at a position corresponding to position 121 of SEQ ID NO: 5; vv) an M at a position corresponding to position 105 of SEQ ID NO: 5, and an M at a position corresponding to position 145 of SEQ ID NO: 5; ww) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a Q at a position corresponding to position 159 of SEQ ID NO: 5; xx) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a V at a position corresponding to position 121 of SEQ ID NO: 5; NO:5, a W at a position corresponding to position 160; yy) a V at a position corresponding to position 121 of SEQ ID NO:5, and an M at a position corresponding to position 145 of SEQ ID NO:5; zz) a V at a position corresponding to position 121 of SEQ ID NO:5, and a Q at a position corresponding to position 159 of SEQ ID NO:5; aaa) a V at a position corresponding to position 121 of SEQ ID NO:5, and a W at a position corresponding to position 160 of SEQ ID NO:5; bbb) an M at a position corresponding to position 145 of SEQ ID NO:5, and a Q at a position corresponding to position 159 of SEQ ID NO:5; ccc) an M at a position corresponding to position 145 of SEQ ID NO:5, and a W at a position corresponding to position 160 of SEQ ID NO:5; ddd) a NO:5 position 159 corresponding to a Q, and a W corresponding to a position 160 corresponding to a W; eee) a S at a position corresponding to a position 81 of SEQ ID NO:5, a M at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 160 of SEQ ID NO:5; fff) a S at a position corresponding to a position 81 of SEQ ID NO:5, a V at a position corresponding to a position 121 of SEQ ID NO:5, and a Q at a position corresponding to a position 159 of SEQ ID NO:5; ggg) an A at a position corresponding to a position 68 of SEQ ID NO:5, and a S at a position corresponding to a position 81 of SEQ ID NO:5; hhh) a G at a position corresponding to a position 76 of SEQ ID NO:5, and a S at a position corresponding to a position 81 of SEQ ID NO:5; iii) an S at a position corresponding to position 81 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; jjj) an A at a position corresponding to position 68 of SEQ ID NO: 5, and a G at a position corresponding to position 76 of SEQ ID NO: 5; kkk) an A at a position corresponding to position 68 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; lll) a G at a position corresponding to position 76 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; mmm) an A at a position corresponding to position 68 of SEQ ID NO: 5, a G at a position corresponding to position 76 of SEQ ID NO: 5, and an S at a position corresponding to position 81 of SEQ ID NO: 5; nnn) a G at a position corresponding to position 68 of SEQ ID NO: 5, and an S at a position corresponding to position 81 of SEQ ID NO: 5; NO:5 position 68 corresponding to an A, a position corresponding to an S, and a position corresponding to an L in a position corresponding to a position 117 of SEQ ID NO:5; ooo) a G at a position corresponding to a position 76 of SEQ ID NO:5, a S at a position corresponding to a position 81 of SEQ ID NO:5, and a L in a position corresponding to a position 117 of SEQ ID NO:5; ppp) an A at a position corresponding to a position 68 of SEQ ID NO:5, a G at a position corresponding to a position 76 of SEQ ID NO:5, and a L in a position corresponding to a position 117 of SEQ ID NO:5; qqq) an A at a position corresponding to a position 68 of SEQ ID NO:5, a G at a position corresponding to a position 76 of SEQ ID NO:5, a S at a position corresponding to a position 81 of SEQ ID NO:5, and a L in a position corresponding to a position 117 of SEQ ID NO:5 NO:5 position 117 - L; rrr) SEQ ID NO:5 position 81 - S, SEQ ID NO:5 position 109 - L, SEQ ID NO:5 position 153 - E, SEQ ID NO:5 position 155 - W, and SEQ ID NO:5 position 160 - D; sss) SEQ ID NO:5 position 75 - A, SEQ ID NO:5 position 81 - S, SEQ ID NO:5 position 117 - L, SEQ ID NO:5 position 121 - A, SEQ ID NO:5 position 145 - A, SEQ ID NO:5 position 155 - W, and SEQ ID NO:5 position 160 - D; NO:5 position 160 corresponding to a D; ttt) a Q at a position corresponding to a position 75 of SEQ ID NO:5, an S at a position corresponding to a position 81 of SEQ ID NO:5, an I at a position corresponding to a position 117 of SEQ ID NO:5, a Q at a position corresponding to a position 145 of SEQ ID NO:5, a W at a position corresponding to a position 155 of SEQ ID NO:5, and a D at a position corresponding to a position 160 of SEQ ID NO:5; uuu) a Y at a position corresponding to a position 75 of SEQ ID NO:5, an S at a position corresponding to a position 81 of SEQ ID NO:5, an L at a position corresponding to a position 117 of SEQ ID NO:5, a G at a position corresponding to a position 121 of SEQ ID NO:5, an L at a position corresponding to a position 145 of SEQ ID NO:5, a a W at a position corresponding to position 155 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; vvv) a C at a position corresponding to position 22 of SEQ ID NO: 5, an A at a position corresponding to position 68 of SEQ ID NO: 5, a Y at a position corresponding to position 75 of SEQ ID NO: 5, a G at a position corresponding to position 76 of SEQ ID NO: 5, an S at a position corresponding to position 81 of SEQ ID NO: 5, an H at a position corresponding to position 108 of SEQ ID NO: 5, an L at a position corresponding to position 117 of SEQ ID NO: 5, an H at a position corresponding to position 122 of SEQ ID NO: 5, a Y at a position corresponding to position 138 of SEQ ID NO: 5, an L at a position corresponding to position 139 of SEQ ID NO: 5, an H at a position corresponding to position 140 of SEQ ID NO: 5, an H at a position corresponding to position 141 of SEQ ID NO: 5, an L at a position corresponding to position 142 of SEQ ID NO: 5, an L at a position corresponding to position 143 of SEQ ID NO: 5, an L at a position corresponding to position 144 of SEQ ID NO: 5, an L at a position corresponding to position 145 of SEQ ID NO: 5, an L at a position corresponding to position 146 of SEQ ID NO: 5, an L at a position corresponding to position 147 of SEQ ID NO: 5, an L at a position corresponding to position 148 of SEQ ID NO: 5, an L at a position corresponding to position 149 of SEQ ID NO: 5, an L at a position corresponding to position 150 of SEQ ID NO: 5, an L at a position corresponding to position 151 of SEQ ID NO: 5, an L at a position NO:5 position 142 corresponding to an A, SEQ ID NO:5 position 145 corresponding to an A, SEQ ID NO:5 position 153 corresponding to an R, SEQ ID NO:5 position 155 corresponding to a W, SEQ ID NO:5 position 156 corresponding to an R, SEQ ID NO:5 position 160 corresponding to a D, and SEQ ID NO:5 position 162 corresponding to an H; or www) SEQ ID NO:5 position 81 corresponding to an S. The nucleic acid molecule of claim 120 or claim 121, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 300-414, 596-598, and 720-723. A nucleic acid molecule as described in claim 120 or claim 121, wherein the deaminase has the amino acid sequence shown in any one of SEQ ID NOs: 300-414, 596-598, and 720-723. A nucleic acid molecule as described in claim 120 or claim 121, wherein the fusion protein is selected from the group consisting of: a) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 375 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; b) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 375 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 52; c) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 319 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: ID NO: 50 having an amino acid sequence with at least 90% sequence identity after an amino acid position corresponding to position 922 of SEQ ID NO: 2; d) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 319 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 52; e) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 375 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 49; f) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 319 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 52; NO:375 has an amino acid sequence with at least 90% sequence identity and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; g) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:319 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; h) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:597 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; i) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 319 and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; j) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 406 and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; k) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; NO: 2 after an amino acid position corresponding to position 678; l) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 596 and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; m) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 406 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 52; n) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: NO:52 has an amino acid sequence with at least 90% sequence identity after the amino acid position corresponding to position 910 of SEQ ID NO:4; o) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; p) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:596 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:52; q) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; NO:596 has an amino acid sequence with at least 90% sequence identity and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; r) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:406 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; s) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:596 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; and t) A fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49. A nucleic acid molecule as described in claim 120 or claim 121, wherein the fusion protein is selected from the group consisting of: a) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 375 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having the amino acid sequence shown in SEQ ID NO: 50; b) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 375 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having the amino acid sequence shown in SEQ ID NO: 52; c) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 319 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having the amino acid sequence shown in SEQ ID NO: 50; NO: 2 after an amino acid position corresponding to position 922; d) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 319 and is inserted in the RGN having the amino acid sequence shown in SEQ ID NO: 52 after an amino acid position corresponding to position 910 of SEQ ID NO: 4; e) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 375 and is inserted in the RGN having the amino acid sequence shown in SEQ ID NO: 49 after an amino acid position corresponding to position 772 of SEQ ID NO: 1; f) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 375 and is inserted in the RGN having the amino acid sequence shown in SEQ ID NO: 50 after an amino acid position corresponding to position 678 of SEQ ID NO: 2; g) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 319 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having the amino acid sequence shown in SEQ ID NO: 49; h) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 597 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having the amino acid sequence shown in SEQ ID NO: 50; i) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 319 and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having the amino acid sequence shown in SEQ ID NO: 50; j) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: NO:406 and inserted after an amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having the amino acid sequence as shown in SEQ ID NO:50; k) a fusion protein, wherein the deaminase has the amino acid sequence as shown in SEQ ID NO:597 and inserted after an amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having the amino acid sequence as shown in SEQ ID NO:50; l) a fusion protein, wherein the deaminase has the amino acid sequence as shown in SEQ ID NO:596 and inserted after an amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having the amino acid sequence as shown in SEQ ID NO:50; m) a fusion protein, wherein the deaminase has the amino acid sequence as shown in SEQ ID NO:406 and inserted after an amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having the amino acid sequence as shown in SEQ ID NO:50; NO:52 after an amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having the amino acid sequence shown in SEQ ID NO:597; n) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:597 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having the amino acid sequence shown in SEQ ID NO:52; o) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:406 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:50; p) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:596 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:52; NO:4 after an amino acid position corresponding to position 910; q) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:596 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:50; r) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:406 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having the amino acid sequence shown in SEQ ID NO:49; s) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:596 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having the amino acid sequence shown in SEQ ID NO:49; and t) A fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 597 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having the amino acid sequence shown in SEQ ID NO: 49. A nucleic acid molecule as described in claim 125, wherein the fusion protein has the sequence shown in any one of SEQ ID NOs: 599, 600, 602, 603, 606, 610, 612, 614, 615, 617, 619-624, 626, and 630-632. A system as described in claim 57, wherein the adenine deaminase comprises an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 5, and at least one of the following amino acid residues: a) a C at a position corresponding to position 2 of SEQ ID NO: 5; b) an F or C at a position corresponding to position 22 of SEQ ID NO: 5; c) a Q at a position corresponding to position 23 of SEQ ID NO: 5; d) an N at a position corresponding to position 35 of SEQ ID NO: 5; e) an L at a position corresponding to position 40 of SEQ ID NO: 5; f) a Q at a position corresponding to position 46 of SEQ ID NO: 5; g) an A or M at a position corresponding to position 68 of SEQ ID NO: 5; h) an H at a position corresponding to position 72 of SEQ ID NO: 5; i) an N at a position corresponding to position 35 of SEQ ID NO: 5; e) an L at a position corresponding to position 40 of SEQ ID NO: 5; f) a Q at a position corresponding to position 46 of SEQ ID NO: 5; g) an A or M at a position corresponding to position 68 of SEQ ID NO: 5; h) an H at a position corresponding to position 72 of SEQ ID NO: 5; i) an N at a position corresponding to position 35 of SEQ ID NO: 5; NO:5 position 75 corresponding to a W, A, Q, Y, or D; j) a G at a position corresponding to a position 76 corresponding to a position 81 corresponding to a position 81 of SEQ ID NO:5; l) an M at a position corresponding to a position 105 of SEQ ID NO:5; m) an H at a position corresponding to a position 108 of SEQ ID NO:5; n) an L at a position corresponding to a position 109 of SEQ ID NO:5; o) an I or L at a position corresponding to a position 117 of SEQ ID NO:5; p) an F at a position corresponding to a position 120 of SEQ ID NO:5; q) an E, T, A, G, or V at a position corresponding to a position 121 of SEQ ID NO:5; r) an I or H at a position corresponding to a position 122 of SEQ ID NO:5; s) an L at a position corresponding to a position 117 of SEQ ID NO:5; NO:5 position 125 corresponding to a K; t) an A at a position corresponding to a position 126 corresponding to a SEQ ID NO:5; u) an H at a position corresponding to a position 135 corresponding to a SEQ ID NO:5; v) a V at a position corresponding to a position 137 corresponding to a SEQ ID NO:5; w) a Y at a position corresponding to a position 138 corresponding to a SEQ ID NO:5; x) an L at a position corresponding to a position 139 corresponding to a SEQ ID NO:5; y) a K or A at a position corresponding to a position 142 corresponding to a SEQ ID NO:5; z) an A, Q, L, or M at a position corresponding to a position 145 corresponding to a SEQ ID NO:5; aa) a K at a position corresponding to a position 148 corresponding to a SEQ ID NO:5; bb) a Q at a position corresponding to a position 151 corresponding to a SEQ ID NO:5; cc) a K at a position corresponding to a position 152 corresponding to a SEQ ID NO:5. NO:5 position 153 corresponding to an E or R; dd) a W at a position corresponding to a position 155 corresponding to a SEQ ID NO:5; ee) an R or V at a position corresponding to a position 156 corresponding to a SEQ ID NO:5; ff) an F at a position corresponding to a position 157 corresponding to a SEQ ID NO:5; gg) an R at a position corresponding to a position 158 corresponding to a SEQ ID NO:5; hh) a Q at a position corresponding to a position 159 corresponding to a SEQ ID NO:5; ii) a D or W at a position corresponding to a position 160 corresponding to a SEQ ID NO:5; jj) a W, H, V, or A at a position corresponding to a position 162 corresponding to a SEQ ID NO:5; kk) an R at a position corresponding to a position 165 corresponding to a SEQ ID NO:5; and ll) an H at a position corresponding to a position 166 corresponding to a SEQ ID NO:5. A system as described in claim 127, wherein the adenine deaminase comprises: a) an N at a position corresponding to position 35 of SEQ ID NO: 5 and a W at a position corresponding to position 162 of SEQ ID NO: 5; b) an N at a position corresponding to position 35 of SEQ ID NO: 5 and a Q at a position corresponding to position 46 of SEQ ID NO: 5; c) an S at a position corresponding to position 81 of SEQ ID NO: 5 and an R at a position corresponding to position 156 of SEQ ID NO: 5; d) a Q at a position corresponding to position 46 of SEQ ID NO: 5 and an R at a position corresponding to position 156 of SEQ ID NO: 5; e) an R at a position corresponding to position 156 of SEQ ID NO: 5 and a W at a position corresponding to position 162 of SEQ ID NO: 5; f) an A at a position corresponding to position 68 of SEQ ID NO: 5 and a 162 of SEQ ID NO:5; i) a W at a position corresponding to position 155 of SEQ ID NO:5, a R at a position corresponding to position 156 of SEQ ID NO:5, and a W at a position corresponding to position 162 of SEQ ID NO:5; j) a N at a position corresponding to position 35 of SEQ ID NO:5, a Q at a position corresponding to position 46 of SEQ ID NO:5, and a W at a position corresponding to position 162 of SEQ ID NO:5; NO:5 position 162 corresponding to a W; k) a N at a position corresponding to a position 35 of SEQ ID NO:5, a S at a position corresponding to a position 81 of SEQ ID NO:5, a R at a position corresponding to a position 156 of SEQ ID NO:5, and a W at a position corresponding to a position 162 of SEQ ID NO:5; l) a M at a position corresponding to a position 68 of SEQ ID NO:5, a H at a position corresponding to a position 108 of SEQ ID NO:5, a R at a position corresponding to a position 156 of SEQ ID NO:5, and a W at a position corresponding to a position 162 of SEQ ID NO:5; m) a Q at a position corresponding to a position 46 of SEQ ID NO:5, a M at a position corresponding to a position 68 of SEQ ID NO:5, a H at a position corresponding to a position 108 of SEQ ID NO:5, a NO:5 position 156 corresponding to an R, and a position corresponding to position 162 corresponding to SEQ ID NO:5; n) a M at a position corresponding to position 68 of SEQ ID NO:5, a S at a position corresponding to position 81 of SEQ ID NO:5, a H at a position corresponding to position 108 of SEQ ID NO:5, a R at a position corresponding to position 156 of SEQ ID NO:5, and a W at a position corresponding to position 162 of SEQ ID NO:5; o) a Q at a position corresponding to position 46 of SEQ ID NO:5, a N at a position corresponding to position 35, a M at a position corresponding to position 68 of SEQ ID NO:5, a S at a position corresponding to position 81 of SEQ ID NO:5, a H at a position corresponding to position 108 of SEQ ID NO:5, a W at a position corresponding to position 155 of SEQ ID NO:5, and a W at a position corresponding to position 162 of SEQ ID NO:5; NO: 5 position 156 corresponding to an R, and a position corresponding to a W corresponding to a position 162 of SEQ ID NO: 5; p) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and a W at a position corresponding to a position 155 of SEQ ID NO: 5; q) a W at a position corresponding to a position 75 of SEQ ID NO: 5, and an S at a position corresponding to a position 81 of SEQ ID NO: 5; r) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and a D at a position corresponding to a position 160 of SEQ ID NO: 5; s) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and an A at a position corresponding to a position 145 of SEQ ID NO: 5; t) a W at a position corresponding to a position 75 of SEQ ID NO: 5, and a W at a position corresponding to a position 155 of SEQ ID NO: 5; u) a W at a position corresponding to position 155 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; v) an A at a position corresponding to position 145 of SEQ ID NO: 5, and a W at a position corresponding to position 155 of SEQ ID NO: 5; w) a W at a position corresponding to position 75 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; x) a W at a position corresponding to position 75 of SEQ ID NO: 5, and an A at a position corresponding to position 145 of SEQ ID NO: 5; y) an A at a position corresponding to position 145 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; z) a W at a position corresponding to position 75 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5 NO:5 position 81 corresponding to an S, and a position corresponding to a W corresponding to a position 155 of SEQ ID NO:5; aa) an S at a position corresponding to a S, a W at a position corresponding to a W, and a D at a position corresponding to a position 160 of SEQ ID NO:5; bb) an S at a position corresponding to a S, a A at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 155 of SEQ ID NO:5; cc) a W at a position corresponding to a W, a S at a position corresponding to a S, and a D at a position corresponding to a position 160 of SEQ ID NO:5; dd) a W at a position corresponding to a W, a A at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 155 of SEQ ID NO:5; NO:5 position 81 corresponding to an S, and a position corresponding to a position 145 corresponding to SEQ ID NO:5; ee) an S at a position corresponding to a position 81 corresponding to SEQ ID NO:5, an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5; ff) a W at a position corresponding to a position 75 corresponding to SEQ ID NO:5, a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5; gg) a W at a position corresponding to a position 75 corresponding to SEQ ID NO:5, an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, and a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5; hh) an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5. NO:5 position 155 corresponding to a W, and a position corresponding to a D at a position corresponding to a position 160 of SEQ ID NO:5; ii) a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a NO:5 position 155 corresponding to a W; ll) a S at a position corresponding to the 81st position of SEQ ID NO:5, an A at a position corresponding to the 145th position of SEQ ID NO:5, a W at a position corresponding to the 155th position of SEQ ID NO:5, and a D at a position corresponding to the 160th position of SEQ ID NO:5; mm) a W at a position corresponding to the 75th position of SEQ ID NO:5, an S at a position corresponding to the 81st position of SEQ ID NO:5, an A at a position corresponding to the 145th position of SEQ ID NO:5, and a D at a position corresponding to the 160th position of SEQ ID NO:5; nn) a W at a position