WO2025137123A1

WO2025137123A1 - Compositions and methods for circularizing donor nucleic acids

Info

Publication number: WO2025137123A1
Application number: PCT/US2024/060799
Authority: WO
Inventors: Timothy Robert ABBOTT; Brian R. CHAIKIND; Benjamin Julius RAUCH; Brent Edward SAGE
Original assignee: Mammoth Biosciences Inc
Current assignee: Mammoth Biosciences Inc
Priority date: 2023-12-20
Filing date: 2024-12-18
Publication date: 2025-06-26
Anticipated expiration: 2026-06-20

Abstract

Disclosed herein are composition and methods of modifying a target double-stranded DNA (dsDNA) molecule in a cell. Compositions and methods are useful for circularizing a linear DNA plasmid (e.g., an AAV vector) and integrating it into a target genome. Systems, compositions, and methods may comprise a CRISPR-associated (Cas) protein, an RNA-dependent DNA polymerase, an LSR, and/or one or more guide nucleic acids or uses thereof.

Description

COMPOSITIONS AND METHODS FOR CIRCULARIZING DONOR NUCLEIC ACIDS CROSS-REFERENCE TO RELATED APPLICATIONS [1] The present application claims priority to U.S. Provisional Application 63/612,437, filed December 20, 2023; U.S. Provisional Application 63/664,225, filed June 26, 2024; U.S. Provisional Application 63/671,603, filed July 15, 2024, the contents each of which are incorporated herein by reference in their entireties. REFERENCE TO THE ELECTRONIC SEQUENCE FILE [2] The contents of the electronic sequence listing (MABI_050_03WO_SeqList_ST26.xml; Size: 10,291,161 bytes; and Date of Creation: December 12, 2024) are herein incorporated by reference in its entirety. BACKGROUND [3] Large serine recombinases (LSRs), also sometimes referred to as integrases, catalyze the movement of DNA elements into and out of bacterial chromosomes using site-specific recombination between short DNA "attachment sites". The LSRs that function as bacteriophage integrases carry out integration between attachment sites in the phage (attP) and in the host (attB). Large serine recombinases (LSRs) perform unidirectional integration. Though they can integrate linear DNA, for efficient and error free integration, circular DNA donor is the preferred substrate. [4] Site-specific recombinases, such as large serine recombinases, have evolved to catalyze the transfer of large genetic payloads that are often tens of kilobases in length, from one organism to another, without relying on recipient genetic repair machinery. By recognizing attachment sites found in donor and target sequence DNA, recombinases are capable of catalyzing target cleavage, strand exchange and DNA rejoining within their synaptic complexes. This mechanism enables site-specific DNA insertion without requiring any cellular cofactors and without generating exposed DSBs. Furthermore, unlike tyrosine recombinases, LSRs do not have to be engineered to prevent excision of the integration product once integration occurs. An LSR is usually 400-700 amino acids in length including a catalytic site and several domains that are used for sequence recognition and placement for the integration to occur. [5] Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and associated proteins (Cas proteins), sometimes referred to as a CRISPR/Cas system, were first identified in certain bacterial species and are now understood to form part of a prokaryotic acquired immune system. CRISPR/Cas systems provide immunity in bacteria and archaea against viruses and plasmids by targeting the nucleic acids of the viruses and plasmids in a sequence- specific manner. Native systems contain a CRISPR array, which includes direct repeats flanking short spacer sequences that, in part, guide Cas proteins to their targets. The discovery of CRISPR/Cas systems has revolutionized the field of genomic manipulation and engineering, and therapeutic applications of these systems are being explored. SUMMARY [6] Stable adeno-associated virus (AAV) transduction occurs after a process involving uptake, intracellular trafficking, endosomal escape, nuclear import, and double strand synthesis. The process ends either when double stranded DNA is integrated in the genome (a relatively rare event) or stabilized in circular DNA episomes. These processes, including the synthesis and stability of double stranded DNA, as well as the circularization of the DNA, are reported to be inefficient processes, reliant on the cell’s innate DNA damage machinery. [7] Many current clinical trials and preclinical research studies rely on AAVs as a donor for integration which is enhanced by Cas-based cleavage. However, this process is stochastic and often creates more unwanted indels than desired integration events. In contrast, LSRs can mediate unidirectional, specific integration of a donor with a mechanism that avoids exposed DSBs and unwanted indels. [8] LSRs rely on circular DNA for efficient, errorless insertion and there are few well- established methods of effectively delivering a circular DNA donor in vivo. AAVs, one of the most commonly used methods of delivering DNA in vivo, does circularize and can be used as a donor for LSR-integration. However, the circularization process is often inefficient, limiting the availability of the donor DNA. Minicircle DNA has been created by LSRs to remove unwanted sequences from plasmids and then used in subsequent integration. However, efficient delivery of DNA in vivo is still not a well-developed technology. [9] Compositions and methods of the instant disclosure use recombinases (e.g., LSRs) to circularize linear DNA, from AAVs or other donor vectors, in order to enhance (relative to non-circularized AAVs) (1) viral transduction, (2) long-term expression by catalyzing the circularization and stabilization of the AAV, (3) integration in vivo, or any combination thereof. These compositions and methods enable more efficient transduction relative to relying on DNA repair machinery alone by enzymatically driving the formation of circular DNA from the relatively unstable linear dsDNA form. These compositions and methods provide a means for increasing the efficiency of AAV (or any delivery vector containing a linear ds donor) circularization–which can then be used either for donor integration or maintained in the cell for years as an episome. Further, by enzymatically forming circular DNA, the recombinase can enhance the production of its own preferred integration substrate, increasing the efficiency of recombinase-based integration. Circularization will remove unwanted sequences such as ITRs that would otherwise get incorporated into the genome. By way of non-limiting example, recombinases may be delivered as an LNP, plasmid, or virus and the donor may be delivered as any virus/donor that has or converts into a double stranded DNA form (AAV/AdV/Lentivirus). AAV vectors include self-inactivating AAVs capable of single AAV- based integration in various tissues, including, e.g., in extrahepatic tissue. [10] For use as a donor in recombinase-based integration, the concept relies on the fact that recombinases create a staggered overhang at compatible recombinase recognition sites (RRS) (e.g., an AttB site and an AttP site). Exchange and re-ligation of the two staggered cut sites enables recombination. One can make orthogonal sets of RRSs, using the same recombinase by simply changing the internal bases of these staggered cuts, but keeping the rest of the RRS sequences the same. Thus, the self-circularizing AAV contains an RRS pair (e.g., RRS-1a and RRS-1b) with the same internal base pairs. In the correct orientation, a recombinase will react to form a circular template, but only after the cell converts the AAV from a mostly single- stranded genome, to a double stranded genome. The AAV may also contain a recombination site (e.g., RRS-2a) that is orthogonal to (e.g., incompatible with) RRS-1a and RRS1-b. This site can be used for recombination-catalyzed integration in the genome at a recombinase recognition site that is compatible with RRS-2a (e.g., RRS-2b). CRISPR/Cas systems, including but not limited to precision editing systems (e.g., RT editing, base editing), may be employed to generate an RRS-2b at a site of interest. In some embodiments, the AAV does not contain an RRS-2a, and the recombinase merely circularizes the donor vector for long-term stability and expression. [11] Additionally or alternatively, the recombinase may be encoded on the AAV vector that contains the recombinase recognition sites. If placed on the outside of these three sites, the recombinase may be removed from the circular template prior to episome formation and/or integration. In such a scheme, production of the AAV may rely on coexpression of a recombinase directionality factor (RDF) or siRNA to limit recombinase activity during viral production. These systems are valuable because they enable a self-inactivating AAV vector. Further, having the recombinase present on the same substrate for integration may also be valuable due to the lengthy period of AAV unpackaging (known to take weeks) and the relative instability of AAV double stranded linear DNA. The instability coupled with this slow rate of unpacking, logically, makes it more difficult for AAV donor and recombinase, delivered separately, to be present in the same cell at the same time. However, expressing the recombinase on the same nucleic acid as the donor, means that there will be recombinase expressed whenever the AAV has unpacked the linear DNA and converted it to dsDNA. Furthermore, by encoding the recombinase on the AAV(or other viral-based dsDNA intermediate) itself, the strategy can enable integration in extrahepatic tissue, which is not possible (in a targeted manner) by other means. [12] In some aspects, the present disclosure provides systems or compositions for the modification of a target nucleic acid comprising: a) a recombinase or a nucleic acid encoding a recombinase; and b) a donor vector comprising i) a sequence of insertion (SOI); ii) a pair of recombinase recognition sites (RRS-1a and RRS-1b) that are compatible with one another; and iii) optionally, a donor recombinase recognition site (RRS-2a) that is compatible with a target nucleic acid recombinase recognition site (RRS-2b), wherein the donor vector is a linear vector, wherein RRS-1a and RRS-1b are orthogonal to RRS-2a and RRS-2b, and wherein the recombinase recognizes RRS-1a, RRS-1b, RRS-2a and RRS-2b. [13] In some aspects, the present disclosure provides systems or compositions for the modification of a target nucleic acid comprising a donor vector, wherein the donor vector comprises: i) a sequence encoding a recombinase; ii) a sequence of insertion (SOI); iii) a pair of recombinase recognition sites (RRS-1a and RRS-1b) that are compatible with one another; and iv) optionally, a donor recombinase recognition site (RRS-2a) that is compatible with a target nucleic acid recombinase recognition site (RRS-2b), wherein the donor vector is a linear vector, wherein RRS-1a and RRS-1b are orthogonal to RRS-2a and RRS-2b, and wherein the recombinase recognizes RRS-1a, RRS-1b, RRS-2a and RRS-2b. In some embodiments, the sequence encoding the recombinase is located 5’ or 3’ of the SOI, RRS-1a, RRS-1b, and RRS- 2a. In some embodiments, RRS-1a is located 5’ of the SOI, 5’ of the RRS-2a, 5’ of the RRS- 1b, or any combination thereof. In some embodiments, the SOI and RRS-2a are located between the RRS-1a and RRS-1b. In some embodiments, the RRS-1b is located 3’ of the SOI, 3’ of the RRS-1a, 3’ of the RRS-2a, or any combination thereof. In some embodiments, the recombinase generates staggered cuts at RRS-1a and RRS-1b, wherein the staggered cuts at RRS-1a and RRS-1b are the same. In some embodiments, the recombinase recombines the staggered cuts at RRS-1a and RRS-1b to form a circular nucleic acid of the donor vector. In some embodiments, the circular nucleic acid comprises the SOI and RRS-2a. In some embodiments, the recombinase generates staggered cuts at RRS-2a and RRS-2b, wherein the staggered cuts at RRS-2a and RRS-2b are the same, and wherein at least one of the nucleotides of the staggered cuts at RRS-1a and RRS-1b are different from one of the nucleotides of the staggered cuts at RRS-2a and RRS-2b. In some embodiments, the recombinase recombines the staggered cuts at RRS-2a and RRS-2b to insert the SOI to the target nucleic acid. In some embodiments, the donor vector is an adeno-associated viral (AAV) vector. In some embodiments, the donor vector is a self-inactivating AAV vector. In some embodiments, the recombinase is a large serine recombinase. In some embodiments, a) RRS-1a comprises a first AttB site and RRS-1b comprises a first AttP site or vice versa; and b) RRS-2a comprises a second AttP site and RRS-2b comprises a second AttB site or vice versa, wherein the first AttB site is compatible with the first AttP site, and the second AttP site is compatible with the second AttB site, and wherein the first AttB site is incompatible with the second AttP site, and wherein the second AttB site is incompatible with the first AttP site. In some embodiments, the recombinase comprises an amino acid sequence that is at least 35%, 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 95%, at least 97%, at least 98%, at least 99%, or 100% identical to a sequence selected from TABLES 1-3. In some embodiments, the recombinase comprises an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% identical to a sequence selected from SEQ ID NOs: 1-2523 and 9272-9274, the