corresponding to the 75th position of SEQ ID NO:5, an A at a position corresponding to the 145th position of SEQ ID NO:5, a W at a position corresponding to the 155th position of SEQ ID NO:5, and a D at a position corresponding to the 160th position of SEQ ID NO:5. NO:5 position 160 corresponding to a D; oo) a W at a position corresponding to a W at a position corresponding to a S ... an L at a position corresponding to position 40 of SEQ ID NO: 5, and a Q at a position corresponding to position 159 of SEQ ID NO: 5; tt) an L at a position corresponding to position 40 of SEQ ID NO: 5, and a W at a position corresponding to position 160 of SEQ ID NO: 5; uu) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a V at a position corresponding to position 121 of SEQ ID NO: 5; vv) an M at a position corresponding to position 105 of SEQ ID NO: 5, and an M at a position corresponding to position 145 of SEQ ID NO: 5; ww) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a Q at a position corresponding to position 159 of SEQ ID NO: 5; xx) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a V at a position corresponding to position 121 of SEQ ID NO: 5; NO:5, a W at a position corresponding to position 160; yy) a V at a position corresponding to position 121 of SEQ ID NO:5, and an M at a position corresponding to position 145 of SEQ ID NO:5; zz) a V at a position corresponding to position 121 of SEQ ID NO:5, and a Q at a position corresponding to position 159 of SEQ ID NO:5; aaa) a V at a position corresponding to position 121 of SEQ ID NO:5, and a W at a position corresponding to position 160 of SEQ ID NO:5; bbb) an M at a position corresponding to position 145 of SEQ ID NO:5, and a Q at a position corresponding to position 159 of SEQ ID NO:5; ccc) an M at a position corresponding to position 145 of SEQ ID NO:5, and a W at a position corresponding to position 160 of SEQ ID NO:5; ddd) a NO:5 position 159 corresponding to a Q, and a W corresponding to a position 160 corresponding to a W; eee) a S at a position corresponding to a position 81 of SEQ ID NO:5, a M at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 160 of SEQ ID NO:5; fff) a S at a position corresponding to a position 81 of SEQ ID NO:5, a V at a position corresponding to a position 121 of SEQ ID NO:5, and a Q at a position corresponding to a position 159 of SEQ ID NO:5; ggg) an A at a position corresponding to a position 68 of SEQ ID NO:5, and a S at a position corresponding to a position 81 of SEQ ID NO:5; hhh) a G at a position corresponding to a position 76 of SEQ ID NO:5, and a S at a position corresponding to a position 81 of SEQ ID NO:5; iii) an S at a position corresponding to position 81 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; jjj) an A at a position corresponding to position 68 of SEQ ID NO: 5, and a G at a position corresponding to position 76 of SEQ ID NO: 5; kkk) an A at a position corresponding to position 68 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; lll) a G at a position corresponding to position 76 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; mmm) an A at a position corresponding to position 68 of SEQ ID NO: 5, a G at a position corresponding to position 76 of SEQ ID NO: 5, and an S at a position corresponding to position 81 of SEQ ID NO: 5; nnn) a G at a position corresponding to position 68 of SEQ ID NO: 5, and an S at a position corresponding to position 81 of SEQ ID NO: 5; NO:5 position 68 corresponding to an A, a position corresponding to an S, and a position corresponding to an L in a position corresponding to a position 117 of SEQ ID NO:5; ooo) a G at a position corresponding to a position 76 of SEQ ID NO:5, a S at a position corresponding to a position 81 of SEQ ID NO:5, and a L in a position corresponding to a position 117 of SEQ ID NO:5; ppp) an A at a position corresponding to a position 68 of SEQ ID NO:5, a G at a position corresponding to a position 76 of SEQ ID NO:5, and a L in a position corresponding to a position 117 of SEQ ID NO:5; qqq) an A at a position corresponding to a position 68 of SEQ ID NO:5, a G at a position corresponding to a position 76 of SEQ ID NO:5, a S at a position corresponding to a position 81 of SEQ ID NO:5, and a L in a position corresponding to a position 117 of SEQ ID NO:5 NO:5 position 117 - L; rrr) SEQ ID NO:5 position 81 - S, SEQ ID NO:5 position 109 - L, SEQ ID NO:5 position 153 - E, SEQ ID NO:5 position 155 - W, and SEQ ID NO:5 position 160 - D; sss) SEQ ID NO:5 position 75 - A, SEQ ID NO:5 position 81 - S, SEQ ID NO:5 position 117 - L, SEQ ID NO:5 position 121 - A, SEQ ID NO:5 position 145 - A, SEQ ID NO:5 position 155 - W, and SEQ ID NO:5 position 160 - D; NO:5 position 160 corresponding to a D; ttt) a Q at a position corresponding to a position 75 of SEQ ID NO:5, an S at a position corresponding to a position 81 of SEQ ID NO:5, an I at a position corresponding to a position 117 of SEQ ID NO:5, a Q at a position corresponding to a position 145 of SEQ ID NO:5, a W at a position corresponding to a position 155 of SEQ ID NO:5, and a D at a position corresponding to a position 160 of SEQ ID NO:5; uuu) a Y at a position corresponding to a position 75 of SEQ ID NO:5, an S at a position corresponding to a position 81 of SEQ ID NO:5, an L at a position corresponding to a position 117 of SEQ ID NO:5, a G at a position corresponding to a position 121 of SEQ ID NO:5, an L at a position corresponding to a position 145 of SEQ ID NO:5, a NO:5 position 155 corresponding to a W, and a D corresponding to a position 160 corresponding to a D of SEQ ID NO:5; vvv) a C corresponding to a position 22 corresponding to a position 68 corresponding to a position 75 corresponding to a Y of SEQ ID NO:5, a G corresponding to a position 76 corresponding to a position 81 corresponding to a S of SEQ ID NO:5, a H corresponding to a position 108 corresponding to a position 117 corresponding to a L of SEQ ID NO:5, a H corresponding to a position 122 corresponding to a position 138 corresponding to a Y of SEQ ID NO:5, a L corresponding to a position 139 corresponding to a L of SEQ ID NO:5, a H corresponding to a position 140 corresponding to a position 141 corresponding to a position 142 corresponding to a position 143 corresponding to a position 147 corresponding to a position 149 corresponding to a position 150 corresponding to a position 151 corresponding to a position 152 corresponding to a position 153 corresponding to a position 154 corresponding to a position 156 corresponding to a position 157 corresponding to a position 158 corresponding to a position 15 ... NO:5 position 142 corresponding to an A, SEQ ID NO:5 position 145 corresponding to an A, SEQ ID NO:5 position 153 corresponding to an R, SEQ ID NO:5 position 155 corresponding to a W, SEQ ID NO:5 position 156 corresponding to an R, SEQ ID NO:5 position 160 corresponding to a D, and SEQ ID NO:5 position 162 corresponding to an H; or www) SEQ ID NO:5 position 81 corresponding to an S. The system of claim 127 or claim 128, wherein the deaminase has an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 300-414, 596-598, and 720-723. The system of claim 127 or claim 128, wherein the deaminase has the amino acid sequence shown in any one of SEQ ID NOs: 300-414, 596-598, and 720-723. A system as described in claim 127 or claim 128, wherein the fusion protein is selected from the group consisting of: a) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 375 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; b) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 375 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 52; c) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 319 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: ID NO: 50 having an amino acid sequence with at least 90% sequence identity after an amino acid position corresponding to position 922 of SEQ ID NO: 2; d) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 319 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 52; e) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 375 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 49; f) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 319 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 52; NO:375 has an amino acid sequence with at least 90% sequence identity and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; g) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:319 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; h) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:597 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; i) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 319 and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; j) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 406 and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; k) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; NO: 2 after an amino acid position corresponding to position 678; l) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 596 and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; m) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 406 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 52; n) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: NO:52 has an amino acid sequence with at least 90% sequence identity after the amino acid position corresponding to position 910 of SEQ ID NO:4; o) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; p) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:596 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:52; q) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; NO:596 has an amino acid sequence with at least 90% sequence identity and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; r) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:406 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; s) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:596 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; and t) A fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49. A system as described in claim 127 or claim 128, a) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 375 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having the amino acid sequence shown in SEQ ID NO: 50; a) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 375 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having the amino acid sequence shown in SEQ ID NO: 52; b) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 319 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having the amino acid sequence shown in SEQ ID NO: 50; c) A fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 319 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having the amino acid sequence shown in SEQ ID NO: 52; d) A fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 375 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having the amino acid sequence shown in SEQ ID NO: 49; e) A fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 375 and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having the amino acid sequence shown in SEQ ID NO: 50; f) A fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 376 and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having the amino acid sequence shown in SEQ ID NO: 50; NO:319 and inserted after an amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having the amino acid sequence as shown in SEQ ID NO:49; g) a fusion protein, wherein the deaminase has the amino acid sequence as shown in SEQ ID NO:597 and inserted after an amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having the amino acid sequence as shown in SEQ ID NO:50; h) a fusion protein, wherein the deaminase has the amino acid sequence as shown in SEQ ID NO:319 and inserted after an amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having the amino acid sequence as shown in SEQ ID NO:50; i) a fusion protein, wherein the deaminase has the amino acid sequence as shown in SEQ ID NO:406 and inserted after an amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having the amino acid sequence as shown in SEQ ID NO:50; NO:50 after an amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:597; j) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:597 and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:50; k) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:596 and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:50; l) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:406 and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:52; NO:4 after an amino acid position corresponding to position 910; m) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:597 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having the amino acid sequence shown in SEQ ID NO:52; n) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:406 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:50; o) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:596 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having the amino acid sequence shown in SEQ ID NO:52; p) A fusion protein, wherein the deaminase has the amino acid sequence as shown in SEQ ID NO: 596 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having the amino acid sequence as shown in SEQ ID NO: 50; q) A fusion protein, wherein the deaminase has the amino acid sequence as shown in SEQ ID NO: 406 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having the amino acid sequence as shown in SEQ ID NO: 49; r) A fusion protein, wherein the deaminase has the amino acid sequence as shown in SEQ ID NO: 596 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having the amino acid sequence as shown in SEQ ID NO: 49; and s) A fusion protein, wherein the deaminase has the amino acid sequence as shown in SEQ ID NO: The amino acid sequence shown in SEQ ID NO: 597 is inserted after an amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having the amino acid sequence shown in SEQ ID NO: 49. The system of claim 132, wherein the fusion protein has the sequence shown in any one of SEQ ID NOs: 599, 600, 602, 603, 606, 610, 612, 614, 615, 617, 619-624, 626, and 630-632. A method as described in claim 88, wherein the adenine deaminase comprises an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 5, and at least one of the following amino acid residues: a) a C at a position corresponding to position 2 of SEQ ID NO: 5; b) an F or C at a position corresponding to position 22 of SEQ ID NO: 5; c) a Q at a position corresponding to position 23 of SEQ ID NO: 5; d) an N at a position corresponding to position 35 of SEQ ID NO: 5; e) an L at a position corresponding to position 40 of SEQ ID NO: 5; f) a Q at a position corresponding to position 46 of SEQ ID NO: 5; g) an A or M at a position corresponding to position 68 of SEQ ID NO: 5; h) an H at a position corresponding to position 72 of SEQ ID NO: 5; i) an N at a position corresponding to position 35 of SEQ ID NO: 5; e) an L at a position corresponding to position 40 of SEQ ID NO: 5; f) a Q at a position corresponding to position 46 of SEQ ID NO: 5; g) an A or M at a position corresponding to position 68 of SEQ ID NO: 5; h) an H at a position corresponding to position 72 of SEQ ID NO: 5; i) an N at a position corresponding to position 35 of SEQ ID NO: 5; NO:5 position 75 corresponding to a W, A, Q, Y, or D; j) a G at a position corresponding to a position 76 corresponding to a position 81 corresponding to a position 81 of SEQ ID NO:5; l) an M at a position corresponding to a position 105 of SEQ ID NO:5; m) an H at a position corresponding to a position 108 of SEQ ID NO:5; n) an L at a position corresponding to a position 109 of SEQ ID NO:5; o) an I or L at a position corresponding to a position 117 of SEQ ID NO:5; p) an F at a position corresponding to a position 120 of SEQ ID NO:5; q) an E, T, A, G, or V at a position corresponding to a position 121 of SEQ ID NO:5; r) an I or H at a position corresponding to a position 122 of SEQ ID NO:5; s) an L at a position corresponding to a position 117 of SEQ ID NO:5; NO:5 position 125 corresponding to a K; t) an A at a position corresponding to a position 126 corresponding to a SEQ ID NO:5; u) an H at a position corresponding to a position 135 corresponding to a SEQ ID NO:5; v) a V at a position corresponding to a position 137 corresponding to a SEQ ID NO:5; w) a Y at a position corresponding to a position 138 corresponding to a SEQ ID NO:5; x) an L at a position corresponding to a position 139 corresponding to a SEQ ID NO:5; y) a K or A at a position corresponding to a position 142 corresponding to a SEQ ID NO:5; z) an A, Q, L, or M at a position corresponding to a position 145 corresponding to a SEQ ID NO:5; aa) a K at a position corresponding to a position 148 corresponding to a SEQ ID NO:5; bb) a Q at a position corresponding to a position 151 corresponding to a SEQ ID NO:5; cc) a K at a position corresponding to a position 152 corresponding to a SEQ ID NO:5. NO:5 position 153 corresponding to an E or R; dd) a W at a position corresponding to a position 155 corresponding to a SEQ ID NO:5; ee) an R or V at a position corresponding to a position 156 corresponding to a SEQ ID NO:5; ff) an F at a position corresponding to a position 157 corresponding to a SEQ ID NO:5; gg) an R at a position corresponding to a position 158 corresponding to a SEQ ID NO:5; hh) a Q at a position corresponding to a position 159 corresponding to a SEQ ID NO:5; ii) a D or W at a position corresponding to a position 160 corresponding to a SEQ ID NO:5; jj) a W, H, V, or A at a position corresponding to a position 162 corresponding to a SEQ ID NO:5; kk) an R at a position corresponding to a position 165 corresponding to a SEQ ID NO:5; and ll) an H at a position corresponding to a position 166 corresponding to a SEQ ID NO:5. A method as described in claim 134, wherein the adenine deaminase comprises: a) an N at a position corresponding to position 35 of SEQ ID NO: 5 and a W at a position corresponding to position 162 of SEQ ID NO: 5; b) an N at a position corresponding to position 35 of SEQ ID NO: 5 and a Q at a position corresponding to position 46 of SEQ ID NO: 5; c) an S at a position corresponding to position 81 of SEQ ID NO: 5 and an R at a position corresponding to position 156 of SEQ ID NO: 5; d) a Q at a position corresponding to position 46 of SEQ ID NO: 5 and an R at a position corresponding to position 156 of SEQ ID NO: 5; e) an R at a position corresponding to position 156 of SEQ ID NO: 5 and a W at a position corresponding to position 162 of SEQ ID NO: 5; f) an A at a position corresponding to position 68 of SEQ ID NO: 5 and a NO:5 position 81 corresponding to an S; g) an N at a position corresponding to the 35th position of SEQ ID NO:5, an S at a position corresponding to the 81st position of SEQ ID NO:5, and a W at a position corresponding to the 162nd position of SEQ ID NO:5; h) an N at a position corresponding to the 35th position of SEQ ID NO:5, a Q at a position corresponding to the 46th position of SEQ ID NO:5, and a W at a position corresponding to the 162nd position of SEQ ID NO:5; i) a W at a position corresponding to the 155th position of SEQ ID NO:5, an R at a position corresponding to the 156th position of SEQ ID NO:5, and a W at a position corresponding to the 162nd position of SEQ ID NO:5; j) an N at a position corresponding to the 35th position of SEQ ID NO:5, an R at a position corresponding to the 156th position of SEQ ID NO:5, and a W at a position corresponding to the 162nd position of SEQ ID NO:5 NO:5 position 162 corresponding to a W; k) a N at a position corresponding to a position 35 of SEQ ID NO:5, a S at a position corresponding to a position 81 of SEQ ID NO:5, a R at a position corresponding to a position 156 of SEQ ID NO:5, and a W at a position corresponding to a position 162 of SEQ ID NO:5; l) a M at a position corresponding to a position 68 of SEQ ID NO:5, a H at a position corresponding to a position 108 of SEQ ID NO:5, a R at a position corresponding to a position 156 of SEQ ID NO:5, and a W at a position corresponding to a position 162 of SEQ ID NO:5; m) a Q at a position corresponding to a position 46 of SEQ ID NO:5, a M at a position corresponding to a position 68 of SEQ ID NO:5, a H at a position corresponding to a position 108 of SEQ ID NO:5, a NO:5 position 156 corresponding to an R, and a position corresponding to position 162 corresponding to SEQ ID NO:5; n) a M at a position corresponding to position 68 of SEQ ID NO:5, a S at a position corresponding to position 81 of SEQ ID NO:5, a H at a position corresponding to position 108 of SEQ ID NO:5, a R at a position corresponding to position 156 of SEQ ID NO:5, and a W at a position corresponding to position 162 of SEQ ID NO:5; o) a Q at a position corresponding to position 46 of SEQ ID NO:5, a N at a position corresponding to position 35, a M at a position corresponding to position 68 of SEQ ID NO:5, a S at a position corresponding to position 81 of SEQ ID NO:5, a H at a position corresponding to position 108 of SEQ ID NO:5, a W at a position corresponding to position 155 of SEQ ID NO:5, and a W at a position corresponding to position 162 of SEQ ID NO:5; NO: 5 position 156 corresponding to an R, and a position corresponding to a W corresponding to a position 162 of SEQ ID NO: 5; p) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and a W at a position corresponding to a position 155 of SEQ ID NO: 5; q) a W at a position corresponding to a position 75 of SEQ ID NO: 5, and an S at a position corresponding to a position 81 of SEQ ID NO: 5; r) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and a D at a position corresponding to a position 160 of SEQ ID NO: 5; s) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and an A at a position corresponding to a position 145 of SEQ ID NO: 5; t) a W at a position corresponding to a position 75 of SEQ ID NO: 5, and a W at a position corresponding to a position 155 of SEQ ID NO: 5; u) a W at a position corresponding to position 155 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; v) an A at a position corresponding to position 145 of SEQ ID NO: 5, and a W at a position corresponding to position 155 of SEQ ID NO: 5; w) a W at a position corresponding to position 75 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; x) a W at a position corresponding to position 75 of SEQ ID NO: 5, and an A at a position corresponding to position 145 of SEQ ID NO: 5; y) an A at a position corresponding to position 145 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; z) a W at a position corresponding to position 75 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5 NO:5 position 81 corresponding to an S, and a position corresponding to a W corresponding to a position 155 of SEQ ID NO:5; aa) an S at a position corresponding to a S, a W at a position corresponding to a W, and a D at a position corresponding to a position 160 of SEQ ID NO:5; bb) an S at a position corresponding to a S, a A at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 155 of SEQ ID NO:5; cc) a W at a position corresponding to a W, a S at a position corresponding to a S, and a D at a position corresponding to a position 160 of SEQ ID NO:5; dd) a W at a position corresponding to a W, a A at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 155 of SEQ ID NO:5; NO:5 position 81 corresponding to an S, and a position corresponding to a position 145 corresponding to SEQ ID NO:5; ee) an S at a position corresponding to a position 81 corresponding to SEQ ID NO:5, an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5; ff) a W at a position corresponding to a position 75 corresponding to SEQ ID NO:5, a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5; gg) a W at a position corresponding to a position 75 corresponding to SEQ ID NO:5, an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, and a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5; hh) an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5. NO:5 position 155 corresponding to a W, and a position corresponding to a D at a position corresponding to a position 160 of SEQ ID