RRS-1a and/or RRS-2a comprises a nucleotide sequence that is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical to a sequence selected from SEQ ID NOs: 6442-8964 and 9278-9280, and the RRS-1b and/or RRS-2b comprises a nucleotide sequence that is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical to a sequence selected from SEQ ID NOs: 3919-6441 and 9275-9277, wherein the recombinase, RRS-1 and RRS-2 are in the same row of TABLE 1 or TABLE 2. In some embodiments, the RRS-2b is located in or near a safe harbor locus. In some embodiments, the safe harbor locus is in or near an AAVS1 (PPPIR12C) gene, an ALB gene, an Angptl3 gene, an ApoC3 gene, an ASGR2 gene, a CCR5 gene, a FIX (F9) gene, a G6PC gene, a Gys2 gene, an HGD gene, a Lp(a) gene, a Pcsk9 gene, a Serpina1 gene, a TF gene, and a TTR gene, and an intron thereof. In some embodiments, the RRS-2b is located in or near a target sequence of the human albumin gene (ALB) or AAVS1 gene. In some embodiments, the nucleic acid encoding the recombinase and the donor DNA vector are combined in a single composition. In some embodiments, the system or composition comprises a lipid nanoparticle (LNP), wherein the nucleic acid encoding the recombinase is associated with the LNP, optionally wherein the nucleic acid encoding the recombinase comprises a messenger RNA (mRNA). In some embodiments, the donor vector is linked to or codelivered with the nucleic acid encoding a recombinase in a delivery vector. In some embodiments, the system or composition comprises: a) an effector protein or a nucleic acid encoding the same, b) an effector partner protein or a nucleic acid encoding the same, c) a guide nucleic acid or a DNA molecule encoding the same, or d) a combination thereof. In some embodiments, the effector partner protein is selected from an RNA dependent DNA polymerase (RDDP) and a base editing enzyme. In some embodiments, the effector protein is a CRISPR associated (Cas) protein. In some embodiments, the Cas protein is a Type II protein or a Type V Cas protein. In some embodiments, the Cas protein comprises an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NOs: 9267-9268. In some embodiments, the length of the Cas protein is 350 to 500, 350-600, 350-700, 350-800, 350- 900, or 350-1000 amino acids. In some embodiments, the Cas protein comprises nickase activity. In some embodiments, the effector partner protein comprises an RDDP. In some embodiments, the system or composition comprises at least one guide nucleic acid, wherein the at least one guide nucleic acid comprises: i) a protein binding sequence, wherein the effector protein is capable of binding the protein binding sequence, ii) a spacer sequence that hybridizes to a first target sequence on a first strand of the target nucleic acid, iii) a primer binding sequence, optionally wherein a portion of the primer binding sequence hybridizes to a first portion of the second strand of the target nucleic acid; and iv) a template sequence that hybridizes to a second portion of the second strand of the target nucleic acid. In some embodiments, the protein binding sequence comprises a nucleic acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NOs: 9269-9271. [14] In some aspects, the present disclosure provides methods of modifying a target nucleic acid comprising contacting the target nucleic acid with the composition or components of the system of any of the above aspects or embodiments. In some embodiments, the SOI is inserted into the target nucleic acid at RRS-2b. In some embodiments, the method comprises contacting the target nucleic acid with the effector protein, the effector partner protein, and the guide nucleic acid prior to contacting the target nucleic acid with the nucleic acid encoding the recombinase and the donor DNA vector. In some embodiments, the method comprises modifying the target nucleic acid to produce the RRS-2b. In some embodiments, the method comprises contacting a cell with the composition or components of the system. In some embodiments, the cell is a eukaryotic cell. [15] In some aspects, the present disclosure provides recombinant adeno-associated virus (AAV) vectors comprising a) a 5’ inverted terminal repeat (ITR) sequence; b) a donor nucleic acid comprising: i) a sequence of insertion (SOI), ii) two recombinase recognition sites (RRS- 1a and RRS-1b) that are compatible with one another, and iii) optionally, a donor recombinase recognition site (RRS-2a) that is compatible with a target nucleic acid recombinase recognition site (RRS-2b), wherein RRS-1a and RRS-1b are orthogonal to RRS-2a and RRS-2b; c) a sequence encoding a recombinase that is operably linked to a promoter, wherein the recombinase recognizes RRS-1a, RRS-1b, RRS-2a and RRS-2b; and d) a 3’ ITR sequence. In some embodiments, the SOI, the donor recombinase recognition site, and the promoter that is operably linked to the sequence encoding the recombinase are placed between RRS1-a and RRS-1b. In some embodiments, the sequence encoding the recombinase is placed outside of RRS1-a, RRS-1b and RRS-2a. In some embodiments, the recombinase is a large serine recombinase (LSR). In some embodiments, the promoter is a mammalian promoter. In some embodiments, the promoter is a CMV promoter. [16] In some aspects, the present disclosure provides AAV transfer plasmids comprising: a) a 5’ inverted terminal repeat (ITR) sequence; b) a donor nucleic acid comprising: : i) a sequence of insertion (SOI), ii) two recombinase recognition sites (RRS-1a and RRS-1b) that are compatible with one another, and iii) optionally, a donor recombinase recognition site (RRS- 2a) that is compatible with a target nucleic acid recombinase recognition site (RRS-2b), wherein RRS-1a and RRS-1b are orthogonal to RRS-2a and RRS-2b; c) a sequence encoding a recombinase that is operably linked to a promoter, wherein the recombinase recognizes RRS- 1a, RRS-1b, RRS-2a and RRS-2b and wherein the opposite strand of the sequence encoding the recombinase is operably linked to a bacterial promoter that expresses an antisense RNA of the recombinase; d) a 3’ ITR sequence; e) a sequence encoding an shRNA that targets the recombinase, wherein the sequence encoding the shRNA is operably linked to a Pol III promoter; and f) a sequence encoding a recombinase directionality factor (RDF) that is operably linked to a mammalian promoter followed by a bacterial promoter. In some embodiments, the sequence encoding the recombinase and the donor nucleic acid are flanked by the 5’ ITR sequence and the 3’ ITR sequence. In some embodiments, the sequence encoding the shRNA and the sequence encoding the RDF are placed outside of the 5’ ITR sequence and the 3’ ITR sequence. In some embodiments, the bacterial promoter that is operably linked to the opposite strand of the sequence encoding the recombinase is a J23119 promoter. In some embodiments, the Pol III promoter is a hU6 promoter. In some embodiments, the bacterial promoter that is operably linked to the sequence encoding the RDF is a J23104 promoter. In some embodiments, the mammalian promoter that is operably linked to the sequence encoding the RDF is a CMV promoter or a SFFV promoter. DESCRIPTION OF FIGURES [17] FIG. 1 shows an LSR circularizing its own donor DNA, thereby increasing the efficiency of LSR integration and removing ITR or other components from the donor DNA. The AAV has three LSR sites: a pair of RRS-1a/1b sites (left and right most triangles), and an RRS-2a site (first triangle right of the sequence of insertion (SOI)) that is orthogonal to the pair of RRS-1a/1b sites. The LSR recombines the outermost RRS-1a/1b sites, circularizing the AAV donor, and then integrates into a genomic site that is compatible with the intact orthogonal RRS-2a site. [18] FIG.2A shows how standard AAV dsDNA creation and circularization, which can be inefficient and dependent on DNA repair machinery. FIG. 2B shows how compositions and methods of the instant disclosure increase substrate available for integration. [19] FIGs. 3A and 3B shows how compatible recombinase recognition sites recombine (FIG. 3A), but incompatible (orthogonal) sites do not (FIG. 3B). In the case of compatible sites, an LSR can mediate a staggered cut and recombine at complementary overhangs (FIG. 3A). Precision editing (e.g., base editing, RT editing) with Cas guided systems may be employed to generate compatible or orthogonal sites. Changing one or more than one nucleotide in the staggered region may be sufficient to make sites orthogonal. [20] FIG. 4 shows an assay for measuring integration of a donor DNA. A promoterless linear donor and a plasmid encoding an LSR (e.g., PhiC31) are transfected into a cell line with an integrated promoter upstream of an LSR AttP or AttB (e.g., RRS-2b) site. The linear plasmid with donor DNA must circularize and integrate to result in GFP fluorescence. Alternatively (not shown), the recombinase may be encoded on an AAV or AdV vector that contains the SOI and recombinase recognition sites, enabling a single, self inactivating virus capable of integration. [21] FIG. 5 shows various reporters for assessing circularization, integration, and both circularization and integration of linear DNA. [22] FIG.6 shows how the reporter for circularization and integration is expected to perform upon transfection and integration into a cell line landing pad. [23] FIG.7 shows a diagram of an exemplary AAV construct co-expressing a donor nucleic acid and a recombinase (e.g., LSR). The AAV construct also expresses an antisense RNA driven by a J23119 promoter to silence LSR transcript, an shRNA driving by a hU6 promoter, and an RDF driven by a CMV promoter followed by a J23104 promoter. DETAILED DESCRIPTION [24] It is to be understood that both the foregoing general description and the following detailed description are exemplary, and explanatory only, and are not restrictive of the disclosure. [25] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, and treatises, are hereby expressly incorporated by reference in their entirety for any purpose. Definitions [26] Unless otherwise indicated, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Unless otherwise indicated or obvious from context, the following terms have the following meanings: [27] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. [28] Any reference to “or” herein is intended to encompass “and/or” unless otherwise stated. As used herein, the term “and/or” includes any and all combinations of one or more of the associated listed items. [29] Use of the term “including” as well as other forms, such as “includes” and “included,” is not limiting. [30] As used herein, the term “comprise” and its grammatical equivalents specifies the presence of stated features, integers, steps, operations, elements, and/or components, but does not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. [31] As used herein, the term “about” in reference to a number or range of numbers is understood to mean the stated number and numbers +/- 10% thereof, or 10% below the lower listed limit and 10% above the higher listed limit for the values listed for a range. [32] The terms “% identical,” “% identity,” and “percent identity,” or grammatical equivalents thereof, with reference to an amino acid sequence or nucleotide sequence, refer to the percent of residues that are identical between respective positions of two sequences when the two sequences are aligned for maximum sequence identity. The % identity is calculated by dividing the total number of the aligned residues by the number of the residues that are identical between the respective positions of the at least two sequences and multiplying by 100. Generally, computer programs can be employed for such calculations. Illustrative programs that compare and align pairs of sequences, include ALIGN (Myers and Miller, Comput Appl Biosci.1988 Mar;4(1):11-7), FASTA (Pearson and Lipman, Proc Natl Acad Sci U S A.1988 Apr;85(8):2444-8; Pearson, Methods Enzymol.1990;183:63-98) and gapped BLAST (Altschul et al., Nucleic Acids Res. 1997 Sep 1;25(17):3389-40), BLASTP, BLASTN, or GCG (Devereux et al., Nucleic Acids Res.1984 Jan 11;12(1 Pt 1):387-95). To determine sequence identity, sequences can be aligned using various convenient methods and computer programs (e.g., BLAST, T-COFFEE, MUSCLE, MAFFT, etc.), available over the world wide web at sites including ncbi.nlm.nili.gov/BLAST, ebi.ac.uk/Tools/msa/tcoffee/, ebi.ac.uk/Tools/msa/muscle/, mafft.cbrc.jp/alignment/software/. See, e.g., Altschul et al. (1990), J. Mol. Bioi.215:403-10. [33] The terms "polynucleotide" and "nucleic acid," used interchangeably herein, refer to a polymeric form of nucleotides of any length, either ribonucleotides or deoxyribonucleotides. Thus, this term includes, but is not limited to, single-, double-, or multi-stranded DNA or RNA, genomic DNA, cDNA, DNA-RNA hybrids, or a polymer comprising purine and pyrimidine bases or other natural, chemically or biochemically modified, non-natural, or derivatized nucleotide bases. [34] "Binding" as used herein (e.g., with reference to an RNA-binding domain of a polypeptide, binding to a target nucleic acid, and the like) refers to a non-covalent interaction between macromolecules (e.g., between a protein and a nucleic acid; between a CAS polypeptide/guide RNA complex and a target nucleic acid; and the like). While in a state of non-covalent interaction, the macromolecules are said to be "associated" or "interacting" or "binding" (e.g., when a molecule X is said to interact with a molecule Y, it is meant the molecule X binds to molecule Y in a non-covalent manner). Not all components of a binding interaction need be sequence-specific (e.g., contacts with phosphate residues in a DNA backbone), but some portions of a binding interaction may be sequence-specific. Binding interactions are generally characterized by a dissociation constant (KD) of less than 10^-6 M, less than 10^-7 M, less than 10^-8 M, less than 10^-9 M, less than 10^-10 M, less than 10^-11 M, less than 10^-12 M, less than 10^-13 M, less than 10^-14 M, or less than 10^-15 M. "Affinity" refers to the strength of binding, increased binding affinity being correlated with a lower KD. [35] By "binding domain'' it is meant a protein or nucleic acid domain that is able to bind non-covalently to another molecule. A binding domain can bind to, for example, a DNA molecule (a DNA-binding domain), an RNA molecule (an RNA-binding domain) and/or a protein molecule (a protein-binding domain). In the case of a protein having a protein-binding domain, it can in some cases bind to itself (to form homodimers, homotrimers, etc.) and/or it can bind to one or more regions of a different protein or proteins. [36] The term, “cis cleavage,” as used herein, refers to cleavage (hydrolysis of a phosphodiester bond) of a target nucleic acid by a complex of an effector protein and a guide nucleic acid, wherein at least a portion of the guide nucleic acid is hybridized to at least a portion of the target nucleic acid. Cleavage may occur within or directly adjacent to the portion of the target nucleic acid that is hybridized to the portion of the guide nucleic acid. [37] The terms, “cleave,” “cleaving,” and “cleavage,” as used herein, with reference to a nucleic acid molecule or nuclease activity of an effector protein, refer to the hydrolysis of a phosphodiester bond of a nucleic acid molecule that results in breakage of that bond. The result of this breakage can be a nick (hydrolysis of a single phosphodiester bond on one side of a double-stranded molecule), single strand break (hydrolysis of a single phosphodiester bond on a single-stranded molecule) or double strand break (hydrolysis of two phosphodiester bonds on both sides of a double-stranded molecule) depending upon whether the nucleic acid molecule is single-stranded (e.g., ssDNA or ssRNA) or double-stranded (e.g., dsDNA) and the type of nuclease activity being catalyzed by the effector protein. [38] The terms, “complementary” and “complementarity,” as used herein, with reference to a nucleic acid molecule or nucleotide sequence, refer to the characteristic of a polynucleotide having nucleotides that base pair with their Watson-Crick counterparts (C with G; or A with T) in a reference nucleic acid. For example, when every nucleotide in a polynucleotide forms a base pair with a reference nucleic acid, that polynucleotide is said to be 100% complementary to the reference nucleic acid. In a double stranded DNA or RNA sequence, the upper (sense) strand sequence is in general, understood as going in the direction from its 5′- to 3′-end, and the complementary sequence is thus understood as the sequence of the lower (antisense) strand in the same direction as the upper strand. Following the same logic, the reverse sequence is understood as the sequence of the upper strand in the direction from its 3′- to its 5′-end, while the ‘reverse complement’ sequence or the ‘reverse complementary’ sequence is understood as the sequence of the lower strand in the direction of its 5′- to its 3′-end. Each nucleotide in a double stranded DNA or RNA molecule that is paired with its Watson-Crick counterpart called its complementary nucleotide. [39] The term, “conservative substitution” as used herein refers to the replacement of one amino acid for another such that the replacement takes place within a family of amino acids that are related in their side chains. Conversely, the term “non-conservative substitution” as used herein refers to the replacement of one amino acid residue for another that does not have a related side chain. Genetically encoded amino acids can be divided into four families having related side chains: (1) acidic (negatively charged): Asp (D), Glu (G); (2) basic (positively charged): Lys (K), Arg (R), His (H); (3) non-polar (hydrophobic): Cys (C), Ala (A), Val (V), Leu (L), Ile (I), Pro (P), Phe (F), Met (M), Trp (W), Gly (G), Tyr (Y), with non-polar also being subdivided into: (i) strongly hydrophobic: Ala (A), Val (V), Leu (L), Ile (I), Met (M), Phe (F); and (ii) moderately hydrophobic: Gly (G), Pro (P), Cys (C), Tyr (Y), Trp (W); and (4) uncharged polar: Asn (N), Gln (Q), Ser (S), Thr (T). Amino acids may be related by aliphatic side chains: Gly (G), Ala (A), Val (V), Leu (L), Ile (I), Ser (S), Thr (T), with Ser (S) and Thr (T) optionally being grouped separately as aliphatic-hydroxyl. Amino acids may be related by aromatic side chains: Phe (F), Tyr (Y), Trp (W). Amino acids may be related by amide side chains: Asn (N), Glu (Q). Amino acids may be related by sulfur-containing side chains: Cys (C) and Met (M). [40] The term, “clustered regularly interspaced short palindromic repeats (CRISPR),” as used herein, refers to a segment of DNA found in the genomes of certain prokaryotic organisms, including some bacteria and archaea, that includes repeated short sequences of nucleotides interspersed at regular intervals between unique sequences of nucleotides derived from another organism. [41] The term, “donor nucleic acid,” as used herein, refers to a nucleic acid that is (designed or intended to be) incorporated into a target nucleic acid or target sequence. [42] The term, “% editing efficiency,” as used herein, refers to the percent of target nucleic acids in a sample or population of cells exhibiting an edited target nucleic acid. Editing efficiency may also be referred to as % editing level or % edited. There are multiple approaches to evaluate % editing efficiency, including, but not limited to, next generation sequence and real time PCR. [43] The term, “target nucleic acid,” as used herein, refers to a nucleic acid that is selected as the nucleic acid for modification, binding, hybridization or any other activity of or interaction with a nucleic acid, protein, polypeptide, or peptide described herein. A target nucleic acid may comprise RNA, DNA, or a combination thereof. A target nucleic acid may be single-stranded (e.g., single-stranded RNA or single-stranded DNA) or double-stranded (e.g., double-stranded DNA). [44] The term, “target sequence,” as used herein, when used in reference to a target nucleic acid, refers to a sequence of nucleotides found within a target