NO:5; ii) a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a NO:5 position 155 corresponding to a W; ll) a S at a position corresponding to the 81st position of SEQ ID NO:5, an A at a position corresponding to the 145th position of SEQ ID NO:5, a W at a position corresponding to the 155th position of SEQ ID NO:5, and a D at a position corresponding to the 160th position of SEQ ID NO:5; mm) a W at a position corresponding to the 75th position of SEQ ID NO:5, an S at a position corresponding to the 81st position of SEQ ID NO:5, an A at a position corresponding to the 145th position of SEQ ID NO:5, and a D at a position corresponding to the 160th position of SEQ ID NO:5; nn) a W at a position corresponding to the 75th position of SEQ ID NO:5, an A at a position corresponding to the 145th position of SEQ ID NO:5, a W at a position corresponding to the 155th position of SEQ ID NO:5, and a D at a position corresponding to the 160th position of SEQ ID NO:5; NO:5 position 160 corresponding to a D; oo) a W at a position corresponding to a W at a position corresponding to a S ... an L at a position corresponding to position 40 of SEQ ID NO: 5, and a Q at a position corresponding to position 159 of SEQ ID NO: 5; tt) an L at a position corresponding to position 40 of SEQ ID NO: 5, and a W at a position corresponding to position 160 of SEQ ID NO: 5; uu) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a V at a position corresponding to position 121 of SEQ ID NO: 5; vv) an M at a position corresponding to position 105 of SEQ ID NO: 5, and an M at a position corresponding to position 145 of SEQ ID NO: 5; ww) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a Q at a position corresponding to position 159 of SEQ ID NO: 5; xx) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a V at a position corresponding to position 121 of SEQ ID NO: 5; NO:5, a W at a position corresponding to position 160; yy) a V at a position corresponding to position 121 of SEQ ID NO:5, and an M at a position corresponding to position 145 of SEQ ID NO:5; zz) a V at a position corresponding to position 121 of SEQ ID NO:5, and a Q at a position corresponding to position 159 of SEQ ID NO:5; aaa) a V at a position corresponding to position 121 of SEQ ID NO:5, and a W at a position corresponding to position 160 of SEQ ID NO:5; bbb) an M at a position corresponding to position 145 of SEQ ID NO:5, and a Q at a position corresponding to position 159 of SEQ ID NO:5; ccc) an M at a position corresponding to position 145 of SEQ ID NO:5, and a W at a position corresponding to position 160 of SEQ ID NO:5; ddd) a NO:5 position 159 corresponding to a Q, and a W corresponding to a position 160 corresponding to a W; eee) a S at a position corresponding to a position 81 of SEQ ID NO:5, a M at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 160 of SEQ ID NO:5; fff) a S at a position corresponding to a position 81 of SEQ ID NO:5, a V at a position corresponding to a position 121 of SEQ ID NO:5, and a Q at a position corresponding to a position 159 of SEQ ID NO:5; ggg) an A at a position corresponding to a position 68 of SEQ ID NO:5, and a S at a position corresponding to a position 81 of SEQ ID NO:5; hhh) a G at a position corresponding to a position 76 of SEQ ID NO:5, and a S at a position corresponding to a position 81 of SEQ ID NO:5; iii) an S at a position corresponding to position 81 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; jjj) an A at a position corresponding to position 68 of SEQ ID NO: 5, and a G at a position corresponding to position 76 of SEQ ID NO: 5; kkk) an A at a position corresponding to position 68 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; lll) a G at a position corresponding to position 76 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; mmm) an A at a position corresponding to position 68 of SEQ ID NO: 5, a G at a position corresponding to position 76 of SEQ ID NO: 5, and an S at a position corresponding to position 81 of SEQ ID NO: 5; nnn) a G at a position corresponding to position 68 of SEQ ID NO: 5, and an S at a position corresponding to position 81 of SEQ ID NO: 5; NO:5 position 68 corresponding to an A, a position corresponding to an S, and a position corresponding to an L in a position corresponding to a position 117 of SEQ ID NO:5; ooo) a G at a position corresponding to a position 76 of SEQ ID NO:5, a S at a position corresponding to a position 81 of SEQ ID NO:5, and a L in a position corresponding to a position 117 of SEQ ID NO:5; ppp) an A at a position corresponding to a position 68 of SEQ ID NO:5, a G at a position corresponding to a position 76 of SEQ ID NO:5, and a L in a position corresponding to a position 117 of SEQ ID NO:5; qqq) an A at a position corresponding to a position 68 of SEQ ID NO:5, a G at a position corresponding to a position 76 of SEQ ID NO:5, a S at a position corresponding to a position 81 of SEQ ID NO:5, and a L in a position corresponding to a position 117 of SEQ ID NO:5 NO:5 position 117 - L; rrr) SEQ ID NO:5 position 81 - S, SEQ ID NO:5 position 109 - L, SEQ ID NO:5 position 153 - E, SEQ ID NO:5 position 155 - W, and SEQ ID NO:5 position 160 - D; sss) SEQ ID NO:5 position 75 - A, SEQ ID NO:5 position 81 - S, SEQ ID NO:5 position 117 - L, SEQ ID NO:5 position 121 - A, SEQ ID NO:5 position 145 - A, SEQ ID NO:5 position 155 - W, and SEQ ID NO:5 position 160 - D; NO:5 position 160 corresponding to a D; ttt) a Q at a position corresponding to ... NO:5 position 155 corresponding to a W, and a D corresponding to a position 160 corresponding to a D of SEQ ID NO:5; vvv) a C corresponding to a position 22 corresponding to a position 68 corresponding to a position 75 corresponding to a Y of SEQ ID NO:5, a G corresponding to a position 76 corresponding to a position 81 corresponding to a S of SEQ ID NO:5, a H corresponding to a position 108 corresponding to a position 117 corresponding to a L of SEQ ID NO:5, a H corresponding to a position 122 corresponding to a position 138 corresponding to a Y of SEQ ID NO:5, a L corresponding to a position 139 corresponding to a L of SEQ ID NO:5, a H corresponding to a position 140 corresponding to a position 141 corresponding to a position 142 corresponding to a position 143 corresponding to a position 147 corresponding to a position 149 corresponding to a position 150 corresponding to a position 151 corresponding to a position 152 corresponding to a position 153 corresponding to a position 154 corresponding to a position 156 corresponding to a position 157 corresponding to a position 158 corresponding to a position 15 ... NO:5 position 142 corresponding to an A, SEQ ID NO:5 position 145 corresponding to an A, SEQ ID NO:5 position 153 corresponding to an R, SEQ ID NO:5 position 155 corresponding to a W, SEQ ID NO:5 position 156 corresponding to an R, SEQ ID NO:5 position 160 corresponding to a D, and SEQ ID NO:5 position 162 corresponding to an H; or www) SEQ ID NO:5 position 81 corresponding to an S. The method of claim 134 or claim 135, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 300-414, 596-598, and 720-723. The method of claim 134 or claim 135, wherein the deaminase has the amino acid sequence shown in any one of SEQ ID NOs: 300-414, 596-598, and 720-723. A method as described in claim 134 or claim 135, wherein the fusion protein is selected from the group consisting of: a) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 375 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; b) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 375 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 52; c) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 319 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 52; NO:50 having an amino acid sequence with at least 90% sequence identity after an amino acid position corresponding to position 922 of SEQ ID NO:2; d) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:319 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:52; e) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:375 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; f) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:319 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:52; NO:375 has an amino acid sequence with at least 90% sequence identity and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; g) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:319 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; h) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:597 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; i) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 319 and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; j) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 406 and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; k) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; NO: 2 after an amino acid position corresponding to position 678; l) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 596 and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 50; m) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 406 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 52; n) a fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: NO:52 has an amino acid sequence with at least 90% sequence identity after the amino acid position corresponding to position 910 of SEQ ID NO:4; o) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; p) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:596 and is inserted after the amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:52; q) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:406 and is inserted after the amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; NO:596 has an amino acid sequence with at least 90% sequence identity and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:50; r) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:406 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; s) a fusion protein, wherein the deaminase has an amino acid sequence with at least 90% sequence identity to SEQ ID NO:596 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO:1 in the RGN having an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; and t) A fusion protein, wherein the deaminase has an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49. A method as described in claim 134 or claim 135, wherein the fusion protein is selected from the group consisting of: a) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 375 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having the amino acid sequence shown in SEQ ID NO: 50; b) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 375 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having the amino acid sequence shown in SEQ ID NO: 52; c) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 319 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO: 4 in the RGN having the amino acid sequence shown in SEQ ID NO: 50; NO: 2 after an amino acid position corresponding to position 922; d) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 319 and is inserted in the RGN having the amino acid sequence shown in SEQ ID NO: 52 after an amino acid position corresponding to position 910 of SEQ ID NO: 4; e) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 375 and is inserted in the RGN having the amino acid sequence shown in SEQ ID NO: 49 after an amino acid position corresponding to position 772 of SEQ ID NO: 1; f) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 375 and is inserted in the RGN having the amino acid sequence shown in SEQ ID NO: 50 after an amino acid position corresponding to position 678 of SEQ ID NO: 2; g) a fusion protein, wherein the deaminase has the amino acid sequence as shown in SEQ ID NO: 319 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having the amino acid sequence as shown in SEQ ID NO: 49; h) a fusion protein, wherein the deaminase has the amino acid sequence as shown in SEQ ID NO: 597 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO: 2 in the RGN having the amino acid sequence as shown in SEQ ID NO: 50; i) a fusion protein, wherein the deaminase has the amino acid sequence as shown in SEQ ID NO: 319 and is inserted after an amino acid position corresponding to position 678 of SEQ ID NO: 2 in the RGN having the amino acid sequence as shown in SEQ ID NO: 50; j) a fusion protein, wherein the deaminase has the amino acid sequence as shown in SEQ ID NO: NO:406 and inserted after an amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having the amino acid sequence as shown in SEQ ID NO:50; k) a fusion protein, wherein the deaminase has the amino acid sequence as shown in SEQ ID NO:597 and inserted after an amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having the amino acid sequence as shown in SEQ ID NO:50; l) a fusion protein, wherein the deaminase has the amino acid sequence as shown in SEQ ID NO:596 and inserted after an amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having the amino acid sequence as shown in SEQ ID NO:50; m) a fusion protein, wherein the deaminase has the amino acid sequence as shown in SEQ ID NO:406 and inserted after an amino acid position corresponding to position 678 of SEQ ID NO:2 in the RGN having the amino acid sequence as shown in SEQ ID NO:50; NO:52 after an amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having the amino acid sequence shown in SEQ ID NO:597; n) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:597 and is inserted after an amino acid position corresponding to position 910 of SEQ ID NO:4 in the RGN having the amino acid sequence shown in SEQ ID NO:52; o) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:406 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:50; p) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:596 and is inserted after an amino acid position corresponding to position 922 of SEQ ID NO:2 in the RGN having the amino acid sequence shown in SEQ ID NO:52; NO:4 after an amino acid position corresponding to position 910; q) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:596 and is inserted in the RGN having the amino acid sequence shown in SEQ ID NO:50 after an amino acid position corresponding to position 922 of SEQ ID NO:2; r) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:406 and is inserted in the RGN having the amino acid sequence shown in SEQ ID NO:49 after an amino acid position corresponding to position 772 of SEQ ID NO:1; s) a fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO:596 and is inserted in the RGN having the amino acid sequence shown in SEQ ID NO:49 after an amino acid position corresponding to position 772 of SEQ ID NO:1; and t) A fusion protein, wherein the deaminase has the amino acid sequence shown in SEQ ID NO: 597 and is inserted after an amino acid position corresponding to position 772 of SEQ ID NO: 1 in the RGN having the amino acid sequence shown in SEQ ID NO: 49. The method of claim 139, wherein the fusion protein has the sequence shown in any one of SEQ ID NOs: 599, 600, 602, 603, 606, 610, 612, 614, 615, 617, 619-624, 626, and 630-632. A deaminase comprising an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 5, and at least one of the following amino acid residues: a) a C at a position corresponding to position 2 of SEQ ID NO: 5; b) an F or C at a position corresponding to position 22 of SEQ ID NO: 5; c) a Q at a position corresponding to position 23 of SEQ ID NO: 5; d) an N at a position corresponding to position 35 of SEQ ID NO: 5; e) an L at a position corresponding to position 40 of SEQ ID NO: 5; f) a Q at a position corresponding to position 46 of SEQ ID NO: 5; g) an A or M at a position corresponding to position 68 of SEQ ID NO: 5; h) an H at a position corresponding to position 72 of SEQ ID NO: 5; i) a W, A, Q, Y, or D at a position corresponding to position 75 of SEQ ID NO: 5; j) a G at a position corresponding to position 76 of SEQ ID NO: 5; k) an S at a position corresponding to position 81 of SEQ ID NO: 5; l) an M at a position corresponding to position 105 of SEQ ID NO: 5; m) an H at a position corresponding to position 108 of SEQ ID NO: 5; n) an L at a position corresponding to position 109 of SEQ ID NO: 5; o) an I or L at a position corresponding to position 117 of SEQ ID NO: 5; p) an F at a position corresponding to position 120 of SEQ ID NO: 5; q) an E, T, A, G, or V at a position corresponding to position 121 of SEQ ID NO: 5; r) an I or H at a position corresponding to position 122 of SEQ ID NO: 5; s) a K at a position corresponding to position 125 of SEQ ID NO: 5; t) an F at a position corresponding to position 120 of SEQ ID NO: 5; NO:5 position 126 corresponding to an A; u) an H at a position corresponding to a position 135 corresponding to a position 137 corresponding to a position 138 corresponding to a position 138 of a SEQ ID NO:5; x) an L at a position corresponding to a position 139 of a SEQ ID NO:5; y) a K or an A at a position corresponding to a position 142 of a SEQ ID NO:5; z) an A, Q, L, or M at a position corresponding to a position 145 of a SEQ ID NO:5; aa) a K at a position corresponding to a position 148 of a SEQ ID NO:5; bb) a Q at a position corresponding to a position 151 of a SEQ ID NO:5; cc) an E or R at a position corresponding to a position 153 of a SEQ ID NO:5; dd) a NO:5 position 155 corresponding to a W; ee) a R or V at a position corresponding to a position 156 corresponding to a SEQ ID NO:5; ff) a F at a position corresponding to a position 157 corresponding to a SEQ ID NO:5; gg) a R at a position corresponding to a position 158 corresponding to a SEQ ID NO:5; hh) a Q at a position corresponding to a position 159 corresponding to a SEQ ID NO:5; ii) a D or W at a position corresponding to a position 160 corresponding to a SEQ ID NO:5; jj) a W, H, V, or A at a position corresponding to a position 162 corresponding to a SEQ ID NO:5; kk) a R at a position corresponding to a position 165 corresponding to a SEQ ID NO:5; and ll) a H at a position corresponding to a position 166 corresponding to a SEQ ID NO:5. A deaminase as described in claim 141, wherein the deaminase comprises: a) an N at a position corresponding to position 35 of SEQ ID NO: 5 and a W at a position corresponding to position 162 of SEQ ID NO: 5; b) an N at a position corresponding to position 35 of SEQ ID NO: 5 and a Q at a position corresponding to position 46 of SEQ ID NO: 5; c) an S at a position corresponding to position 81 of SEQ ID NO: 5 and an R at a position corresponding to position 156 of SEQ ID NO: 5; d) a Q at a position corresponding to position 46 of SEQ ID NO: 5 and an R at a position corresponding to position 156 of SEQ ID NO: 5; e) an R at a position corresponding to position 156 of SEQ ID NO: 5 and a W at a position corresponding to position 162 of SEQ ID NO: 5; f) an A at a position corresponding to position 68 of SEQ ID NO: 5 and a NO:5 position 81 corresponding to an S; g) an N at a position corresponding to the 35th position of SEQ ID NO:5, an S at a position corresponding to the 81st position of SEQ ID NO:5, and a W at a position corresponding to the 162nd position of SEQ ID NO:5; h) an N at a position corresponding to the 35th position of SEQ ID NO:5, a Q at a position corresponding to the 46th position of SEQ ID NO:5, and a W at a position corresponding to the 162nd position of SEQ ID NO:5; i) a W at a position corresponding to the 155th position of SEQ ID NO:5, an R at a position corresponding to the 156th position of SEQ ID NO:5, and a W at a position corresponding to the 162nd position of SEQ ID NO:5; j) an N at a position corresponding to the 35th position of SEQ ID NO:5, an R at a position corresponding to the 156th position of SEQ ID NO:5, and a W at a position corresponding to the 162nd position of SEQ ID NO:5 NO:5 position 162 corresponding to a W; k) a N at a position corresponding to a position 35 of SEQ ID NO:5, a S at a position corresponding to a position 81 of SEQ ID NO:5, a R at a position corresponding to a position 156 of SEQ ID NO:5, and a W at a position corresponding to a position 162 of SEQ ID NO:5; l) a M at a position corresponding to a position 68 of SEQ ID NO:5, a H at a position corresponding to a position 108 of SEQ ID NO:5, a R at a position corresponding to a position 156 of SEQ ID NO:5, and a W at a position corresponding to a position 162 of SEQ ID NO:5; m) a Q at a position corresponding to a position 46 of SEQ ID NO:5, a M at a position corresponding to a position 68 of SEQ ID NO:5, a H at a position corresponding to a position 108 of SEQ ID NO:5, a NO:5 position 156 corresponding to an R, and a position corresponding to position 162 corresponding to SEQ ID NO:5; n) a M at a position corresponding to position 68 of SEQ ID NO:5, a S at a position corresponding to position 81 of SEQ ID NO:5, a H at a position corresponding to position 108 of SEQ ID NO:5, a R at a position corresponding to position 156 of SEQ ID NO:5, and a W at a position corresponding to position 162 of SEQ ID NO:5; o) a Q at a position corresponding to position 46 of SEQ ID NO:5, a N at a position corresponding to position 35, a M at a position corresponding to position 68 of SEQ ID NO:5, a S at a position corresponding to position 81 of SEQ ID NO:5, a H at a position corresponding to position 108 of SEQ ID NO:5, a W at a position corresponding to position 155 of SEQ ID NO:5, and a W at a position corresponding to position 162 of SEQ ID NO:5; NO: 5 position 156 corresponding to an R, and a position corresponding to a W corresponding to a position 162 of SEQ ID NO: 5; p) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and a W at a position corresponding to a position 155 of SEQ ID NO: 5; q) a W at a position corresponding to a position 75 of SEQ ID NO: 5, and an S at a position corresponding to a position 81 of SEQ ID NO: 5; r) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and a D at a position corresponding to a position 160 of SEQ ID NO: 5; s) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and an A at a position corresponding to a position 145 of SEQ ID NO: 5; t) a W at a position corresponding to a position 75 of SEQ ID NO: 5, and a W at a position corresponding to a position 155 of SEQ ID NO: 5; u) a W at a position corresponding to position 155 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; v) an A at a position corresponding to position 145 of SEQ ID NO: 5, and a W at a position corresponding to position 155 of SEQ ID NO: 5; w) a W at a position corresponding to position 75 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; x) a W at a position corresponding to position 75 of SEQ ID NO: 5, and an A at a position corresponding to position 145 of SEQ ID NO: 5; y) an A at a position corresponding to position 145 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; z) a W at a position corresponding to position 75 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5 NO:5 position 81 corresponding to an S, and a position corresponding to a W corresponding to a position 155 of SEQ ID NO:5; aa) an S at a position corresponding to a S, a W at a position corresponding to a W, and a D at a position corresponding to a position 160 of SEQ ID NO:5; bb) an S at a position corresponding to a S, a A at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 155 of SEQ ID NO:5; cc) a W at a position corresponding to a W, a S at a position corresponding to a S, and a D at a position corresponding to a position 160 of SEQ ID NO:5; dd) a W at a position corresponding to a W, a A at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 155 of SEQ ID NO:5; NO:5 position 81 corresponding to an S, and a position corresponding to a position 145 corresponding to SEQ ID NO:5; ee) an S at a position corresponding to a position 81 corresponding to SEQ ID NO:5, an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5; ff) a W at a position corresponding to a position 75 corresponding to SEQ ID NO:5, a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5; gg) a W at a position corresponding to a position 75 corresponding to SEQ ID NO:5, an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, and