nucleic acid. Such a sequence of nucleotides can, for example, hybridize to a respective length portion of a guide nucleic acid. Hybridization of the guide nucleic acid to the target sequence may bring an effector protein into contact with the target nucleic acid. [45] A nucleotide sequence that “encodes” a particular polypeptide or protein, is a nucleotide sequence that is transcribed into mRNA (in the case of DNA) and/or is translated (in the case of mRNA) into a polypeptide. [46] The term “transgene” as used herein refers to a nucleotide sequence that is inserted into a cell for expression of said nucleotide sequence in the cell. A transgene is meant to include (1) a nucleotide sequence that is not naturally found in the cell (e.g., a heterologous nucleotide sequence); (2) a nucleotide sequence that is a mutant form of a nucleotide sequence naturally found in the cell into which it has been introduced; (3) a nucleotide sequence that serves to add additional copies of the same (e.g., exogenous or homologous) or a similar nucleotide sequence naturally occurring in the cell into which it has been introduced; or (4) a silent naturally occurring or homologous nucleotide sequence whose expression is induced in the cell into which it has been introduced. A donor nucleic acid can comprise a transgene. The cell in which transgene expression occurs can be a target cell, such as a host cell. [47] The term, “functional fragment,” as used herein, refers to a fragment of a protein that retains some function relative to the entire protein. Non-limiting examples of functions are nucleic acid binding, protein binding, nuclease activity, nickase activity, deaminase activity, demethylase activity, or acetylation activity. A functional fragment may be a recognized functional domain, e.g., a catalytic domain such as, but not limited to, a RuvC domain. [48] The terms, “fusion effector protein,” “fusion protein,” and “fusion polypeptide,” may be used interchangeably herein and refer to a protein comprising at least two heterologous polypeptides. Often a fusion effector protein comprises an effector protein and a fusion partner protein. In general, the fusion partner protein is not an effector protein. Examples of fusion partner proteins are provided herein. [49] The terms “effector partner protein,” “fusion partner protein,” “effector partner,” or “fusion partner,” as used interchangeably herein, refer to a protein, polypeptide or peptide that impart a function, in combination with an effector protein and guide nucleic acid, that can be used to effectuate modification(s) of a target nucleic acid described herein and/or change expression of the target nucleic acid or other nucleic acids associated with the target nucleic acid. [50] The term, “effector protein,” as used herein, refers to a polypeptide that non-covalently binds to a guide nucleic acid to form a complex that contacts a target nucleic acid, wherein at least a portion of the guide nucleic acid hybridizes to a target sequence of the target nucleic acid. A complex between an effector protein and a guide nucleic acid can include multiple effector proteins or a single effector protein. In some instances, the effector protein modifies the target nucleic acid when the complex contacts the target nucleic acid. In some instances, the effector protein does not modify the target nucleic acid, but it is fused to a fusion partner protein that modifies the target nucleic acid when the complex contacts the target nucleic acid. A non-limiting example of an effector protein modifying a target nucleic acid is cleaving of a phosphodiester bond of the target nucleic acid. Additional examples of modifications an effector protein can make to target nucleic acids are described herein and throughout. [51] The term, “genetic disease,” as used herein, refers to a disease, disorder, condition, or syndrome associated with or caused by one or more mutations in the DNA of an organism having the genetic disease. [52] The term, “guide nucleic acid,” as used herein, refers to at least one nucleic acid comprising: a first nucleotide sequence that complexes to an effector protein on either the 5’ or 3’ terminus and the first nucleotide sequence can be fused to a second nucleotide sequence that hybridizes to a target nucleic acid. The first sequence may be referred to herein as a repeat sequence or guide sequence. The second sequence may be referred to herein as a spacer sequence. A guide nucleic acid may be referred to interchangeably with the term, “guide RNA.” It is understood that guide nucleic acids may comprise DNA, RNA, or a combination thereof (e.g., RNA with a thymine base). Guide nucleic acids may include a chemically modified nucleobase or phosphate backbone. [53] The term, “extended guide RNA (rtgRNA),” as used herein refers to a single nucleic acid molecule comprising (not necessarily in the following order) (1) a guide RNA comprising (a) a protein binding sequence and (b) a spacer sequence; (2) optionally, a linker; and (3) a template RNA (retRNA) comprising (a) a primer binding sequence and (b) a template sequence. In some embodiments, the orientation of the rtgRNA from 5’ to 3’ is: guide nucleic acid, optional linker, and template RNA. In some embodiments, the orientation of the rtgRNA from 5’ to 3’ is: template RNA, linker, and guide RNA. It is understood that extended guide RNAs may comprise DNA, RNA, or a combination thereof (e.g., RNA with a thymine base). [54] The term “template RNA (retRNA)” as used herein, refers to a nucleic acid comprising: a primer binding sequence and a template sequence. It is understood that template RNAs may comprise DNA, RNA, or a combination thereof (e.g., RNA with a thymine base). In some instances, the template RNA is linked to a guide RNA via a linker sequence to form an rtgRNA. [55] The terms “template sequence” and “RT template” as used herein, refers to a portion of a retRNA that contains a desired nucleotide modification relative to a target sequence or portion thereof. By way of non-limiting example, the desired edit may comprise one or more nucleotide insertions, deletions or substitutions relative to a target sequence or portion thereof. In some embodiments, it is identical to, complementary to, or reverse complementary to a target sequence or portion thereof. In some embodiments, the template sequence is complementary to a sequence of the target nucleic acid that is adjacent to a nick site of a target site to be edited, with the exception that it includes a desired edit. The template sequence (also referred in some instances as the RT template) can be complementary to at least a portion of the target sequence with the exception of at least one nucleotide. [56] The terms, “primer binding sequence (PBS),” as used herein, refer to a portion of a retRNA and serves to bind to a primer sequence of the target nucleic acid. In some embodiments, the primer binding sequence binds to a primer sequence in the target nucleic acid that is formed after the target nucleic acid is cleaved by an effector protein. In some embodiments, the primer binding sequence is linked to the 3’ end of an retRNA. In some embodiments, the primer binding sequence is located at the 5’ end of a retRNA. [57] “Primer sequence” as used herein refers to a portion of the target nucleic acid that is capable of hybridizing with the primer binding sequence portion of an retRNA that is generated after cleavage of the target nucleic acid by an effector protein described herein. [58] The term “handle sequence,” as used herein, refers to a sequence that binds non- covalently with an effector protein. A handle sequence may also be referred to herein as a “scaffold sequence”. In some instances, the handle sequence comprises all, or a portion of, a repeat sequence. In general, a single guide nucleic acid, also referred to as a single guide RNA (sgRNA), comprises a handle sequence that is capable of being non-covalently bound by an effector protein. The nucleotide sequence of a handle sequence may contain a portion of a tracrRNA, but generally does not comprise a sequence that hybridizes to a repeat sequence, also referred to as a repeat hybridization sequence. [59] The term “trans-activating RNA (tracrRNA),” as used herein, refers to a nucleic acid that comprises a first sequence that is capable of being non-covalently bound by an effector protein, and a second sequence that hybridizes to a portion of a crRNA, which may be referred to as a repeat hybridization sequence. [60] The terms, “CRISPR RNA” or “crRNA,” as used herein, refer to a type of guide nucleic acid, wherein the nucleic acid is RNA comprising a first sequence, often referred to herein as a spacer sequence, that hybridizes to a target sequence of a target nucleic acid, and a second sequence, often referred to herein as a repeat sequence or guide sequence, that interacts with an effector protein. In some instances, the second sequence is bound by the effector protein. In some instances, the second sequence hybridizes to a portion of a tracrRNA, wherein the tracrRNA forms a complex with the effector protein. [61] The term, “extension,” as used herein refers to additional nucleotides added to a nucleic acid, RNA, or DNA, or additional amino acids added to a peptide, polypeptide, or protein. Extensions may be processed during the formation of the guide RNA. In some instances, the extension comprises or consists of a template RNA. [62] By "hybridizable" or "complementary" or "substantially complementary" it is meant that a nucleic acid (e.g., RNA, DNA) comprises a sequence of nucleotides that enables it to noncovalently bind, i.e. form Watson-Crick base pairs and/or G/U base pairs, "anneal", or "hybridize," to another nucleic acid in a sequence-specific, antiparallel, manner (i.e., a nucleic acid specifically binds to a complementary nucleic acid) under the appropriate in vitro and/or in vivo conditions of temperature and solution ionic strength. Standard Watson-Crick base- pairing includes: adenine (A) pairing with thymidine (T), adenine (A) pairing with uracil (U), and guanine (G) pairing with cytosine (C) [DNA, RNA]. In addition, for hybridization between two RNA molecules (e.g., dsRNA), and for hybridization of a DNA molecule with an RNA molecule (e.g., when a DNA target nucleic acid base pairs with a guide RNA, etc.): guanine (G) can also base pair with uracil (U). For example, G/U base-pairing is at least partially responsible for the degeneracy (i.e., redundancy) of the genetic code in the context of tRNA anti-codon base-pairing with codons in mRNA. Thus, in the context of this disclosure, a guanine (G) (e.g., of dsRNA duplex of a guide RNA molecule; of a guide RNA base pairing with a target nucleic acid, etc.) is considered complementary to both a uracil (U) and to an adenine (A). For example, when a G/U base-pair can be made at a given nucleotide position of a dsRNA duplex of a guide RNA molecule, the position is not considered to be non- complementary, but is instead considered to be complementary. [63] The conditions of temperature and ionic strength determine the "stringency" of the hybridization. Hybridization requires that the two nucleic acids contain complementary sequences, although mismatches between bases are possible. The conditions appropriate for hybridization between two nucleic acids depend on the length of the nucleic acids and the degree of complementarity, variables well known in the art. The greater the degree of complementarity between two nucleotide sequences, the greater the value of the melting temperature (Tm) for hybrids of nucleic acids having those sequences. For hybridizations between nucleic acids with short stretches of complementarity (e.g., complementarity over 35 or less, 30 or less, 25 or less, 22 or less, 20 or less, or 18 or less nucleotides) the position of mismatches can become important (see Sambrook et al., supra, 11.7-11.8). Typically, the length for a hybridizable nucleic acid is 8 nucleotides or more (e.g., 10 nucleotides or more, 12 nucleotides or more, 15 nucleotides or more, 20 nucleotides or more, 22 nucleotides or more, 25 nucleotides or more, or 30 nucleotides or more). Temperature, wash solution salt concentration, and other conditions may be adjusted as necessary according to factors such as length of the region of complementation and the degree of complementation. [64] While hybridization typically occurs between two nucleotide sequences that are complementary, mismatches between bases are possible. It is understood that two nucleotide sequences need not be 100% complementary to be specifically hybridizable, or for hybridization to occur. Moreover, a nucleotide sequence may hybridize over one or more segments such that intervening or adjacent segments are not involved in the hybridization event (e.g., a bulge, a loop structure or hairpin structure, etc.). A polynucleotide can comprise 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, 99% or more, 99.5% or more, or 100% sequence complementarity to a target region within the target nucleic acid sequence to which it will hybridize. For example, an antisense nucleic acid in which 18 of 20 nucleotides of the antisense compound are complementary to a target region, and would therefore specifically hybridize, would represent 90 percent complementarity. In this example, the remaining noncomplementary nucleotides may be clustered or interspersed with complementary nucleotides and need not be