a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5; hh) an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5. NO:5 position 155 corresponding to a W, and a position corresponding to a D at a position corresponding to a position 160 of SEQ ID NO:5; ii) a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a NO:5 position 155 corresponding to a W; ll) a S at a position corresponding to the 81st position of SEQ ID NO:5, an A at a position corresponding to the 145th position of SEQ ID NO:5, a W at a position corresponding to the 155th position of SEQ ID NO:5, and a D at a position corresponding to the 160th position of SEQ ID NO:5; mm) a W at a position corresponding to the 75th position of SEQ ID NO:5, an S at a position corresponding to the 81st position of SEQ ID NO:5, an A at a position corresponding to the 145th position of SEQ ID NO:5, and a D at a position corresponding to the 160th position of SEQ ID NO:5; nn) a W at a position corresponding to the 75th position of SEQ ID NO:5, an A at a position corresponding to the 145th position of SEQ ID NO:5, a W at a position corresponding to the 155th position of SEQ ID NO:5, and a D at a position corresponding to the 160th position of SEQ ID NO:5. NO:5 position 160 corresponding to a D; oo) a W at a position corresponding to a W at a position corresponding to a S ... an L at a position corresponding to position 40 of SEQ ID NO: 5, and a Q at a position corresponding to position 159 of SEQ ID NO: 5; tt) an L at a position corresponding to position 40 of SEQ ID NO: 5, and a W at a position corresponding to position 160 of SEQ ID NO: 5; uu) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a V at a position corresponding to position 121 of SEQ ID NO: 5; vv) an M at a position corresponding to position 105 of SEQ ID NO: 5, and an M at a position corresponding to position 145 of SEQ ID NO: 5; ww) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a Q at a position corresponding to position 159 of SEQ ID NO: 5; xx) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a V at a position corresponding to position 121 of SEQ ID NO: 5; NO:5, a W at a position corresponding to position 160; yy) a V at a position corresponding to position 121 of SEQ ID NO:5, and an M at a position corresponding to position 145 of SEQ ID NO:5; zz) a V at a position corresponding to position 121 of SEQ ID NO:5, and a Q at a position corresponding to position 159 of SEQ ID NO:5; aaa) a V at a position corresponding to position 121 of SEQ ID NO:5, and a W at a position corresponding to position 160 of SEQ ID NO:5; bbb) an M at a position corresponding to position 145 of SEQ ID NO:5, and a Q at a position corresponding to position 159 of SEQ ID NO:5; ccc) an M at a position corresponding to position 145 of SEQ ID NO:5, and a W at a position corresponding to position 160 of SEQ ID NO:5; ddd) a NO:5 position 159 corresponding to a Q, and a W corresponding to a position 160 corresponding to a W; eee) a S at a position corresponding to a position 81 of SEQ ID NO:5, a M at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 160 of SEQ ID NO:5; fff) a S at a position corresponding to a position 81 of SEQ ID NO:5, a V at a position corresponding to a position 121 of SEQ ID NO:5, and a Q at a position corresponding to a position 159 of SEQ ID NO:5; ggg) an A at a position corresponding to a position 68 of SEQ ID NO:5, and a S at a position corresponding to a position 81 of SEQ ID NO:5; hhh) a G at a position corresponding to a position 76 of SEQ ID NO:5, and a S at a position corresponding to a position 81 of SEQ ID NO:5; iii) an S at a position corresponding to position 81 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; jjj) an A at a position corresponding to position 68 of SEQ ID NO: 5, and a G at a position corresponding to position 76 of SEQ ID NO: 5; kkk) an A at a position corresponding to position 68 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; lll) a G at a position corresponding to position 76 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; mmm) an A at a position corresponding to position 68 of SEQ ID NO: 5, a G at a position corresponding to position 76 of SEQ ID NO: 5, and an S at a position corresponding to position 81 of SEQ ID NO: 5; nnn) a G at a position corresponding to position 68 of SEQ ID NO: 5, and an S at a position corresponding to position 81 of SEQ ID NO: 5; NO:5 position 68 corresponding to an A, a position corresponding to an S, and a position corresponding to an L in a position corresponding to a position 117 of SEQ ID NO:5; ooo) a G at a position corresponding to a position 76 of SEQ ID NO:5, a S at a position corresponding to a S, and a L in a position corresponding to a position 117 of SEQ ID NO:5; ppp) an A at a position corresponding to a position 68 of SEQ ID NO:5, a G at a position corresponding to a position 76 of SEQ ID NO:5, and a L in a position corresponding to a position 117 of SEQ ID NO:5; qqq) an A at a position corresponding to a position 68 of SEQ ID NO:5, a G at a position corresponding to a position 76 of SEQ ID NO:5, a S at a position corresponding to a position 81 of SEQ ID NO:5, and a L in a position corresponding to a position 117 of SEQ ID NO:5; NO:5 position 117 - L; rrr) SEQ ID NO:5 position 81 - S, SEQ ID NO:5 position 109 - L, SEQ ID NO:5 position 153 - E, SEQ ID NO:5 position 155 - W, and SEQ ID NO:5 position 160 - D; sss) SEQ ID NO:5 position 75 - A, SEQ ID NO:5 position 81 - S, SEQ ID NO:5 position 117 - L, SEQ ID NO:5 position 121 - A, SEQ ID NO:5 position 145 - A, SEQ ID NO:5 position 155 - W, and SEQ ID NO:5 position 160 - D; NO:5 position 160 corresponding to a D; ttt) a Q at a position corresponding to ... NO:5 position 155 corresponding to a W, and a D corresponding to a position 160 corresponding to a D of SEQ ID NO:5; vvv) a C corresponding to a position 22 corresponding to a position 68 corresponding to a position 75 corresponding to a Y of SEQ ID NO:5, a G corresponding to a position 76 corresponding to a position 81 corresponding to a S of SEQ ID NO:5, a H corresponding to a position 108 corresponding to a position 117 corresponding to a L of SEQ ID NO:5, a H corresponding to a position 122 corresponding to a position 138 corresponding to a Y of SEQ ID NO:5, a L corresponding to a position 139 corresponding to a L of SEQ ID NO:5, a H corresponding to a position 140 corresponding to a position 141 corresponding to a position 142 corresponding to a position 143 corresponding to a position 147 corresponding to a position 149 corresponding to a position 150 corresponding to a position 151 corresponding to a position 152 corresponding to a position 153 corresponding to a position 154 corresponding to a position 156 corresponding to a position 157 corresponding to a position 158 corresponding to a position 15 ... NO:5 position 142 corresponding to an A, SEQ ID NO:5 position 145 corresponding to an A, SEQ ID NO:5 position 153 corresponding to an R, SEQ ID NO:5 position 155 corresponding to a W, SEQ ID NO:5 position 156 corresponding to an R, SEQ ID NO:5 position 160 corresponding to a D, and SEQ ID NO:5 position 162 corresponding to an H; or www) SEQ ID NO:5 position 81 corresponding to an S. The deaminase of claim 141 or claim 142, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 300-414, 596-598, and 720-723. The deaminase of claim 141 or claim 142, wherein the deaminase comprises an amino acid sequence of any one of SEQ ID NOs: 300-414, 596-598, and 720-723. The deaminase of any one of claims 141 to 144, wherein the deaminase has improved deaminase activity when compared to SEQ ID NO: 5. The deaminase of any one of claims 141 to 145, wherein the deaminase is an adenine deaminase. A nucleic acid molecule comprising a polypeptide encoding a deaminase having at least 85% sequence identity with SEQ ID NO: 5, wherein the deaminase comprises at least one of the following amino acid residues: a) a C at a position corresponding to position 2 of SEQ ID NO: 5; b) an F or C at a position corresponding to position 22 of SEQ ID NO: 5; c) a Q at a position corresponding to position 23 of SEQ ID NO: 5; d) an N at a position corresponding to position 35 of SEQ ID NO: 5; e) an L at a position corresponding to position 40 of SEQ ID NO: 5; f) a Q at a position corresponding to position 46 of SEQ ID NO: 5; g) an A or M at a position corresponding to position 68 of SEQ ID NO: 5; h) an H at a position corresponding to position 72 of SEQ ID NO: 5; i) an N at a position corresponding to position 35 of SEQ ID NO: 5; e) an L at a position corresponding to position 40 of SEQ ID NO: 5; f) a Q at a position corresponding to position 46 of SEQ ID NO: 5; g) an A or M at a position corresponding to position 68 of SEQ ID NO: 5; h) an H at a position corresponding to position 72 of SEQ ID NO: 5; i) an N at a position corresponding to position 35 of SEQ ID NO: 5; NO:5 position 75 corresponding to a W, A, Q, Y, or D; j) a G at a position corresponding to a position 76 corresponding to a position 81 corresponding to a position 81 of SEQ ID NO:5; l) an M at a position corresponding to a position 105 of SEQ ID NO:5; m) an H at a position corresponding to a position 108 of SEQ ID NO:5; n) an L at a position corresponding to a position 109 of SEQ ID NO:5; o) an I or L at a position corresponding to a position 117 of SEQ ID NO:5; p) an F at a position corresponding to a position 120 of SEQ ID NO:5; q) an E, T, A, G, or V at a position corresponding to a position 121 of SEQ ID NO:5; r) an I or H at a position corresponding to a position 122 of SEQ ID NO:5; s) an L at a position corresponding to a position 117 of SEQ ID NO:5; NO:5 position 125 corresponding to a K; t) an A at a position corresponding to a position 126 corresponding to a SEQ ID NO:5; u) an H at a position corresponding to a position 135 corresponding to a SEQ ID NO:5; v) a V at a position corresponding to a position 137 corresponding to a SEQ ID NO:5; w) a Y at a position corresponding to a position 138 corresponding to a SEQ ID NO:5; x) an L at a position corresponding to a position 139 corresponding to a SEQ ID NO:5; y) a K or A at a position corresponding to a position 142 corresponding to a SEQ ID NO:5; z) an A, Q, L, or M at a position corresponding to a position 145 corresponding to a SEQ ID NO:5; aa) a K at a position corresponding to a position 148 corresponding to a SEQ ID NO:5; bb) a Q at a position corresponding to a position 151 corresponding to a SEQ ID NO:5; cc) a K at a position corresponding to a position 152 corresponding to a SEQ ID NO:5. NO:5 position 153 corresponding to an E or R; dd) a W at a position corresponding to a position 155 corresponding to a SEQ ID NO:5; ee) an R or V at a position corresponding to a position 156 corresponding to a SEQ ID NO:5; ff) an F at a position corresponding to a position 157 corresponding to a SEQ ID NO:5; gg) an R at a position corresponding to a position 158 corresponding to a SEQ ID NO:5; hh) a Q at a position corresponding to a position 159 corresponding to a SEQ ID NO:5; ii) a D or W at a position corresponding to a position 160 corresponding to a SEQ ID NO:5; jj) a W, H, V, or A at a position corresponding to a position 162 corresponding to a SEQ ID NO:5; kk) an R at a position corresponding to a position 165 corresponding to a SEQ ID NO:5; and ll) an H at a position corresponding to a position 166 corresponding to a SEQ ID NO:5. A nucleic acid molecule as described in claim 147, wherein the deaminase comprises: a) an N at a position corresponding to position 35 of SEQ ID NO: 5 and a W at a position corresponding to position 162 of SEQ ID NO: 5; b) an N at a position corresponding to position 35 of SEQ ID NO: 5 and a Q at a position corresponding to position 46 of SEQ ID NO: 5; c) an S at a position corresponding to position 81 of SEQ ID NO: 5 and an R at a position corresponding to position 156 of SEQ ID NO: 5; d) a Q at a position corresponding to position 46 of SEQ ID NO: 5 and an R at a position corresponding to position 156 of SEQ ID NO: 5; e) an R at a position corresponding to position 156 of SEQ ID NO: 5 and a W at a position corresponding to position 162 of SEQ ID NO: 5; f) an A at a position corresponding to position 68 of SEQ ID NO: 5 and a NO:5 position 81 corresponding to an S; g) an N at a position corresponding to the 35th position of SEQ ID NO:5, an S at a position corresponding to the 81st position of SEQ ID NO:5, and a W at a position corresponding to the 162nd position of SEQ ID NO:5; h) an N at a position corresponding to the 35th position of SEQ ID NO:5, a Q at a position corresponding to the 46th position of SEQ ID NO:5, and a W at a position corresponding to the 162nd position of SEQ ID NO:5; i) a W at a position corresponding to the 155th position of SEQ ID NO:5, an R at a position corresponding to the 156th position of SEQ ID NO:5, and a W at a position corresponding to the 162nd position of SEQ ID NO:5; j) an N at a position corresponding to the 35th position of SEQ ID NO:5, an R at a position corresponding to the 156th position of SEQ ID NO:5, and a W at a position corresponding to the 162nd position of SEQ ID NO:5 NO:5 position 162 corresponding to a W; k) a N at a position corresponding to a position 35 of SEQ ID NO:5, a S at a position corresponding to a position 81 of SEQ ID NO:5, a R at a position corresponding to a position 156 of SEQ ID NO:5, and a W at a position corresponding to a position 162 of SEQ ID NO:5; l) a M at a position corresponding to a position 68 of SEQ ID NO:5, a H at a position corresponding to a position 108 of SEQ ID NO:5, a R at a position corresponding to a position 156 of SEQ ID NO:5, and a W at a position corresponding to a position 162 of SEQ ID NO:5; m) a Q at a position corresponding to a position 46 of SEQ ID NO:5, a M at a position corresponding to a position 68 of SEQ ID NO:5, a H at a position corresponding to a position 108 of SEQ ID NO:5, a NO:5 position 156 corresponding to an R, and a position corresponding to position 162 corresponding to SEQ ID NO:5; n) a M at a position corresponding to position 68 of SEQ ID NO:5, a S at a position corresponding to position 81 of SEQ ID NO:5, a H at a position corresponding to position 108 of SEQ ID NO:5, a R at a position corresponding to position 156 of SEQ ID NO:5, and a W at a position corresponding to position 162 of SEQ ID NO:5; o) a Q at a position corresponding to position 46 of SEQ ID NO:5, a N at a position corresponding to position 35, a M at a position corresponding to position 68 of SEQ ID NO:5, a S at a position corresponding to position 81 of SEQ ID NO:5, a H at a position corresponding to position 108 of SEQ ID NO:5, a W at a position corresponding to position 155 of SEQ ID NO:5, and a W at a position corresponding to position 162 of SEQ ID NO:5; NO: 5 position 156 corresponding to an R, and a position corresponding to a W corresponding to a position 162 of SEQ ID NO: 5; p) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and a W at a position corresponding to a position 155 of SEQ ID NO: 5; q) a W at a position corresponding to a position 75 of SEQ ID NO: 5, and an S at a position corresponding to a position 81 of SEQ ID NO: 5; r) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and a D at a position corresponding to a position 160 of SEQ ID NO: 5; s) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and an A at a position corresponding to a position 145 of SEQ ID NO: 5; t) a W at a position corresponding to a position 75 of SEQ ID NO: 5, and a W at a position corresponding to a position 155 of SEQ ID NO: 5; u) a W at a position corresponding to position 155 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; v) an A at a position corresponding to position 145 of SEQ ID NO: 5, and a W at a position corresponding to position 155 of SEQ ID NO: 5; w) a W at a position corresponding to position 75 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; x) a W at a position corresponding to position 75 of SEQ ID NO: 5, and an A at a position corresponding to position 145 of SEQ ID NO: 5; y) an A at a position corresponding to position 145 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; z) a W at a position corresponding to position 75 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5 NO:5 position 81 corresponding to an S, and a position corresponding to a W corresponding to a position 155 of SEQ ID NO:5; aa) an S at a position corresponding to a S, a W at a position corresponding to a W, and a D at a position corresponding to a position 160 of SEQ ID NO:5; bb) an S at a position corresponding to a S, a A at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 155 of SEQ ID NO:5; cc) a W at a position corresponding to a W, a S at a position corresponding to a S, and a D at a position corresponding to a position 160 of SEQ ID NO:5; dd) a W at a position corresponding to a W, a A at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 155 of SEQ ID NO:5; NO:5 position 81 corresponding to an S, and a position corresponding to a position 145 corresponding to SEQ ID NO:5; ee) an S at a position corresponding to a position 81 corresponding to SEQ ID NO:5, an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5; ff) a W at a position corresponding to a position 75 corresponding to SEQ ID NO:5, a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5; gg) a W at a position corresponding to a position 75 corresponding to SEQ ID NO:5, an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, and a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5; hh) an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5. NO:5 position 155 corresponding to a W, and a position corresponding to a D at a position corresponding to a position 160 of SEQ ID NO:5; ii) a W at a position corresponding to a position 75 of SEQ ID NO:5, an A at a position corresponding to a position 145 of SEQ ID NO:5, and a D at a position corresponding to a position 160 of SEQ ID NO:5; jj) a W at a position corresponding to a position 75 of SEQ ID NO:5, an S at a position corresponding to a position 81 of SEQ ID NO:5, a W at a position corresponding to a position 155 of SEQ ID NO:5, and a D at a position corresponding to a position 160 of SEQ ID NO:5; kk) a W at a position corresponding to a position 75 of SEQ ID NO:5, an S at a position corresponding to a position 81 of SEQ ID NO:5, an A at a position corresponding to a position 145 of SEQ ID NO:5, and a D at a position corresponding to a position 160 of SEQ ID NO:5 NO:5 position 155 corresponding to a W; ll) a S at a position corresponding to SEQ ID NO:5 position 81, an A at a position corresponding to SEQ ID NO:5 position 145, a W at a position corresponding to SEQ ID NO:5 position 155, and a D at a position corresponding to SEQ ID NO:5 position 160; mm) a W at a position corresponding to SEQ ID NO:5 position 75, an S at a position corresponding to SEQ ID NO:5 position 81, an A at a position corresponding to SEQ ID NO:5 position 145, and a D at a position corresponding to SEQ ID NO:5 position 160; nn) a W at a position corresponding to SEQ ID NO:5 position 75, an A at a position corresponding to SEQ ID NO:5 position 145, a W at a position corresponding to SEQ ID NO:5 position 155, and a D at a position corresponding to SEQ ID NO:5 position 160; NO:5 position 160 corresponding to a D; oo) a W at a position corresponding to a W at a position corresponding to a S ... an L at a position corresponding to position 40 of SEQ ID NO: 5, and a Q at a position corresponding to position 159 of SEQ ID NO: 5; tt) an L at a position corresponding to position 40 of SEQ ID NO: 5, and a W at a position corresponding to position 160 of SEQ ID NO: 5; uu) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a V at a position corresponding to position 121 of SEQ ID NO: 5; vv) an M at a position corresponding to position 105 of SEQ ID NO: 5, and an M at a position corresponding to position 145 of SEQ ID NO: 5; ww) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a Q at a position corresponding to position 159 of SEQ ID NO: 5; xx) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a V at a position corresponding to position 121 of SEQ ID NO: 5; NO:5, a W at a position corresponding to position 160; yy) a V at a position corresponding to position 121 of SEQ ID NO:5, and an M at a position corresponding to position 145 of SEQ ID NO:5; zz) a V at a position corresponding to position 121 of SEQ ID NO:5, and a Q at a position corresponding to position 159 of SEQ ID NO:5; aaa) a V at a position corresponding to position 121 of SEQ ID NO:5, and a W at a position corresponding to position 160 of SEQ ID NO:5; bbb) an M at a position corresponding to position 145 of SEQ ID NO:5, and a Q at a position corresponding to position 159 of SEQ ID NO:5; ccc) an M at a position corresponding to position 145 of SEQ ID NO:5, and a W at a position corresponding to position 160 of SEQ ID NO:5; ddd) a NO:5 position 159 corresponding to a Q, and a W corresponding to a position 160 corresponding to a W; eee) a S at a position corresponding to a position 81 of SEQ ID NO:5, a M at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 160 of SEQ ID NO:5; fff) a S at a position corresponding to a position 81 of SEQ ID NO:5, a V at a position corresponding to a position 121 of SEQ ID NO:5, and a Q at a position corresponding to a position 159 of SEQ ID NO:5; ggg) an A at a position corresponding to a position 68 of SEQ ID NO:5, and a S at a position corresponding to a position 81 of SEQ ID NO:5; hhh) a G at a position corresponding to a position 76 of SEQ ID NO:5, and a S at a position corresponding to a position 81 of SEQ ID NO:5; iii) an S at a position corresponding to position 81 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; jjj) an A at a position corresponding to position 68 of SEQ ID NO: 5, and a G at a position corresponding to position 76 of SEQ ID NO: 5; kkk) an A at a position corresponding to position 68 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; lll) a G at a position corresponding to position 76 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; mmm) an A at a position corresponding to position 68 of SEQ ID NO: 5, a G at a position corresponding to position 76 of SEQ ID NO: 5, and an S at a position corresponding to position 81 of SEQ ID NO: 5; nnn) a G at a position corresponding to position 68 of SEQ ID NO: 5, and an S at a position corresponding to position 81 of SEQ ID NO: 5; NO:5 position 68 corresponding to an A, a position corresponding to an S, and a position corresponding to an L in a position corresponding to a position 117 of SEQ ID NO:5; ooo) a G at a position corresponding to a position 76 of SEQ ID NO:5, a S at a position corresponding to a S, and a L in a position corresponding to a position 117 of SEQ ID NO:5; ppp) an A at a position corresponding to a position 68 of SEQ ID NO:5, a G at a position corresponding to a position 76 of SEQ ID NO:5, and a L in a position corresponding to a position 117 of SEQ ID NO:5; qqq) an A at a position corresponding to a position 68 of SEQ ID NO:5, a G at a position corresponding to a position 76 of SEQ ID NO:5, a S at a position corresponding to a position 81 of SEQ ID NO:5, and a L in a position corresponding to a position 117 of SEQ ID NO:5; NO:5 position 117 - L; rrr) SEQ ID NO:5 position 81 - S, SEQ ID NO:5 position 109 - L, SEQ ID NO:5 position 153 - E, SEQ ID NO:5 position 155 - W, and SEQ ID NO:5 position 160 - D; sss) SEQ ID NO:5 position 75 - A, SEQ ID NO:5 position 81 - S, SEQ ID NO:5 position 117 - L, SEQ ID NO:5 position 121 - A, SEQ ID NO:5 position 145 - A, SEQ ID NO:5 position 155 - W, and SEQ ID NO:5 position 160 - D; NO:5 position 160 corresponding to a D; ttt) a Q at a position corresponding to ... NO:5 position 155 corresponding to a W, and a D corresponding to a position 160 corresponding to a D of SEQ ID NO:5; vvv) a C corresponding to a position 22 corresponding to a position 68 corresponding to a position 75 corresponding to a Y of SEQ ID NO:5, a G corresponding to a position 76 corresponding to a position 81 corresponding to a S of SEQ ID NO:5, a H corresponding to a position 108 corresponding to a position 117 corresponding to a L of SEQ ID NO:5, a H corresponding to a position 122 corresponding to a position 138 corresponding to a Y of SEQ ID NO:5, a L corresponding to a position 139 corresponding to a L of SEQ ID NO:5, a H corresponding to a position 140 corresponding to a position 141 corresponding to a position 142 corresponding to a position 143 corresponding to a position 147 corresponding to a position 149 corresponding to a position 150 corresponding to a position 151 corresponding to a position 152 corresponding to a position 153 corresponding to a position 154 corresponding to a position 156 corresponding to a position 157 corresponding to a position 158 corresponding to a position 15 ... NO:5 position 142 corresponding to an A, SEQ ID NO:5 position 145 corresponding to an A, SEQ ID NO:5 position 153 corresponding to an R, SEQ ID NO:5 position 155 corresponding to a W, SEQ ID NO:5 position 156 corresponding to an R, SEQ ID NO:5 position 160 corresponding to a D, and SEQ ID NO:5 position 162 corresponding to an H; or www) SEQ ID NO:5 position 81 corresponding to an S. The nucleic acid molecule of claim 147 or claim 148, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 300-414, 596-598, and 720-723. The nucleic acid molecule of claim 147 or claim 148, wherein the deaminase comprises an amino acid sequence of any one of SEQ ID NOs: 300-414, 596-598, and 720-723. The nucleic acid molecule of any one of claims 147 to 150, wherein the deaminase has improved deaminase activity when compared to SEQ ID NO: 5. A nucleic acid molecule as described in any one of claim 147 to claim 151, wherein the deaminase is an adenine deaminase. The nucleic acid molecule of any one of claim 147 to claim 152 further comprises a heterologous promoter operably linked to the polynucleotide. A vector comprising a nucleic acid molecule as described in any one of claim 147 to claim 153. A cell comprising the deaminase of any one of claims 141 to 146, the nucleic acid molecule of any one of claims 147 to 153, or the vector of claim 154. The cell of claim 155, wherein the cell is a mammalian cell. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the deaminase as described in any one of claims 141 to 146, the nucleic acid molecule as described in any one of claims 147 to 153, the vector as described in claim 154, or the cell as described in claim 156. A fusion protein comprising a DNA binding polypeptide and a deaminase having at least 85% sequence identity with SEQ ID NO: 5, wherein the deaminase comprises at least one of the following amino acid residues: a) a C at a position corresponding to position 2 of SEQ ID NO: 5; b) an F or C at a position corresponding to position 22 of SEQ ID NO: 5; c) a Q at a position corresponding to position 23 of SEQ ID NO: 5; d) an N at a position corresponding to position 35 of SEQ ID NO: 5; e) an L at a position corresponding to position 40 of SEQ ID NO: 5; f) a Q at a position corresponding to position 46 of SEQ ID NO: 5; g) an A or M at a position corresponding to position 68 of SEQ ID NO: 5; h) an H at a position corresponding to position 72 of SEQ ID NO: 5; i) an N at a position corresponding to position 35 of SEQ ID NO: 5; e) an L at a position corresponding to position 40 of SEQ ID NO: 5; f) a Q at a position corresponding to position 46 of SEQ ID NO: 5; g) an A or M at a position corresponding to position 68 of SEQ ID NO: 5; h) an H at a position corresponding to position 72 of SEQ ID NO: 5; i) an N at a position corresponding to position 35 of SEQ ID NO: 5; NO:5 position 75 corresponding to a W, A, Q, Y, or D; j) a G at a position corresponding to a position 76 corresponding to a position 81 corresponding to a position 81 of SEQ ID NO:5; l) an M at a position corresponding to a position 105 of SEQ ID NO:5; m) an H at a position corresponding to a position 108 of SEQ ID NO:5; n) an L at a position corresponding to a position 109 of SEQ ID NO:5; o) an I or L at a position corresponding to a position 117 of SEQ ID NO:5; p) an F at a position corresponding to a position 120 of SEQ ID NO:5; q) an E, T, A, G, or V at a position corresponding to a position 121 of SEQ ID NO:5; r) an I or H at a position corresponding to a position 122 of SEQ ID NO:5; s) an L at a position corresponding to a position 117 of SEQ ID NO:5; NO:5 position 125 corresponding to a K; t) an A at a position corresponding to a position 126 corresponding to a SEQ ID NO:5; u) an H at a position corresponding to a position 135 corresponding to a SEQ ID NO:5; v) a V at a position corresponding to a position 137 corresponding to a SEQ ID NO:5; w) a Y at a position corresponding to a position 138 corresponding to a SEQ ID NO:5; x) an L at a position corresponding to a position 139 corresponding to a SEQ ID NO:5; y) a K or A at a position corresponding to a position 142 corresponding to a SEQ ID NO:5; z) an A, Q, L, or M at a position corresponding to a position 145 corresponding to a SEQ ID NO:5; aa) a K at a position corresponding to a position 148 corresponding to a SEQ ID NO:5; bb) a Q at a position corresponding to a position 151 corresponding to a SEQ ID NO:5; cc) a K at a position corresponding to a position 152 corresponding to a SEQ ID NO:5. NO:5 position 153 corresponding to an E or R; dd) a W at a position corresponding to a position 155 corresponding to a SEQ ID NO:5; ee) an R or V at a position corresponding to a position 156 corresponding to a SEQ ID NO:5; ff) an F at a position corresponding to a position 157 corresponding to a SEQ ID NO:5; gg) an R at a position corresponding to a position 158 corresponding to a SEQ ID NO:5; hh) a Q at a position corresponding to a position 159 corresponding to a SEQ ID NO:5; ii) a D or W at a position corresponding to a position 160 corresponding to a SEQ ID NO:5; jj) a W, H, V, or A at a position corresponding to a position 162 corresponding to a SEQ ID NO:5; kk) an R at a position corresponding to a position 165 corresponding to a SEQ ID NO:5; and ll) an H at a position corresponding to a position 166 corresponding to a SEQ ID NO:5. A fusion protein as described in claim 158, wherein the deaminase comprises: a) an N at a position corresponding to position 35 of SEQ ID NO: 5 and a W at a position corresponding to position 162 of SEQ ID NO: 5; b) an N at a position corresponding to position 35 of SEQ ID NO: 5 and a Q at a position corresponding to position 46 of SEQ ID NO: 5; c) an S at a position corresponding to position 81 of SEQ ID NO: 5 and an R at a position corresponding to position 156 of SEQ ID NO: 5; d) a Q at a position corresponding to position 46 of SEQ ID NO: 5 and an R at a position corresponding to position 156 of SEQ ID NO: 5; e) an R at a position corresponding to position 156 of SEQ ID NO: 5 and a W at a position corresponding to position 162 of SEQ ID NO: 5; f) an A at a position corresponding to position 68 of SEQ ID NO: 5 and a NO:5 position 81 corresponding to an S; g) an N at a position corresponding to the 35th position of SEQ ID NO:5, an S at a position corresponding to the 81st position of SEQ ID NO:5, and a W at a position corresponding to the 162nd position of SEQ ID NO:5; h) an N at a position corresponding to the 35th position of SEQ ID NO:5, a Q at a position corresponding to the 46th position of SEQ ID NO:5, and a W at a position corresponding to the 162nd position of SEQ ID NO:5; i) a W at a position corresponding to the 155th position of SEQ ID NO:5, an R at a position corresponding to the 156th position of SEQ ID NO:5, and a W at a position corresponding to the 162nd position of SEQ ID NO:5; j) an N at a position corresponding to the 35th position of SEQ ID NO:5, an R at a position corresponding to the 156th position of SEQ ID NO:5, and a W at a position corresponding to the 162nd position of SEQ ID NO:5 NO:5 position 162 corresponding to a W; k) a N at a position corresponding to a position 35 of SEQ ID NO:5, a S at a position corresponding to a position 81 of SEQ ID NO:5, a R at a position corresponding to a position 156 of SEQ ID NO:5, and a W at a position corresponding to a position 162 of SEQ ID NO:5; l) a M at a position corresponding to a position 68 of SEQ ID NO:5, a H at a position corresponding to a position 108 of SEQ ID NO:5, a R at a position corresponding to a position 156 of SEQ ID NO:5, and a W at a position corresponding to a position 162 of SEQ ID NO:5; m) a Q at a position corresponding to a position 46 of SEQ ID NO:5, a M at a position corresponding to a position 68 of SEQ ID NO:5, a H at a position corresponding to a position 108 of SEQ ID NO:5, a NO:5 position 156 corresponding to an R, and a position corresponding to position 162 corresponding to SEQ ID NO:5; n) a M at a position corresponding to position 68 of SEQ ID NO:5, a S at a position corresponding to position 81 of SEQ ID NO:5, a H at a position corresponding to position 108 of SEQ ID NO:5, a R at a position corresponding to position 156 of SEQ ID NO:5, and a W at a position corresponding to position 162 of SEQ ID NO:5; o) a Q at a position corresponding to position 46 of SEQ ID NO:5, a N at a position corresponding to position 35, a M at a position corresponding to position 68 of SEQ ID NO:5, a S at a position corresponding to position 81 of SEQ ID NO:5, a H at a position corresponding to position 108 of SEQ ID NO:5, a W at a position corresponding to position 155 of SEQ ID NO:5, and a W at a position corresponding to position 162 of SEQ ID NO:5; NO: 5 position 156 corresponding to an R, and a position corresponding to a W corresponding to a position 162 of SEQ ID NO: 5; p) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and a W at a position corresponding to a position 155 of SEQ ID NO: 5; q) a W at a position corresponding to a position 75 of SEQ ID NO: 5, and an S at a position corresponding to a position 81 of SEQ ID NO: 5; r) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and a D at a position corresponding to a position 160 of SEQ ID NO: 5; s) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and an A at a position corresponding to a position 145 of SEQ ID NO: 5; t) a W at a position corresponding to a position 75 of SEQ ID NO: 5, and a W at a position corresponding to a position 155 of SEQ ID NO: 5; u) a W at a position corresponding to position 155 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; v) an A at a position corresponding to position 145 of SEQ ID NO: 5, and a W at a position corresponding to position 155 of SEQ ID NO: 5; w) a W at a position corresponding to position 75 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; x) a W at a position corresponding to position 75 of SEQ ID NO: 5, and an A at a position corresponding to position 145 of SEQ ID NO: 5; y) an A at a position corresponding to position 145 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; z) a W at a position corresponding to position 75 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5 NO:5 position 81 corresponding to an S, and a position corresponding to a W corresponding to a position 155 of SEQ ID NO:5; aa) an S at a position corresponding to a S, a W at a position corresponding to a W, and a D at a position corresponding to a position 160 of SEQ ID NO:5; bb) an S at a position corresponding to a S, a A at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 155 of SEQ ID NO:5; cc) a W at a position corresponding to a W, a S at a position corresponding to a S, and a D at a position corresponding to a position 160 of SEQ ID NO:5; dd) a W at a position corresponding to a W, a A at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 155 of SEQ ID NO:5; NO:5 position 81 corresponding to an S, and a position corresponding to a position 145 corresponding to SEQ ID NO:5; ee) an S at a position corresponding to a position 81 corresponding to SEQ ID NO:5, an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5; ff) a W at a position corresponding to a position 75 corresponding to SEQ ID NO:5, a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5; gg) a W at a position corresponding to a position 75 corresponding to SEQ ID NO:5, an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, and a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5; hh) an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5. NO:5 position 155 corresponding to a W, and a position corresponding to a D at a position corresponding to a position 160 of SEQ ID NO:5; ii) a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a NO:5 position 155 corresponding to a W; ll) a S at a position corresponding to the 81st position of SEQ ID NO:5, an A at a position corresponding to the 145th position of SEQ ID NO:5, a W at a position corresponding to the 155th position of SEQ ID NO:5, and a D at a position corresponding to the 160th position of SEQ ID NO:5; mm) a W at a position corresponding to the 75th position of SEQ ID NO:5, an S at a position corresponding to the 81st position of SEQ ID NO:5, an A at a position corresponding to the 145th position of SEQ ID NO:5, and a D at a position corresponding to the 160th position of SEQ ID NO:5; nn) a W at a position corresponding to the 75th position of SEQ ID NO:5, an A at a position corresponding to the 145th position of SEQ ID NO:5, a W at a position corresponding to the 155th position of SEQ ID NO:5, and a D at a position corresponding to the 160th position of SEQ ID NO:5. NO:5 position 160 corresponding to a D; oo) a W at a position corresponding to a W at a position corresponding to a S ... an L at a position corresponding to position 40 of SEQ ID NO: 5, and a Q at a position corresponding to position 159 of SEQ ID NO: 5; tt) an L at a position corresponding to position 40 of SEQ ID NO: 5, and a W at a position corresponding to position 160 of SEQ ID NO: 5; uu) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a V at a position corresponding to position 121 of SEQ ID NO: 5; vv) an M at a position corresponding to position 105 of SEQ ID NO: 5, and an M at a position corresponding to position 145 of SEQ ID NO: 5; ww) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a Q at a position corresponding to position 159 of SEQ ID NO: 5; xx) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a V at a position corresponding to position 121 of SEQ ID NO: 5; NO:5, a W at a position corresponding to position 160; yy) a V at a position corresponding to position 121 of SEQ ID NO:5, and an M at a position corresponding to position 145 of SEQ ID NO:5; zz) a V at a position corresponding to position 121 of SEQ ID NO:5, and a Q at a position corresponding to position 159 of SEQ ID NO:5; aaa) a V at a position corresponding to position 121 of SEQ ID NO:5, and a W at a position corresponding to position 160 of SEQ ID NO:5; bbb) an M at a position corresponding to position 145 of SEQ ID NO:5, and a Q at a position corresponding to position 159 of SEQ ID NO:5; ccc) an M at a position corresponding to position 145 of SEQ ID NO:5, and a W at a position corresponding to position 160 of SEQ ID NO:5; ddd) a NO:5 position 159 corresponding to a Q, and a W corresponding to a position 160 corresponding to a W; eee) a S at a position corresponding to a position 81 of SEQ ID NO:5, a M at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 160 of SEQ ID NO:5; fff) a S at a position corresponding to a position 81 of SEQ ID NO:5, a V at a position corresponding to a position 121 of SEQ ID NO:5, and a Q at a position corresponding to a position 159 of SEQ ID NO:5; ggg) an A at a position corresponding to a position 68 of SEQ ID NO:5, and a S at a position corresponding to a position 81 of SEQ ID NO:5; hhh) a G at a position corresponding to a position 76 of SEQ ID NO:5, and a S at a position corresponding to a position 81 of SEQ ID NO:5; iii) an S at a position corresponding to position 81 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; jjj) an A at a position corresponding to position 68 of SEQ ID NO: 5, and a G at a position corresponding to position 76 of SEQ ID NO: 5; kkk) an A at a position corresponding to position 68 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; lll) a G at a position corresponding to position 76 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; mmm) an A at a position corresponding to position 68 of SEQ ID NO: 5, a G at a position corresponding to position 76 of SEQ ID NO: 5, and an S at a position corresponding to position 81 of SEQ ID NO: 5; nnn) a G at a position corresponding to position 68 of SEQ ID NO: 5, and an S at a position corresponding to position 81 of SEQ ID NO: 5; NO:5 position 68 corresponding to an A, a position corresponding to an S, and a position corresponding to an L in a position corresponding to a position 117 of SEQ ID NO:5; ooo) a G at a position corresponding to a position 76 of SEQ ID NO:5, a S at a position corresponding to a position 81 of SEQ ID NO:5, and a L in a position corresponding to a position 117 of SEQ ID NO:5; ppp) an A at a position corresponding to a position 68 of SEQ ID NO:5, a G at a position corresponding to a position 76 of SEQ ID NO:5, and a L in a position corresponding to a position 117 of SEQ ID NO:5; qqq) an A at a position corresponding to a position 68 of SEQ ID NO:5, a G at a position corresponding to a position 76 of SEQ ID NO:5, a S at a position corresponding to a position 81 of SEQ ID NO:5, and a L in a position corresponding to a position 117 of SEQ ID NO:5 NO:5 position 117 - L; rrr) SEQ ID NO:5 position 81 - S, SEQ ID NO:5 position 109 - L, SEQ ID NO:5 position 153 - E, SEQ ID NO:5 position 155 - W, and SEQ ID NO:5 position 160 - D; sss) SEQ ID NO:5 position 75 - A, SEQ ID NO:5 position 81 - S, SEQ ID NO:5 position 117 - L, SEQ ID NO:5 position 121 - A, SEQ ID NO:5 position 145 - A, SEQ ID NO:5 position 155 - W, and SEQ ID NO:5 position 160 - D; NO:5 position 160 corresponding to a D; ttt) a Q at a position corresponding to a position 75 of SEQ ID NO:5, an S at a position corresponding to a position 81 of SEQ ID NO:5, an I at a position corresponding to a position 117 of SEQ ID NO:5, a Q at a position corresponding to a position 145 of SEQ ID NO:5, a W at a position corresponding to a position 155 of SEQ ID NO:5, and a D at a position corresponding to a position 160 of SEQ ID NO:5; uuu) a Y at a position corresponding to a position 75 of SEQ ID NO:5, an S at a position corresponding to a position 81 of SEQ ID NO:5, an L at a position corresponding to a position 117 of SEQ ID NO:5, a G at a position corresponding to a position 121 of SEQ ID NO:5, an L at a position corresponding to a position 145 of SEQ ID NO:5, a a W at a position corresponding to position 155 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; vvv) a C at a position corresponding to position 22 of SEQ ID NO: 5, an A at a position corresponding to position 68 of SEQ ID NO: 5, a Y at a position corresponding to position 75 of SEQ ID NO: 5, a G at a position corresponding to position 76 of SEQ ID NO: 5, an S at a position corresponding to position 81 of SEQ ID NO: 5, an H at a position corresponding to position 108 of SEQ ID NO: 5, an L at a position corresponding to position 117 of SEQ ID NO: 5, an H at a position corresponding to position 122 of SEQ ID NO: 5, a Y at a position corresponding to position 138 of SEQ ID NO: 5, an L at a position corresponding to position 139 of SEQ ID NO: 5, an H at a position corresponding to position 140 of SEQ ID NO: 5, an H at a position corresponding to position 141 of SEQ ID NO: 5, an L at a position corresponding to position 142 of SEQ ID NO: 5, an L at a position corresponding to position 143 of SEQ ID NO: 5, an L at a position corresponding to position 144 of SEQ ID NO: 5, an L at a position corresponding to position 145 of SEQ ID NO: 5, an L at a position corresponding to position 146 of SEQ ID NO: 5, an L at a position corresponding to position 147 of SEQ ID NO: 5, an L at a position corresponding to position 148 of SEQ ID NO: 5, an L at a position corresponding to position 149 of SEQ ID NO: 5, an L at a position corresponding to position 150 of SEQ ID NO: 5, an L at a position corresponding to position 151 of SEQ ID NO: 5, an L at a position NO:5 position 142 corresponding to an A, SEQ ID NO:5 position 145 corresponding to an A, SEQ ID NO:5 position 153 corresponding to an R, SEQ ID NO:5 position 155 corresponding to a W, SEQ ID NO:5 position 156 corresponding to an R, SEQ ID NO:5 position 160 corresponding to a D, and SEQ ID NO:5 position 162 corresponding to an H; or www) SEQ ID NO:5 position 81 corresponding to an S. The fusion protein of claim 158 or claim 159, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 300-414, 596-598, and 720-723. The fusion protein of claim 158 or claim 159, wherein the deaminase comprises an amino acid sequence of any one of SEQ ID NOs: 300-414, 596-598, and 720-723. The fusion protein of any one of claims 158 to 161, wherein the deaminase has improved deaminase activity when compared to SEQ ID NO: 5. A fusion protein as described in any one of claim 158 to claim 162, wherein the deaminase is an adenine deaminase. A fusion protein as described in any one of claim 158 to claim 163, wherein the DNA binding polypeptide is an RNA-guided nuclease (RGN) polypeptide. The fusion protein of claim 164, wherein the RGN is an RGN nickase. The fusion protein of claim 164, wherein the RGN has an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698 and 699. The fusion protein of claim 165, wherein the RGN nickase has the amino acid sequence shown in any one of SEQ ID NOs: 49-52 and 698. A fusion protein as described in claim 158 or claim 159, wherein the fusion protein is selected from the group consisting of: a) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 319 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; b) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 375 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; c) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 406 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: NO:49 having at least 90% sequence identity to the N-terminus of an RGN; d) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO:596 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO:49; e) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO:597 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO:49; f) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO:303 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO:49; g) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 366 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; and h) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 720 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49. A fusion protein as described in claim 158 or claim 159, wherein the fusion protein is selected from the group consisting of: a) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO: 319 and is fused to the N-terminus of an RGN comprising the amino acid sequence as shown in SEQ ID NO: 49; b) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO: 375 and is fused to the N-terminus of an RGN comprising the amino acid sequence as shown in SEQ ID NO: 49; c) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO: 406 and is fused to the N-terminus of an RGN comprising the amino acid sequence as shown in SEQ ID NO: 49; d) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO: 509 and is fused to the N-terminus of an RGN comprising the amino acid sequence as shown in SEQ ID NO: 510; NO:596, and fused to the N-terminus of an RGN comprising the amino acid sequence as shown in SEQ ID NO:49; e) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO:597, and fused to the N-terminus of an RGN comprising the amino acid sequence as shown in SEQ ID NO:49; f) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO:303, and fused to the N-terminus of an RGN comprising the amino acid sequence as shown in SEQ ID NO:49; g) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO:366, and fused to the N-terminus of an RGN comprising the amino acid sequence as shown in SEQ ID NO:49; and h) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO: NO:720, and fused to the N-terminus of an RGN comprising the amino acid sequence as shown in SEQ ID NO:49. A fusion protein as described in claim 158 or claim 159, wherein the fusion protein has the sequence shown in any one of SEQ ID NOs: 577, 578, 582, 584, 588, 593, 594, 604, 605, 616, and 729. A ribonucleoprotein (RNP) complex comprising the fusion protein of any one of claims 158 to 170 and a guide RNA bound to the fusion protein. A nucleic acid molecule comprising a polynucleotide encoding a fusion protein, the fusion protein comprising a DNA binding polypeptide and a deaminase, wherein the deaminase comprises at least one of the following amino acid residues: a) a C at a position corresponding to position 2 of SEQ ID NO: 5; b) an F or C at a position corresponding to position 22 of SEQ ID NO: 5; c) a Q at a position corresponding to position 23 of SEQ ID NO: 5; d) an N at a position corresponding to position 35 of SEQ ID NO: 5; e) an L at a position corresponding to position 40 of SEQ ID NO: 5; f) a Q at a position corresponding to position 46 of SEQ ID NO: 5; g) an A or M at a position corresponding to position 68 of SEQ ID NO: 5; h) an H at a position corresponding to position 72 of SEQ ID NO: 5; i) an N at a position corresponding to position 35 of SEQ ID NO: 5; e) an L at a position corresponding to position 40 of SEQ ID NO: 5; f) a Q at a position corresponding to position 46 of SEQ ID NO: 5; g) an A or M at a position corresponding to position 68 of SEQ ID NO: 5; h) an H at a position corresponding to position 72 of SEQ ID NO: 5; i) an N at a position corresponding to position 35 of SEQ ID NO: 5; NO:5 position 75 corresponding to a W, A, Q, Y, or D; j) a G at a position corresponding to a position 76 corresponding to a position 81 corresponding to a position 81 of SEQ ID NO:5; l) an M at a position corresponding to a position 105 of SEQ ID NO:5; m) an H at a position corresponding to a position 108 of SEQ ID NO:5; n) an L at a position corresponding to a position 109 of SEQ ID NO:5; o) an I or L at a position corresponding to a position 117 of SEQ ID NO:5; p) an F at a position corresponding to a position 120 of SEQ ID NO:5; q) an E, T, A, G, or V at a position corresponding to a position 121 of SEQ ID NO:5; r) an I or H at a position corresponding to a position 122 of SEQ ID NO:5; s) an L at a position corresponding to a position 117 of SEQ ID NO:5; NO:5 position 125 corresponding to a K; t) an A at a position corresponding to a position 126 corresponding to a SEQ ID NO:5; u) an H at a position corresponding to a position 135 corresponding to a SEQ ID NO:5; v) a V at a position corresponding to a position 137 corresponding to a SEQ ID NO:5; w) a Y at a position corresponding to a position 138 corresponding to a SEQ ID NO:5; x) an L at a position corresponding to a position 139 corresponding to a SEQ ID NO:5; y) a K or A at a position corresponding to a position 142 corresponding to a SEQ ID NO:5; z) an A, Q, L, or M at a position corresponding to a position 145 corresponding to a SEQ ID NO:5; aa) a K at a position corresponding to a position 148 corresponding to a SEQ ID NO:5; bb) a Q at a position corresponding to a position 151 corresponding to a SEQ ID NO:5; cc) a K at a position corresponding to a position 152 corresponding to a SEQ ID NO:5. NO:5 position 153 corresponding to an E or R; dd) a W at a position corresponding to a position 155 corresponding to a SEQ ID NO:5; ee) an R or V at a position corresponding to a position 156 corresponding to a SEQ ID NO:5; ff) an F at a position corresponding to a position 157 corresponding to a SEQ ID NO:5; gg) an R at a position corresponding to a position 158 corresponding to a SEQ ID NO:5; hh) a Q at a position corresponding to a position 159 corresponding to a SEQ ID NO:5; ii) a D or W at a position corresponding to a position 160 corresponding to a SEQ ID NO:5; jj) a W, H, V, or A at a position corresponding to a position 162 corresponding to a SEQ ID NO:5; kk) an R at a position corresponding to a position 165 corresponding to a SEQ ID NO:5; and ll) an H at a position corresponding to a position 166 corresponding to a SEQ ID NO:5. A nucleic acid molecule as described in claim 172, wherein the deaminase comprises: a) an N at a position corresponding to position 35 of SEQ ID NO: 5 and a W at a position corresponding to position 162 of SEQ ID NO: 5; b) an N at a position corresponding to position 35 of SEQ ID NO: 5 and a Q at a position corresponding to position 46 of SEQ ID NO: 5; c) an S at a position corresponding to position 81 of SEQ ID NO: 5 and an R at a position corresponding to position 156 of SEQ ID NO: 5; d) a Q at a position corresponding to position 46 of SEQ ID NO: 5 and an R at a position corresponding to position 156 of SEQ ID NO: 5; e) an R at a position corresponding to position 156 of SEQ ID NO: 5 and a W at a position corresponding to position 162 of SEQ ID NO: 5; f) an A at a position corresponding to position 68 of SEQ ID NO: 5 and a NO:5 position 81 corresponding to an S; g) an N at a position corresponding to the 35th position of SEQ ID NO:5, an S at a position corresponding to the 81st position of SEQ ID NO:5, and a W at a position corresponding to the 162nd position of SEQ ID NO:5; h) an N at a position corresponding to the 35th position of SEQ ID NO:5, a Q at a position corresponding to the 46th position of SEQ ID NO:5, and a W at a position corresponding to the 162nd position of SEQ ID NO:5; i) a W at a position corresponding to the 155th position of SEQ ID NO:5, an R at a position corresponding to the 156th position of SEQ ID NO:5, and a W at a position corresponding to the 162nd position of SEQ ID NO:5; j) an N at a position corresponding to the 35th position of SEQ ID NO:5, an R at a position corresponding to the 156th position of SEQ ID NO:5, and a W at a position corresponding to the 162nd position of SEQ ID NO:5 NO:5 position 162 corresponding to a W; k) a N at a position corresponding to a position 35 of SEQ ID NO:5, a S at a position corresponding to a position 81 of SEQ ID NO:5, a R at a position corresponding to a position 156 of SEQ ID NO:5, and a W at a position corresponding to a position 162 of SEQ ID NO:5; l) a M at a position corresponding to a position 68 of SEQ ID NO:5, a H at a position corresponding to a position 108 of SEQ ID NO:5, a R at a position corresponding to a position 156 of SEQ ID NO:5, and a W at a position corresponding to a position 162 of SEQ ID NO:5; m) a Q at a position corresponding to a position 46 of SEQ ID NO:5, a M at a position corresponding to a position 68 of SEQ ID NO:5, a H at a position corresponding to a position 108 of SEQ ID NO:5, a NO:5 position 156 corresponding to an R, and a position corresponding to position 162 corresponding to SEQ ID NO:5; n) a M at a position corresponding to position 68 of SEQ ID NO:5, a S at a position corresponding to position 81 of SEQ ID NO:5, a H at a position corresponding to position 108 of SEQ ID NO:5, a R at a position corresponding to position 156 of SEQ ID NO:5, and a W at a position corresponding to position 162 of SEQ ID NO:5; o) a Q at a position corresponding to position 46 of SEQ ID NO:5, a N at a position corresponding to position 35, a M at a position corresponding to position 68 of SEQ ID NO:5, a S at a position corresponding to position 81 of SEQ ID NO:5, a H at a position corresponding to position 108 of SEQ ID NO:5, a W at a position corresponding to position 155 of SEQ ID NO:5, and a W at a position corresponding to position 162 of SEQ ID NO:5; NO: 5 position 156 corresponding to an R, and a position corresponding to a W corresponding to a position 162 of SEQ ID NO: 5; p) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and a W at a position corresponding to a position 155 of SEQ ID NO: 5; q) a W at a position corresponding to a position 75 of SEQ ID NO: 5, and an S at a position corresponding to a position 81 of SEQ ID NO: 5; r) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and a D at a position corresponding to a position 160 of SEQ ID NO: 5; s) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and an A at a position corresponding to a position 145 of SEQ ID NO: 5; t) a W at a position corresponding to a position 75 of SEQ ID NO: 5, and a W at a position corresponding to a position 155 of SEQ ID NO: 5; u) a W at a position corresponding to position 155 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; v) an A at a position corresponding to position 145 of SEQ ID NO: 5, and a W at a position corresponding to position 155 of SEQ ID NO: 5; w) a W at a position corresponding to position 75 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; x) a W at a position corresponding to position 75 of SEQ ID NO: 5, and an A at a position corresponding to position 145 of SEQ ID NO: 5; y) an A at a position corresponding to position 145 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; z) a W at a position corresponding to position 75 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5 NO:5 position 81 corresponding to an S, and a position corresponding to a W corresponding to a position 155 of SEQ ID NO:5; aa) an S at a position corresponding to a S, a W at a position corresponding to a W, and a D at a position corresponding to a position 160 of SEQ ID NO:5; bb) an S at a position corresponding to a S, a A at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 155 of SEQ ID NO:5; cc) a W at a position corresponding to a W, a S at a position corresponding to a S, and a D at a position corresponding to a position 160 of SEQ ID NO:5; dd) a W at a position corresponding to a W, a A at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 155 of SEQ ID NO:5; NO:5 position 81 corresponding to an S, and a position corresponding to a position 145 corresponding to SEQ ID NO:5; ee) an S at a position corresponding to a position 81 corresponding to SEQ ID NO:5, an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5; ff) a W at a position corresponding to a position 75 corresponding to SEQ ID NO:5, a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5; gg) a W at a position corresponding to a position 75 corresponding to SEQ ID NO:5, an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, and a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5; hh) an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5. NO:5 position 155 corresponding to a W, and a D corresponding to a position 160 corresponding to a SEQ ID NO:5; ii) a W at a position corresponding to a SEQ ID NO:5 position 75 corresponding to a W, an A at a position corresponding to a SEQ ID NO:5 position 145 corresponding to a SEQ ID NO:5 position 160 corresponding to a D; jj) a W at a position corresponding to a SEQ ID NO:5 position 75 corresponding to a S at a position corresponding to a SEQ ID NO:5 position 81 corresponding to a W at a position corresponding to a SEQ ID NO:5 position 155 corresponding to a D at a position corresponding to a SEQ ID NO:5 position 160 corresponding to a D; kk) a W at a position corresponding to a SEQ ID NO:5 position 75 corresponding to a SEQ ID NO:5 position 81 corresponding to a S, an A at a position corresponding to a SEQ ID NO:5 position 145 corresponding to a SEQ ID NO:5 position 160 corresponding to a D; NO:5 position 155 corresponding to a W; ll) a S at a position corresponding to the 81st position of SEQ ID NO:5, an A at a position corresponding to the 145th position of SEQ ID NO:5, a W at a position corresponding to the 155th position of SEQ ID NO:5, and a D at a position corresponding to the 160th position of SEQ ID NO:5; mm) a W at a position corresponding to the 75th position of SEQ ID NO:5, an S at a position corresponding to the 81st position of SEQ ID NO:5, an A at a position corresponding to the 145th position of SEQ ID NO:5, and a D at a position corresponding to the 160th position of SEQ ID NO:5; nn) a W at a position corresponding to the 75th position of SEQ ID NO:5, an A at a position corresponding to the 145th position of SEQ ID NO:5, a W at a position corresponding to the 155th position of SEQ ID NO:5, and a D at a position corresponding to the 160th position of SEQ ID NO:5. NO:5 position 160 corresponding to a D; oo) a W at a position corresponding to a W at a position corresponding to a S ... an L at a position corresponding to position 40 of SEQ ID NO: 5, and a Q at a position corresponding to position 159 of SEQ ID NO: 5; tt) an L at a position corresponding to position 40 of SEQ ID NO: 5, and a W at a position corresponding to position 160 of SEQ ID NO: 5; uu) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a V at a position corresponding to position 121 of SEQ ID NO: 5; vv) an M at a position corresponding to position 105 of SEQ ID NO: 5, and an M at a position corresponding to position 145 of SEQ ID NO: 5; ww) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a Q at a position corresponding to position 159 of SEQ ID NO: 5; xx) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a V at a position corresponding to position 121 of SEQ ID NO: 5; NO:5, a W at a position corresponding to position 160; yy) a V at a position corresponding to position 121 of SEQ ID NO:5, and an M at a position corresponding to position 145 of SEQ ID NO:5; zz) a V at a position corresponding to position 121 of SEQ ID NO:5, and a Q at a position corresponding to position 159 of SEQ ID NO:5; aaa) a V at a position corresponding to position 121 of SEQ ID NO:5, and a W at a position corresponding to position 160 of SEQ ID NO:5; bbb) an M at a position corresponding to position 145 of SEQ ID NO:5, and a Q at a position corresponding to position 159 of SEQ ID NO:5; ccc) an M at a position corresponding to position 145 of SEQ ID NO:5, and a W at a position corresponding to position 160 of SEQ ID NO:5; ddd) a NO:5 position 159 corresponding to a Q, and a W corresponding to a position 160 corresponding to a W; eee) a S at a position corresponding to a position 81 of SEQ ID NO:5, a M at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 160 of SEQ ID NO:5; fff) a S at a position corresponding to a position 81 of SEQ ID NO:5, a V at a position corresponding to a position 121 of SEQ ID NO:5, and a Q at a position corresponding to a position 159 of SEQ ID NO:5; ggg) an A at a position corresponding to a position 68 of SEQ ID NO:5, and a S at a position corresponding to a position 81 of SEQ ID NO:5; hhh) a G at a position corresponding to a position 76 of SEQ ID NO:5, and a S at a position corresponding to a position 81 of SEQ ID NO:5; iii) an S at a position corresponding to position 81 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; jjj) an A at a position corresponding to position 68 of SEQ ID NO: 5, and a G at a position corresponding to position 76 of SEQ ID NO: 5; kkk) an A at a position corresponding to position 68 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; lll) a G at a position corresponding to position 76 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; mmm) an A at a position corresponding to position 68 of SEQ ID NO: 5, a G at a position corresponding to position 76 of SEQ ID NO: 5, and an S at a position corresponding to position 81 of SEQ ID NO: 5; nnn) an A at a position corresponding to position 68 of SEQ ID NO: 5, a G at a position corresponding to position 76 of SEQ ID NO: 5, and an S at a position corresponding to position 81 of SEQ ID NO: 5 NO:5 position 68 corresponding to an A, a position corresponding to an S, and a position corresponding to an L in a position corresponding to a position 117 of SEQ ID NO:5; ooo) a G at a position corresponding to a position 76 of SEQ ID NO:5, a S at a position corresponding to a S, and a L in a position corresponding to a position 117 of SEQ ID NO:5; ppp) an A at a position corresponding to a position 68 of SEQ ID NO:5, a G at a position corresponding to a position 76 of SEQ ID NO:5, and a L in a position corresponding to a position 117 of SEQ ID NO:5; qqq) an A at a position corresponding to a position 68 of SEQ ID NO:5, a G at a position corresponding to a position 76 of SEQ ID NO:5, a S at a position corresponding to a position 81 of SEQ ID NO:5, and a L in a position corresponding to a position 117 of SEQ ID NO:5; NO:5 position 117 - L; rrr) SEQ ID NO:5 position 81 - S, SEQ ID NO:5 position 109 - L, SEQ ID NO:5 position 153 - E, SEQ ID NO:5 position 155 - W, and SEQ ID NO:5 position 160 - D; sss) SEQ ID NO:5 position 75 - A, SEQ ID NO:5 position 81 - S, SEQ ID NO:5 position 117 - L, SEQ ID NO:5 position 121 - A, SEQ ID NO:5 position 145 - A, SEQ ID NO:5 position 155 - W, and SEQ ID NO:5 position 160 - D; NO:5 position 160 corresponding to a D; ttt) a Q at a position corresponding to ... NO:5 position 155 corresponding to a W, and a D corresponding to a position 160 corresponding to a D of SEQ ID NO:5; vvv) a C corresponding to a position 22 corresponding to a position 68 corresponding to a position 75 corresponding to a Y of SEQ ID NO:5, a G corresponding to a position 76 corresponding to a position 81 corresponding to a S of SEQ ID NO:5, a H corresponding to a position 108 corresponding to a position 117 corresponding to a L of SEQ ID NO:5, a H corresponding to a position 122 corresponding to a position 138 corresponding to a Y of SEQ ID NO:5, a L corresponding to a position 139 corresponding to a L of SEQ ID NO:5, a H corresponding to a position 140 corresponding to a position 141 corresponding to a position 142 corresponding to a position 143 corresponding to a position 147 corresponding to a position 149 corresponding to a position 150 corresponding to a position 151 corresponding to a position 152 corresponding to a position 153 corresponding to a position 154 corresponding to a position 156 corresponding to a position 157 corresponding to a position 158 corresponding to a position 15 ... NO:5 position 142 corresponding to an A, SEQ ID NO:5 position 145 corresponding to an A, SEQ ID NO:5 position 153 corresponding to an R, SEQ ID NO:5 position 155 corresponding to a W, SEQ ID NO:5 position 156 corresponding to an R, SEQ ID NO:5 position 160 corresponding to a D, and SEQ ID NO:5 position 162 corresponding to an H; or www) SEQ ID NO:5 position 81 corresponding to an S. The nucleic acid molecule of claim 172 or claim 173, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 300-414, 596-598, and 720-723. The nucleic acid molecule of claim 172 or claim 173, wherein the deaminase comprises an amino acid sequence of any one of SEQ ID NOs: 300-414, 596-598, and 720-723. The nucleic acid molecule of any one of claims 172 to 175, wherein the deaminase has improved deaminase activity when compared to SEQ ID NO: 5. A nucleic acid molecule as described in any one of claim 172 to claim 176, wherein the deaminase is an adenine deaminase. A nucleic acid molecule as described in any one of claim 172 to claim 177, wherein the DNA binding polypeptide is an RNA-guided nuclease (RGN) polypeptide. The nucleic acid molecule of claim 178, wherein the RGN is an RGN nickase. The nucleic acid molecule of claim 178, wherein the RGN has an amino acid sequence having at least 95% sequence identity to any one of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698 and 699. The nucleic acid molecule of claim 179, wherein the RGN nickase has the amino acid sequence shown in any one of SEQ ID NOs: 49-52 and 698. A nucleic acid molecule as described in claim 172 or claim 173, wherein the fusion protein is selected from the group consisting of: a) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 319 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; b) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 375 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; c) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 406 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: NO:49 having at least 90% sequence identity to the N-terminus of an RGN; d) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO:596 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO:49; e) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO:597 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO:49; f) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO:303 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO:49; g) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 366 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; and h) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 720 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49. A nucleic acid molecule as described in claim 172 or claim 173, wherein the fusion protein is selected from the group consisting of: a) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence shown in SEQ ID NO: 319 and is fused to the N-terminus of an RGN comprising the amino acid sequence shown in SEQ ID NO: 49; b) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence shown in SEQ ID NO: 375 and is fused to the N-terminus of an RGN comprising the amino acid sequence shown in SEQ ID NO: 49; c) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence shown in SEQ ID NO: 406 and is fused to the N-terminus of an RGN comprising the amino acid sequence shown in SEQ ID NO: 49; d) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence shown in SEQ ID NO: 596, and fused to the N-terminus of an RGN comprising the amino acid sequence as shown in SEQ ID NO: 49; e) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO: 597, and fused to the N-terminus of an RGN comprising the amino acid sequence as shown in SEQ ID NO: 49; f) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO: 303, and fused to the N-terminus of an RGN comprising the amino acid sequence as shown in SEQ ID NO: 49; g) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO: 366, and fused to the N-terminus of an RGN comprising the amino acid sequence as shown in SEQ ID NO: 49; and h) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO: NO:720, and fused to the N-terminus of an RGN comprising the amino acid sequence as shown in SEQ ID NO:49. A nucleic acid molecule as described in claim 172 or claim 173, wherein the fusion protein has the sequence shown in any one of SEQ ID NOs: 577, 578, 582, 584, 588, 593, 594, 604, 605, 616, and 729. A vector comprising a nucleic acid molecule as described in any one of claim 172 to claim 184. A vector comprising a nucleic acid molecule as described in any one of claim 172 to claim 184, further comprising at least one nucleotide sequence encoding a guide RNA capable of hybridizing with a non-target strand of a target sequence. A cell comprising the fusion protein of any one of claims 158 to 170 or the RNP complex of claim 171. A cell comprising the fusion protein of any one of claims 158 to 170, wherein the cell further comprises a guide RNA. A cell comprising a nucleic acid molecule as described in any one of claims 172 to 184. A cell comprising the vector of claim 185 or claim 186. A cell as described in any of claims 187 to 190, wherein the cell is a mammalian cell. A cell as described in any of claims 187 to 190, wherein the cell is a plant cell. A plant or a seed comprising the cell of claim 192. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a fusion protein as described in any one of claims 158 to 170, an RNP complex as described in claim 171, a nucleic acid molecule as described in any one of claims 172 to 184, a vector as described in claim 185 or 186, or a cell as described in claim 191. A method for preparing an RGN fusion ribonucleoprotein complex, comprising introducing a nucleic acid molecule as described in any one of claim 172 to claim 184 or a vector as described in claim 185 and a nucleic acid molecule comprising an expression box encoding a guide RNA, or a vector as described in claim 186 into a cell, and culturing the cell under conditions in which the fusion protein and the gRNA are expressed and form an RGN fusion ribonucleoprotein complex. A system for modifying a target DNA molecule including a target DNA sequence, the system comprising: a) a fusion protein comprising an RNA-guided nuclease polypeptide and a deaminase, wherein the deaminase has an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 5, or a nucleotide sequence encoding the fusion protein, wherein the deaminase comprises at least one of the following amino acid residues: i)    a C at a position corresponding to position 2 of SEQ ID NO: 5; ii)   an F or C at a position corresponding to position 22 of SEQ ID NO: 5; iii) a Q at a position corresponding to position 23 of SEQ ID NO: 5; iv) an N at a position corresponding to position 35 of SEQ ID NO: 5; v) an L at a position corresponding to position 40 of SEQ ID NO: 5; vi) a Q at a position corresponding to position 46 of SEQ ID NO: 5; vii) a Q at a position corresponding to position 57 of SEQ ID NO: 5; NO:5 position 68 corresponding to an A or M; viii) a H at a position corresponding to a position 72 corresponding to a position 75 corresponding to a position 76 corresponding to a position 76 of SEQ ID NO:5; xi) an S at a position corresponding to a position 81 of SEQ ID NO:5; xii) an M at a position corresponding to a position 105 of SEQ ID NO:5; xiii) an H at a position corresponding to a position 108 of SEQ ID NO:5; xiv) an L at a position corresponding to a position 109 of SEQ ID NO:5; xv) an I or L at a position corresponding to a position 117 of SEQ ID NO:5; xvi) an F at a position corresponding to a position 120 of SEQ ID NO:5; xvii) an M at a position corresponding to a position 106 of SEQ ID NO:5; NO:5 position 121 corresponding to an E, T, A, G, or V; xviii) an I or H at a position corresponding to a position 122 corresponding to a position 125 corresponding to a position 126 corresponding to a position 127 of SEQ ID NO:5; xx) an A at a position corresponding to a position 126 of SEQ ID NO:5; xxi) an H at a position corresponding to a position 135 of SEQ ID NO:5; xxii) a V at a position corresponding to a position 137 of SEQ ID NO:5; xxiii) a Y at a position corresponding to a position 138 of SEQ ID NO:5; xxiv) an L at a position corresponding to a position 139 of SEQ ID NO:5; xxv) a K or A at a position corresponding to a position 142 of SEQ ID NO:5; xxvi) a NO:5 position 145 corresponding to an A, Q, L, or M; xxvii) a K at a position corresponding to a position 148 corresponding to a position 148 of SEQ ID NO:5; xxviii) a Q at a position corresponding to a position 151 of SEQ ID NO:5; xxix) an E or R at a position corresponding to a position 153 of SEQ ID NO:5; xxx) a W at a position corresponding to a position 155 of SEQ ID NO:5; xxxi) an R or V at a position corresponding to a position 156 of SEQ ID NO:5; xxxii) an F at a position corresponding to a position 157 of SEQ ID NO:5; xxxiii) an R at a position corresponding to a position 158 of SEQ ID NO:5; xxxiv) a Q at a position corresponding to a position 159 of SEQ ID NO:5; xxxv) a D or W at a position corresponding to a position 160 of SEQ ID NO:5; xxxvi) a W, H, V, or A at a position corresponding to position 162 of SEQ ID NO: 5; xxxvii) an R at a position corresponding to position 165 of SEQ ID NO: 5; and xxxviii) an H at a position corresponding to position 166 of SEQ ID NO: 5; and b) one or more guide RNAs capable of hybridizing with a non-target strand of the target DNA sequence or one or more nucleotide sequences encoding the one or more guide RNAs; and wherein the one or more guide RNAs are capable of forming a complex with the fusion protein to guide the fusion protein to bind to the target DNA sequence and modify the target DNA molecule. A system as described in claim 196, wherein the deaminase comprises: a) an N at a position corresponding to position 35 of SEQ ID NO: 5 and a W at a position corresponding to position 162 of SEQ ID NO: 5; b) an N at a position corresponding to position 35 of SEQ ID NO: 5 and a Q at a position corresponding to position 46 of SEQ ID NO: 5; c) an S at a position corresponding to position 81 of SEQ ID NO: 5 and an R at a position corresponding to position 156 of SEQ ID NO: 5; d) a Q at a position corresponding to position 46 of SEQ ID NO: 5 and an R at a position corresponding to position 156 of SEQ ID NO: 5; e) an R at a position corresponding to position 156 of SEQ ID NO: 5 and a W at a position corresponding to position 162 of SEQ ID NO: 5; f) an A at a position corresponding to position 68 of SEQ ID NO: 5 and a NO:5 position 81 corresponding to an S; g) an N at a position corresponding to the 35th position of SEQ ID NO:5, an S at a position corresponding to the 81st position of SEQ ID NO:5, and a W at a position corresponding to the 162nd position of SEQ ID NO:5; h) an N at a position corresponding to the 35th position of SEQ ID NO:5, a Q at a position corresponding to the 46th position of SEQ ID NO:5, and a W at a position corresponding to the 162nd position of SEQ ID NO:5; i) a W at a position corresponding to the 155th position of SEQ ID NO:5, an R at a position corresponding to the 156th position of SEQ ID NO:5, and a W at a position corresponding to the 162nd position of SEQ ID NO:5; j) an N at a position corresponding to the 35th position of SEQ ID NO:5, an R at a position corresponding to the 156th position of SEQ ID NO:5, and a W at a position corresponding to the 162nd position of SEQ ID NO:5 NO:5 position 162 corresponding to a W; k) a N at a position corresponding to a position 35 of SEQ ID NO:5, a S at a position corresponding to a position 81 of SEQ ID NO:5, a R at a position corresponding to a position 156 of SEQ ID NO:5, and a W at a position corresponding to a position 162 of SEQ ID NO:5; l) a M at a position corresponding to a position 68 of SEQ ID NO:5, a H at a position corresponding to a position 108 of SEQ ID NO:5, a R at a position corresponding to a position 156 of SEQ ID NO:5, and a W at a position corresponding to a position 162 of SEQ ID NO:5; m) a Q at a position corresponding to a position 46 of SEQ ID NO:5, a M at a position corresponding to a position 68 of SEQ ID NO:5, a H at a position corresponding to a position 108 of SEQ ID NO:5, a NO:5 position 156 corresponding to an R, and a position corresponding to position 162 corresponding to SEQ ID NO:5; n) a M at a position corresponding to position 68 of SEQ ID NO:5, a S at a position corresponding to position 81 of SEQ ID NO:5, a H at a position corresponding to position 108 of SEQ ID NO:5, a R at a position corresponding to position 156 of SEQ ID NO:5, and a W at a position corresponding to position 162 of SEQ ID NO:5; o) a Q at a position corresponding to position 46 of SEQ ID NO:5, a N at a position corresponding to position 35, a M at a position corresponding to position 68 of SEQ ID NO:5, a S at a position corresponding to position 81 of SEQ ID NO:5, a H at a position corresponding to position 108 of SEQ ID NO:5, a W at a position corresponding to position 155 of SEQ ID NO:5, and a W at a position corresponding to position 162 of SEQ ID NO:5; NO: 5 position 156 corresponding to an R, and a position corresponding to a W corresponding to a position 162 of SEQ ID NO: 5; p) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and a W at a position corresponding to a position 155 of SEQ ID NO: 5; q) a W at a position corresponding to a position 75 of SEQ ID NO: 5, and an S at a position corresponding to a position 81 of SEQ ID NO: 5; r) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and a D at a position corresponding to a position 160 of SEQ ID NO: 5; s) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and an A at a position corresponding to a position 145 of SEQ ID NO: 5; t) a W at a position corresponding to a position 75 of SEQ ID NO: 5, and a W at a position corresponding to a position 155 of SEQ ID NO: 5; u) a W at a position corresponding to position 155 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; v) an A at a position corresponding to position 145 of SEQ ID NO: 5, and a W at a position corresponding to position 155 of SEQ ID NO: 5; w) a W at a position corresponding to position 75 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; x) a W at a position corresponding to position 75 of SEQ ID NO: 5, and an A at a position corresponding to position 145 of SEQ ID NO: 5; y) an A at a position corresponding to position 145 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; z) a W at a position corresponding to position 75 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5 NO:5 position 81 corresponding to an S, and a position corresponding to a W corresponding to a position 155 of SEQ ID NO:5; aa) an S at a position corresponding to a S, a W at a position corresponding to a W, and a D at a position corresponding to a position 160 of SEQ ID NO:5; bb) an S at a position corresponding to a S, a A at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 155 of SEQ ID NO:5; cc) a W at a position corresponding to a W, a S at a position corresponding to a S, and a D at a position corresponding to a position 160 of SEQ ID NO:5; dd) a W at a position corresponding to a W, a A at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 155 of SEQ ID NO:5; NO:5 position 81 corresponding to an S, and a position corresponding to a position 145 corresponding to SEQ ID NO:5; ee) an S at a position corresponding to a position 81 corresponding to SEQ ID NO:5, an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5; ff) a W at a position corresponding to a position 75 corresponding to SEQ ID NO:5, a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5; gg) a W at a position corresponding to a position 75 corresponding to SEQ ID NO:5, an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, and a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5; hh) an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5. NO:5 position 155 corresponding to a W, and a position corresponding to a D at a position corresponding to a position 160 of SEQ ID NO:5; ii) a W at a position corresponding to a position 75 of SEQ ID NO:5, an A at a position corresponding to a position 145 of SEQ ID NO:5, and a D at a position corresponding to a position 160 of SEQ ID NO:5; jj) a W at a position corresponding to a position 75 of SEQ ID NO:5, an S at a position corresponding to a position 81 of SEQ ID NO:5, a W at a position corresponding to a position 155 of SEQ ID NO:5, and a D at a position corresponding to a position 160 of SEQ ID NO:5; kk) a W at a position corresponding to a position 75 of SEQ ID NO:5, an S at a position corresponding to a position 81 of SEQ ID NO:5, an A at a position corresponding to a position 145 of SEQ ID NO:5, and a D at a position corresponding to a position 160 of SEQ ID NO:5 NO:5 position 155 corresponding to a W; ll) a S at a position corresponding to SEQ ID NO:5 position 81, an A at a position corresponding to SEQ ID NO:5 position 145, a W at a position corresponding to SEQ ID NO:5 position 155, and a D at a position corresponding to SEQ ID NO:5 position 160; mm) a W at a position corresponding to SEQ ID NO:5 position 75, an S at a position corresponding to SEQ ID NO:5 position 81, an A at a position corresponding to SEQ ID NO:5 position 145, and a D at a position corresponding to SEQ ID NO:5 position 160; nn) a W at a position corresponding to SEQ ID NO:5 position 75, an A at a position corresponding to SEQ ID NO:5 position 145, a W at a position corresponding to SEQ ID NO:5 position 155, and a D at a position corresponding to SEQ ID NO:5 position 160; NO:5 position 160 corresponding to a D; oo) a W at a position corresponding to a W at a position corresponding to a S ... an L at a position corresponding to position 40 of SEQ ID NO: 5, and a Q at a position corresponding to position 159 of SEQ ID NO: 5; tt) an L at a position corresponding to position 40 of SEQ ID NO: 5, and a W at a position corresponding to position 160 of SEQ ID NO: 5; uu) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a V at a position corresponding to position 121 of SEQ ID NO: 5; vv) an M at a position corresponding to position 105 of SEQ ID NO: 5, and an M at a position corresponding to position 145 of SEQ ID NO: 5; ww) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a Q at a position corresponding to position 159 of SEQ ID NO: 5; xx) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a V at a position corresponding to position 121 of SEQ ID NO: 5; NO:5, a W at a position corresponding to position 160; yy) a V at a position corresponding to position 121 of SEQ ID NO:5, and an M at a position corresponding to position 145 of SEQ ID NO:5; zz) a V at a position corresponding to position 121 of SEQ ID NO:5, and a Q at a position corresponding to position 159 of SEQ ID NO:5; aaa) a V at a position corresponding to position 121 of SEQ ID NO:5, and a W at a position corresponding to position 160 of SEQ ID NO:5; bbb) an M at a position corresponding to position 145 of SEQ ID NO:5, and a Q at a position corresponding to position 159 of SEQ ID NO:5; ccc) an M at a position corresponding to position 145 of SEQ ID NO:5, and a W at a position corresponding to position 160 of SEQ ID NO:5; ddd) a NO:5 position 159 corresponding to a Q, and a W corresponding to a position 160 corresponding to a W; eee) a S at a position corresponding to a position 81 of SEQ ID NO:5, a M at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 160 of SEQ ID NO:5; fff) a S at a position corresponding to a position 81 of SEQ ID NO:5, a V at a position corresponding to a position 121 of SEQ ID NO:5, and a Q at a position corresponding to a position 159 of SEQ ID NO:5; ggg) an A at a position corresponding to a position 68 of SEQ ID NO:5, and a S at a position corresponding to a position 81 of SEQ ID NO:5; hhh) a G at a position corresponding to a position 76 of SEQ ID NO:5, and a S at a position corresponding to a position 81 of SEQ ID NO:5; iii) an S at a position corresponding to position 81 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; jjj) an A at a position corresponding to position 68 of SEQ ID NO: 5, and a G at a position corresponding to position 76 of SEQ ID NO: 5; kkk) an A at a position corresponding to position 68 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; lll) a G at a position corresponding to position 76 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; mmm) an A at a position corresponding to position 68 of SEQ ID NO: 5, a G at a position corresponding to position 76 of SEQ ID NO: 5, and an S at a position corresponding to position 81 of SEQ ID NO: 5; nnn) an A at a position corresponding to position 68 of SEQ ID NO: 5, a G at a position corresponding to position 76 of SEQ ID NO: 5, and an S at a position corresponding to position 81 of SEQ ID NO: 5 NO:5 position 68 corresponding to an A, a position corresponding to an S, and a position corresponding to an L in a position corresponding to a position 117 of SEQ ID NO:5; ooo) a G at a position corresponding to a position 76 of SEQ ID NO:5, a S at a position corresponding to a S, and a L in a position corresponding to a position 117 of SEQ ID NO:5; ppp) an A at a position corresponding to a position 68 of SEQ ID NO:5, a G at a position corresponding to a position 76 of SEQ ID NO:5, and a L in a position corresponding to a position 117 of SEQ ID NO:5; qqq) an A at a position corresponding to a position 68 of SEQ ID NO:5, a G at a position corresponding to a position 76 of SEQ ID NO:5, a S at a position corresponding to a position 81 of SEQ ID NO:5, and a L in a position corresponding to a position 117 of SEQ ID NO:5; NO:5 position 117 - L; rrr) SEQ ID NO:5 position 81 - S, SEQ ID NO:5 position 109 - L, SEQ ID NO:5 position 153 - E, SEQ ID NO:5 position 155 - W, and SEQ ID NO:5 position 160 - D; sss) SEQ ID NO:5 position 75 - A, SEQ ID NO:5 position 81 - S, SEQ ID NO:5 position 117 - L, SEQ ID NO:5 position 121 - A, SEQ ID NO:5 position 145 - A, SEQ ID NO:5 position 155 - W, and SEQ ID NO:5 position 160 - D; NO:5 position 160 corresponding to a D; ttt) a Q at a position corresponding to ... NO:5 position 155 corresponding to a W, and a D corresponding to a position 160 corresponding to a D of SEQ ID NO:5; vvv) a C corresponding to a position 22 corresponding to a position 68 corresponding to a position 75 corresponding to a Y of SEQ ID NO:5, a G corresponding to a position 76 corresponding to a position 81 corresponding to a S of SEQ ID NO:5, a H corresponding to a position 108 corresponding to a position 117 corresponding to a L of SEQ ID NO:5, a H corresponding to a position 122 corresponding to a position 138 corresponding to a Y of SEQ ID NO:5, a L corresponding to a position 139 corresponding to a L of SEQ ID NO:5, a H corresponding to a position 140 corresponding to a position 141 corresponding to a position 142 corresponding to a position 143 corresponding to a position 147 corresponding to a position 149 corresponding to a position 150 corresponding to a position 151 corresponding to a position 152 corresponding to a position 153 corresponding to a position 154 corresponding to a position 156 corresponding to a position 157 corresponding to a position 158 corresponding to a position 15 ... NO:5 position 142 corresponding to an A, SEQ ID NO:5 position 145 corresponding to an A, SEQ ID NO:5 position 153 corresponding to an R, SEQ ID NO:5 position 155 corresponding to a W, SEQ ID NO:5 position 156 corresponding to an R, SEQ ID NO:5 position 160 corresponding to a D, and SEQ ID NO:5 position 162 corresponding to an H; or www) SEQ ID NO:5 position 81 corresponding to an S. The system of claim 196 or claim 197, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 300-414, 596-598, and 720-723. The system of claim 196 or claim 197, wherein the deaminase comprises an amino acid sequence of any one of SEQ ID NOs: 300-414, 596-598, and 720-723. The system of any one of claim 196 to claim 199, wherein the deaminase has improved deaminase activity when compared to SEQ ID NO:5. A system as described in any of claims 196 to 200, wherein the deaminase is an adenine deaminase. A system as described in any of claim 196 to claim 201, wherein at least one of the nucleotide sequence encoding the one or more guide RNAs and the nucleotide sequence encoding the fusion protein is operably linked to a promoter heterologous to the nucleotide sequence. A system as described in any of claim 196 to claim 202, wherein the target DNA sequence is a eukaryotic target DNA sequence. The system of any one of claims 196 to 203, wherein the target DNA sequence is positioned adjacent to a protospacer adjacent motif (PAM) recognized by the RGN. The system of any one of claims 196 to 204, wherein the RGN of the fusion protein has an amino acid sequence having at least 95% sequence identity with any one of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699. The system of any one of claims 196 to 205, wherein the RGN of the fusion protein is a RGN nickase. The system of claim 206, wherein the RGN nickase has the amino acid sequence shown in any one of SEQ ID NOs: 49-52 and 698. A system as described in claim 196 or claim 197, wherein the fusion protein is selected from the group consisting of: a) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 319 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; b) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 375 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; c) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 406 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: NO:49 having at least 90% sequence identity to the N-terminus of an RGN; d) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO:596 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO:49; e) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO:597 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO:49; f) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO:303 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO:49; g) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 366 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; and h) A fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 720 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49. A system as described in claim 196 or claim 197, wherein the fusion protein is selected from the group consisting of: a) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence shown in SEQ ID NO: 319 and is fused to the N-terminus of an RGN comprising the amino acid sequence shown in SEQ ID NO: 49; b) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence shown in SEQ ID NO: 375 and is fused to the N-terminus of an RGN comprising the amino acid sequence shown in SEQ ID NO: 49; c) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence shown in SEQ ID NO: 406 and is fused to the N-terminus of an RGN comprising the amino acid sequence shown in SEQ ID NO: 49; d) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence shown in SEQ ID NO: 407 and is fused to the N-terminus of an RGN comprising the amino acid sequence shown in SEQ ID NO: 49; NO:596, and fused to the N-terminus of an RGN comprising the amino acid sequence as shown in SEQ ID NO:49; e) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO:597, and fused to the N-terminus of an RGN comprising the amino acid sequence as shown in SEQ ID NO:49; f) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO:303, and fused to the N-terminus of an RGN comprising the amino acid sequence as shown in SEQ ID NO:49; g) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO:366, and fused to the N-terminus of an RGN comprising the amino acid sequence as shown in SEQ ID NO:49; and h) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO: NO:720, and fused to the N-terminus of an RGN comprising the amino acid sequence as shown in SEQ ID NO:49. The system of claim 196 or claim 197, wherein the fusion protein has the sequence shown in any one of SEQ ID NOs: 577, 578, 582, 584, 588, 593, 594, 604, 605, 616, and 729. A cell comprising a system as described in any of claim 196 to claim 210. The cell of claim 211, wherein the cell is a mammalian cell The cell of claim 211, wherein the cell is a plant cell. A plant or a seed comprising the cell of claim 213. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the system as described in any one of claims 196 to 210 or the cell as described in claim 212. A method for modifying a target DNA molecule comprising a target DNA sequence, the method comprising delivering a system as described in any one of claim 196 to claim 210 to the target DNA molecule or a cell comprising the target DNA molecule. A method for modifying a target DNA molecule comprising a target sequence, comprising: a) assembling the RGN-deaminase ribonucleotide complex in vitro under conditions suitable for forming the RGN-deaminase ribonucleotide complex by combining the following: i) one or more guide RNAs capable of hybridizing with a non-target strand of the target DNA sequence; and ii) a fusion protein comprising an RNA-guided nuclease polypeptide (RGN) and at least one deaminase, wherein the deaminase has an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 5; wherein the deaminase has at least one of the following amino acid residues: A)      a C at a position corresponding to position 2 of SEQ ID NO: 5; B)      an F or C at a position corresponding to position 22 of SEQ ID NO: 5; C)      at a position corresponding to position 3 of SEQ ID NO: 5; NO:5 position 23 corresponding to a Q; D)      an N at a position corresponding to a position 35 corresponding to a position 5 of SEQ ID NO:5; E)      an L at a position corresponding to a position 40 of SEQ ID NO:5; F)      a Q at a position corresponding to a position 46 of SEQ ID NO:5; G)      an A or M at a position corresponding to a position 68 of SEQ ID NO:5; H)      an H at a position corresponding to a position 72 of SEQ ID NO:5; I) a W, A, Q, Y, or D at a position corresponding to a position 75 of SEQ ID NO:5; J) a G at a position corresponding to a position 76 of SEQ ID NO:5; K)      an S at a position corresponding to a position 81 of SEQ ID NO:5; L) an M at a position corresponding to a position 105 of SEQ ID NO:5; M) at a position corresponding to a position 76 of SEQ ID NO:5; NO:5 position 108 corresponding to an H; N)    an L at a position corresponding to SEQ ID NO:5 position 109; O)      an I or L at a position corresponding to SEQ ID NO:5 position 117; P)      an F at a position corresponding to SEQ ID NO:5 position 120; Q)      an E, T, A, G, or V at a position corresponding to SEQ ID NO:5 position 121; R)      an I or H at a position corresponding to SEQ ID NO:5 position 122; S)      a K at a position corresponding to SEQ ID NO:5 position 125; T)      an A at a position corresponding to SEQ ID NO:5 position 126; U)      an H at a position corresponding to SEQ ID NO:5 position 135; V)      a V at a position corresponding to SEQ ID NO:5 position 137; W)    a Y at a position corresponding to position 138 of SEQ ID NO: 5; X)      an L at a position corresponding to position 139 of SEQ ID NO: 5; Y)     a K or A at a position corresponding to position 142 of SEQ ID NO: 5; Z)      an A, Q, L, or M at a position corresponding to position 145 of SEQ ID NO: 5; AA)   a K at a position corresponding to position 148 of SEQ ID NO: 5; BB)        a Q at a position corresponding to position 151 of SEQ ID NO: 5; CC)        an E or R at a position corresponding to position 153 of SEQ ID NO: 5; DD)   a W at a position corresponding to position 155 of SEQ ID NO: 5; EE)   an R or V at a position corresponding to position 156 of SEQ ID NO: 5; FF)        a NO:5, an F at a position corresponding to position 157; GG)   an R at a position corresponding to position 158 of SEQ ID NO:5; HH)   a Q at a position corresponding to position 159 of SEQ ID NO:5; II)      a D or W at a position corresponding to position 160 of SEQ ID NO:5; JJ)        a W, H, V, or A at a position corresponding to position 162 of SEQ ID NO:5; KK)      an R at a position corresponding to position 165 of SEQ ID NO:5; and LL)    an H at a position corresponding to position 166 of SEQ ID NO:5; and b) contacting the target DNA molecule or a cell comprising the target DNA molecule with the in vitro assembled RGN-deaminase ribonucleotide complex; The one or more guide RNAs hybridize with a non-target strand of the target DNA sequence, thereby guiding the fusion protein to bind to the target DNA sequence and modification of the target DNA molecule occurs. A method as described in claim 217, wherein the deaminase comprises: a) an N at a position corresponding to position 35 of SEQ ID NO: 5 and a W at a position corresponding to position 162 of SEQ ID NO: 5; b) an N at a position corresponding to position 35 of SEQ ID NO: 5 and a Q at a position corresponding to position 46 of SEQ ID NO: 5; c) an S at a position corresponding to position 81 of SEQ ID NO: 5 and an R at a position corresponding to position 156 of SEQ ID NO: 5; d) a Q at a position corresponding to position 46 of SEQ ID NO: 5 and an R at a position corresponding to position 156 of SEQ ID NO: 5; e) an R at a position corresponding to position 156 of SEQ ID NO: 5 and a W at a position corresponding to position 162 of SEQ ID NO: 5; f) an A at a position corresponding to position 68 of SEQ ID NO: 5 and a NO:5 position 81 corresponding to an S; g) an N at a position corresponding to the 35th position of SEQ ID NO:5, an S at a position corresponding to the 81st position of SEQ ID NO:5, and a W at a position corresponding to the 162nd position of SEQ ID NO:5; h) an N at a position corresponding to the 35th position of SEQ ID NO:5, a Q at a position corresponding to the 46th position of SEQ ID NO:5, and a W at a position corresponding to the 162nd position of SEQ ID NO:5; i) a W at a position corresponding to the 155th position of SEQ ID NO:5, an R at a position corresponding to the 156th position of SEQ ID NO:5, and a W at a position corresponding to the 162nd position of SEQ ID NO:5; j) an N at a position corresponding to the 35th position of SEQ ID NO:5, an R at a position corresponding to the 156th position of SEQ ID NO:5, and a W at a position corresponding to the 162nd position of SEQ ID NO:5 NO:5 position 162 corresponding to a W; k) a N at a position corresponding to a position 35 of SEQ ID NO:5, a S at a position corresponding to a position 81 of SEQ ID NO:5, a R at a position corresponding to a position 156 of SEQ ID NO:5, and a W at a position corresponding to a position 162 of SEQ ID NO:5; l) a M at a position corresponding to a position 68 of SEQ ID NO:5, a H at a position corresponding to a position 108 of SEQ ID NO:5, a R at a position corresponding to a position 156 of SEQ ID NO:5, and a W at a position corresponding to a position 162 of SEQ ID NO:5; m) a Q at a position corresponding to a position 46 of SEQ ID NO:5, a M at a position corresponding to a position 68 of SEQ ID NO:5, a H at a position corresponding to a position 108 of SEQ ID NO:5, a NO:5 position 156 corresponding to an R, and a position corresponding to position 162 corresponding to SEQ ID NO:5; n) a M at a position corresponding to position 68 of SEQ ID NO:5, a S at a position corresponding to position 81 of SEQ ID NO:5, a H at a position corresponding to position 108 of SEQ ID NO:5, a R at a position corresponding to position 156 of SEQ ID NO:5, and a W at a position corresponding to position 162 of SEQ ID NO:5; o) a Q at a position corresponding to position 46 of SEQ ID NO:5, a N at a position corresponding to position 35, a M at a position corresponding to position 68 of SEQ ID NO:5, a S at a position corresponding to position 81 of SEQ ID NO:5, a H at a position corresponding to position 108 of SEQ ID NO:5, a W at a position corresponding to position 155 of SEQ ID NO:5, and a W at a position corresponding to position 162 of SEQ ID NO:5; NO: 5 position 156 corresponding to an R, and a position corresponding to a W corresponding to a position 162 of SEQ ID NO: 5; p) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and a W at a position corresponding to a position 155 of SEQ ID NO: 5; q) a W at a position corresponding to a position 75 of SEQ ID NO: 5, and an S at a position corresponding to a position 81 of SEQ ID NO: 5; r) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and a D at a position corresponding to a position 160 of SEQ ID NO: 5; s) an S at a position corresponding to a position 81 of SEQ ID NO: 5, and an A at a position corresponding to a position 145 of SEQ ID NO: 5; t) a W at a position corresponding to a position 75 of SEQ ID NO: 5, and a W at a position corresponding to a position 155 of SEQ ID NO: 5; u) a W at a position corresponding to position 155 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; v) an A at a position corresponding to position 145 of SEQ ID NO: 5, and a W at a position corresponding to position 155 of SEQ ID NO: 5; w) a W at a position corresponding to position 75 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; x) a W at a position corresponding to position 75 of SEQ ID NO: 5, and an A at a position corresponding to position 145 of SEQ ID NO: 5; y) an A at a position corresponding to position 145 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; z) a W at a position corresponding to position 75 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5 NO:5 position 81 corresponding to an S, and a position corresponding to a W corresponding to a position 155 of SEQ ID NO:5; aa) an S at a position corresponding to a S, a W at a position corresponding to a W, and a D at a position corresponding to a position 160 of SEQ ID NO:5; bb) an S at a position corresponding to a S, a A at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 155 of SEQ ID NO:5; cc) a W at a position corresponding to a W, a S at a position corresponding to a S, and a D at a position corresponding to a position 160 of SEQ ID NO:5; dd) a W at a position corresponding to a W, a A at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 155 of SEQ ID NO:5; NO:5 position 81 corresponding to an S, and a position corresponding to a position 145 corresponding to SEQ ID NO:5; ee) an S at a position corresponding to a position 81 corresponding to SEQ ID NO:5, an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5; ff) a W at a position corresponding to a position 75 corresponding to SEQ ID NO:5, a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5; gg) a W at a position corresponding to a position 75 corresponding to SEQ ID NO:5, an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, and a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5; hh) an A at a position corresponding to a position 145 corresponding to SEQ ID NO:5, a W at a position corresponding to a position 155 corresponding to SEQ ID NO:5, and a D at a position corresponding to a position 160 corresponding to SEQ ID NO:5. NO:5 position 155 corresponding to a W, and a position corresponding to a D at a position corresponding to a position 160 of SEQ ID NO:5; ii) a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a W at a position corresponding to a NO:5 position 155 corresponding to a W; ll) a S at a position corresponding to the 81st position of SEQ ID NO:5, an A at a position corresponding to the 145th position of SEQ ID NO:5, a W at a position corresponding to the 155th position of SEQ ID NO:5, and a D at a position corresponding to the 160th position of SEQ ID NO:5; mm) a W at a position corresponding to the 75th position of SEQ ID NO:5, an S at a position corresponding to the 81st position of SEQ ID NO:5, an A at a position corresponding to the 145th position of SEQ ID NO:5, and a D at a position corresponding to the 160th position of SEQ ID NO:5; nn) a W at a position corresponding to the 75th position of SEQ ID NO:5, an A at a position corresponding to the 145th position of SEQ ID NO:5, a W at a position corresponding to the 155th position of SEQ ID NO:5, and a D at a position corresponding to the 160th position of SEQ ID NO:5. NO:5 position 160 corresponding to a D; oo) a W at a position corresponding to a W at a position corresponding to a S ... an L at a position corresponding to position 40 of SEQ ID NO: 5, and a Q at a position corresponding to position 159 of SEQ ID NO: 5; tt) an L at a position corresponding to position 40 of SEQ ID NO: 5, and a W at a position corresponding to position 160 of SEQ ID NO: 5; uu) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a V at a position corresponding to position 121 of SEQ ID NO: 5; vv) an M at a position corresponding to position 105 of SEQ ID NO: 5, and an M at a position corresponding to position 145 of SEQ ID NO: 5; ww) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a Q at a position corresponding to position 159 of SEQ ID NO: 5; xx) an M at a position corresponding to position 105 of SEQ ID NO: 5, and a V at a position corresponding to position 121 of SEQ ID NO: 5; NO:5, a W at a position corresponding to position 160; yy) a V at a position corresponding to position 121 of SEQ ID NO:5, and an M at a position corresponding to position 145 of SEQ ID NO:5; zz) a V at a position corresponding to position 121 of SEQ ID NO:5, and a Q at a position corresponding to position 159 of SEQ ID NO:5; aaa) a V at a position corresponding to position 121 of SEQ ID NO:5, and a W at a position corresponding to position 160 of SEQ ID NO:5; bbb) an M at a position corresponding to position 145 of SEQ ID NO:5, and a Q at a position corresponding to position 159 of SEQ ID NO:5; ccc) an M at a position corresponding to position 145 of SEQ ID NO:5, and a W at a position corresponding to position 160 of SEQ ID NO:5; ddd) a NO:5 position 159 corresponding to a Q, and a W corresponding to a position 160 corresponding to a W; eee) a S at a position corresponding to a position 81 of SEQ ID NO:5, a M at a position corresponding to a position 145 of SEQ ID NO:5, and a W at a position corresponding to a position 160 of SEQ ID NO:5; fff) a S at a position corresponding to a position 81 of SEQ ID NO:5, a V at a position corresponding to a position 121 of SEQ ID NO:5, and a Q at a position corresponding to a position 159 of SEQ ID NO:5; ggg) an A at a position corresponding to a position 68 of SEQ ID NO:5, and a S at a position corresponding to a position 81 of SEQ ID NO:5; hhh) a G at a position corresponding to a position 76 of SEQ ID NO:5, and a S at a position corresponding to a position 81 of SEQ ID NO:5; iii) an S at a position corresponding to position 81 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; jjj) an A at a position corresponding to position 68 of SEQ ID NO: 5, and a G at a position corresponding to position 76 of SEQ ID NO: 5; kkk) an A at a position corresponding to position 68 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; lll) a G at a position corresponding to position 76 of SEQ ID NO: 5, and an L at a position corresponding to position 117 of SEQ ID NO: 5; mmm) an A at a position corresponding to position 68 of SEQ ID NO: 5, a G at a position corresponding to position 76 of SEQ ID NO: 5, and an S at a position corresponding to position 81 of SEQ ID NO: 5; nnn) a G at a position corresponding to position 68 of SEQ ID NO: 5, and an S at a position corresponding to position 81 of SEQ ID NO: 5; NO:5 position 68 corresponding to an A, a position corresponding to an S, and a position corresponding to an L in a position corresponding to a position 117 of SEQ ID NO:5; ooo) a G at a position corresponding to a position 76 of SEQ ID NO:5, a S at a position corresponding to a position 81 of SEQ ID NO:5, and a L in a position corresponding to a position 117 of SEQ ID NO:5; ppp) an A at a position corresponding to a position 68 of SEQ ID NO:5, a G at a position corresponding to a position 76 of SEQ ID NO:5, and a L in a position corresponding to a position 117 of SEQ ID NO:5; qqq) an A at a position corresponding to a position 68 of SEQ ID NO:5, a G at a position corresponding to a position 76 of SEQ ID NO:5, a S at a position corresponding to a position 81 of SEQ ID NO:5, and a L in a position corresponding to a position 117 of SEQ ID NO:5 NO:5 position 117 - L; rrr) SEQ ID NO:5 position 81 - S, SEQ ID NO:5 position 109 - L, SEQ ID NO:5 position 153 - E, SEQ ID NO:5 position 155 - W, and SEQ ID NO:5 position 160 - D; sss) SEQ ID NO:5 position 75 - A, SEQ ID NO:5 position 81 - S, SEQ ID NO:5 position 117 - L, SEQ ID NO:5 position 121 - A, SEQ ID NO:5 position 145 - A, SEQ ID NO:5 position 155 - W, and SEQ ID NO:5 position 160 - D; NO:5 position 160 corresponding to a D; ttt) a Q at a position corresponding to a position 75 of SEQ ID NO:5, an S at a position corresponding to a position 81 of SEQ ID NO:5, an I at a position corresponding to a position 117 of SEQ ID NO:5, a Q at a position corresponding to a position 145 of SEQ ID NO:5, a W at a position corresponding to a position 155 of SEQ ID NO:5, and a D at a position corresponding to a position 160 of SEQ ID NO:5; uuu) a Y at a position corresponding to a position 75 of SEQ ID NO:5, an S at a position corresponding to a position 81 of SEQ ID NO:5, an L at a position corresponding to a position 117 of SEQ ID NO:5, a G at a position corresponding to a position 121 of SEQ ID NO:5, an L at a position corresponding to a position 145 of SEQ ID NO:5, a a W at a position corresponding to position 155 of SEQ ID NO: 5, and a D at a position corresponding to position 160 of SEQ ID NO: 5; vvv) a C at a position corresponding to position 22 of SEQ ID NO: 5, an A at a position corresponding to position 68 of SEQ ID NO: 5, a Y at a position corresponding to position 75 of SEQ ID NO: 5, a G at a position corresponding to position 76 of SEQ ID NO: 5, an S at a position corresponding to position 81 of SEQ ID NO: 5, an H at a position corresponding to position 108 of SEQ ID NO: 5, an L at a position corresponding to position 117 of SEQ ID NO: 5, an H at a position corresponding to position 122 of SEQ ID NO: 5, a Y at a position corresponding to position 138 of SEQ ID NO: 5, an L at a position corresponding to position 139 of SEQ ID NO: 5, an H at a position corresponding to position 140 of SEQ ID NO: 5, an H at a position corresponding to position 141 of SEQ ID NO: 5, an L at a position corresponding to position 142 of SEQ ID NO: 5, an L at a position corresponding to position 143 of SEQ ID NO: 5, an L at a position corresponding to position 144 of SEQ ID NO: 5, an L at a position corresponding to position 145 of SEQ ID NO: 5, an L at a position corresponding to position 146 of SEQ ID NO: 5, an L at a position corresponding to position 147 of SEQ ID NO: 5, an L at a position corresponding to position 148 of SEQ ID NO: 5, an L at a position corresponding to position 149 of SEQ ID NO: 5, an L at a position corresponding to position 150 of SEQ ID NO: 5, an L at a position corresponding to position 151 of SEQ ID NO: 5, an L at a position NO:5 position 142 corresponding to an A, SEQ ID NO:5 position 145 corresponding to an A, SEQ ID NO:5 position 153 corresponding to an R, SEQ ID NO:5 position 155 corresponding to a W, SEQ ID NO:5 position 156 corresponding to an R, SEQ ID NO:5 position 160 corresponding to a D, and SEQ ID NO:5 position 162 corresponding to an H; or www) SEQ ID NO:5 position 81 corresponding to an S. The method of claim 217 or claim 218, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with any one of SEQ ID NOs: 300-414, 596-598, and 720-723. The method of claim 217 or claim 218, wherein the deaminase has the amino acid sequence of any one of SEQ ID NOs: 300-414, 596-598, and 720-723. The method of any one of claims 217 to 220, wherein the deaminase has improved deaminase activity when compared to SEQ ID NO:5. A method as described in any of claim 217 to claim 221, wherein the deaminase is an adenine deaminase. A method as described in any one of claims 217 to 222, wherein the RGN of the fusion protein has an amino acid sequence that has at least 95% sequence identity with any one of SEQ ID NOs: 1-4, 49-162, 435, 575, 576, 698, and 699. The method of any one of claims 217 to 222, wherein the RGN of the fusion protein is an RGN nickase. The method of claim 224, wherein the RGN nickase has the amino acid sequence shown in any one of SEQ ID NOs: 49-52 and 698. A method as described in claim 217 or claim 218, wherein the fusion protein is selected from the group consisting of: a) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 319 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; b) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 375 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; c) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 406 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; d) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 596 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; e) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 597 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; f) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 303 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; g) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 303 and is fused to the N-terminus of an RGN comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 49; NO:366 having an amino acid sequence with at least 90% sequence identity, and fused to the N-terminus of an RGN comprising an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49; and h) a fusion protein comprising the deaminase, wherein the deaminase comprises an amino acid sequence with at least 90% sequence identity to SEQ ID NO:720, and fused to the N-terminus of an RGN comprising an amino acid sequence with at least 90% sequence identity to SEQ ID NO:49. A method as described in claim 217 or claim 218, wherein the fusion protein is selected from the group consisting of: a) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence shown in SEQ ID NO: 319 and is fused to the N-terminus of an RGN comprising the amino acid sequence shown in SEQ ID NO: 49; b) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence shown in SEQ ID NO: 375 and is fused to the N-terminus of an RGN comprising the amino acid sequence shown in SEQ ID NO: 49; c) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence shown in SEQ ID NO: 406 and is fused to the N-terminus of an RGN comprising the amino acid sequence shown in SEQ ID NO: 49; d) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence shown in SEQ ID NO: 509 and is fused to the N-terminus of an RGN comprising the amino acid sequence shown in SEQ ID NO: 510; NO:596, and fused to the N-terminus of an RGN comprising the amino acid sequence as shown in SEQ ID NO:49; e) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO:597, and fused to the N-terminus of an RGN comprising the amino acid sequence as shown in SEQ ID NO:49; f) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO:303, and fused to the N-terminus of an RGN comprising the amino acid sequence as shown in SEQ ID NO:49; g) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO:366, and fused to the N-terminus of an RGN comprising the amino acid sequence as shown in SEQ ID NO:49; and h) a fusion protein comprising the deaminase, wherein the deaminase comprises the amino acid sequence as shown in SEQ ID NO: NO:720, and fused to the N-terminus of an RGN comprising the amino acid sequence as shown in SEQ ID NO:49. A method as described in claim 217 or claim 218, wherein the fusion protein has the sequence shown in any one of SEQ ID NOs: 577, 578, 582, 584, 588, 593, 594, 604, 605, 616, and 729. A method as described in any one of claim 217 to claim 228, wherein the target DNA sequence is a eukaryotic target DNA sequence. A method as described in any of claim 217 to claim 229, wherein the target DNA sequence is positioned adjacent to a protospacer adjacent motif (PAM). A method as described in any of claim 217 to claim 230, wherein the target DNA molecule includes a causal mutation for a disease or condition and wherein the modification of the target DNA molecule corrects the causal mutation. A method as described in claim 231, wherein the correction of the causal mutation includes correcting a meaningless mutation. A method as described in any one of claim 217 to claim 232, wherein the target DNA molecule is within a cell. The method of claim 233, further comprising selecting a cell comprising the modified DNA molecule. A cell comprising a modified target DNA sequence as described in claim 234. The cell of claim 235, wherein the cell is a mammalian cell. The cell of claim 235, wherein the cell is a plant cell. A plant or a seed comprising the cell of claim 237. A pharmaceutical composition comprising the cell as described in claim 236 and a pharmaceutically acceptable carrier. A method for treating an individual suffering from or at risk of developing a disease, disorder or symptom, the method comprising: Administering to the individual a fusion protein as described in any one of claims 158 to 170, an RNP complex as described in claim 171, a nucleic acid molecule as described in any one of claims 172 to 184, a vector as described in claim 185 or 186, a cell as described in any one of claims 191, 212, and 236, a system as described in any one of claims 196 to 210, or a pharmaceutical composition as described in any one of claims 194, 215, and 239. The method of claim 240, wherein the disease is associated with a causal mutation and the treatment comprises correcting the causal mutation. A fusion protein as described in any one of claim 158 to claim 170, an RNP complex as described in claim 171, a nucleic acid molecule as described in any one of claim 172 to claim 184, a vector as described in claim 185 or claim 186, a cell as described in any one of claim 191, claim 212, and claim 236, or a system as described in any one of claim 196 to claim 210 for treating a disease, disorder or symptom in an individual suffering from or at risk of developing the disease, disorder or symptom condition. The use of claim 242, wherein the disease is associated with a causal mutation and the treatment comprises correcting the causal mutation. Use of a fusion protein as described in any one of claims 158 to 170, an RNP complex as described in claim 171, a nucleic acid molecule as described in any one of claims 172 to 184, a vector as described in claim 185 or 186, a cell as described in any one of claims 191, 212, and 236, or a system as described in any one of claims 196 to 210 for the manufacture of a medicament useful for treating a disease, disorder or symptom. The use of claim 244, wherein the disease is associated with a causal mutation and an effective amount of the drug corrects the causal mutation.