contiguous to each other or to complementary nucleotides. Percent complementarity between particular stretches of nucleic acid sequences within nucleic acids can be determined using any convenient method. Example methods include BLAST programs (basic local alignment search tools) and PowerBLAST programs (Altschul et al., J. Mol. Biol., 1990, 215, 403-410; Zhang and Madden, Genome Res., 1997, 7, 649-656), the Gap program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, University Research Park, Madison Wis.), e.g., using default settings, which uses the algorithm of Smith and Waterman (Adv. Appl. Math., 1981, 2, 482-489), and the like. [65] The conditions appropriate for hybridization between two nucleotide sequences depend on the length of the sequence and the degree of complementarity, variables well known in the art. The greater the degree of complementarity between two nucleotide sequences, the greater the value of the melting temperature (Tm) for hybrids of nucleic acids having those sequences. For hybridizations between nucleic acids with short stretches of complementarity (e.g., complementarity over 35 or less, 30 or less, 25 or less, 22 or less, 20 or less, or 18 or less nucleotides) the position of mismatches can become important (see Sambrook et al., supra, 11.7-11.8). Typically, the length for a hybridizable nucleic acid is 8 nucleotides or more (e.g., 10 nucleotides or more, 12 nucleotides or more, 15 nucleotides or more, 20 nucleotides or more, 22 nucleotides or more, 25 nucleotides or more, or 30 nucleotides or more). Temperature, wash solution salt concentration, and other conditions may be adjusted as necessary according to factors such as length of the region of complementation and the degree of complementation. Hybridization and washing conditions are well known and exemplified in Sambrook, J., Fritsch, E. F. and Maniatis, T. Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor (1989), particularly Chapter 11 and Table 11.1 therein; and Sambrook, J. and Russell, W., Molecular Cloning: A Laboratory Manual, Third Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor (2001). The conditions of temperature and ionic strength determine the “stringency” of the hybridization. [66] The term, “heterologous,” as used herein, with reference to at least two different polypeptide sequences, means that the two different polypeptide sequences are not found similarly connected to one another in a native nucleic acid or protein. A protein that is heterologous to the effector protein is a protein that is not covalently linked via an amide bond to the effector protein in nature. In some instances, a heterologous protein is not encoded by a species that encodes the effector protein. A guide nucleic acid may comprise a first sequence and a second sequence, wherein the first sequence and the second sequence are not found covalently linked via a phosphodiester bond in nature. Thus, the first sequence is considered to be heterologous with the second sequence, and the guide nucleic acid may be referred to as a heterologous guide nucleic acid. [67] The term “linked” as used herein in reference to an amino acid or nucleic acid sequence refers to any covalent mechanism by which two amino acid sequences or nucleic acid sequences are connected to each other in sequence. For example, in some embodiments, two sequences are linked directly together by a covalent bond (e.g., an amide bond or phosphodiester bond). In some embodiments, two sequences are linked together by a peptide or nucleic acid linker. [68] The term, “linked amino acids” as used herein, refers to at least two amino acids linked by an amide bond or a peptide bond. [69] The term, “linker,” as used herein, refers to an amino acid sequence or nucleic acid sequence that links a first polypeptide to a second polypeptide or a first nucleic acid to a second nucleic acid. [70] The term, “modified target nucleic acid,” as used herein, refers to a target nucleic acid, wherein the target nucleic acid has undergone a modification, for example, after contact with an LSR and/or effector protein. In some instances, the modification is an alteration in the sequence of the target nucleic acid. In some instances, the modified target nucleic acid comprises an insertion, deletion, or replacement of one or more nucleotides compared to the unmodified target nucleic acid. [71] The terms "peptide," "polypeptide," and "protein" are used interchangeably herein, refer to a polymeric form of amino acids. A polypeptide may include coded and non-coded amino acids, chemically or biochemically modified or derivatized amino acids, and polypeptides having modified peptide backbones. Accordingly, polypeptides as described herein may comprise one or more mutations, one or more sequence modifications, or both. A peptide generally has a length of 100 or fewer linked amino acids. [72] A polynucleotide or polypeptide has a certain percent "sequence identity" to another polynucleotide or polypeptide, meaning that, when aligned, that percentage of bases or amino acids are the same, and in the same relative position, when comparing the two sequences. Sequence identity can be determined in a number of different ways. [73] A DNA sequence that "encodes" a particular RNA is a DNA nucleotide sequence that is transcribed into RNA. A DNA polynucleotide may encode an RNA (mRNA) that is translated into protein (and therefore the DNA and the mRNA both encode the protein), or a DNA polynucleotide may encode an RNA that is not translated into protein (e.g. tRNA, rRNA, microRNA (miRNA), a "non-coding" RNA (ncRNA), a guide RNA, etc.). [74] A "protein coding sequence" or a sequence that encodes a particular protein or polypeptide, is a nucleotide sequence that is transcribed into mRNA (in the case of DNA) and is translated (in the case of mRNA) into a polypeptide in vitro or in vivo when placed under the control of appropriate regulatory sequences. [75] The terms "DNA regulatory sequences," "control elements," and "regulatory elements," used interchangeably herein, refer to transcriptional and translational control sequences, such as promoters, enhancers, polyadenylation signals, terminators, protein degradation signals, and the like, that provide for and/or regulate transcription of a non-coding sequence (e.g., guide RNA) or a coding sequence (e.g., RNA-guided endonuclease and the like) and/or regulate translation of an encoded polypeptide. [76] The term, “promoter” or “promoter sequence,” is a DNA regulatory region capable of binding RNA polymerase and initiating transcription of a downstream (3’ direction) coding or non-coding sequence. A transcription initiation site, as well as protein binding domains responsible for the binding of RNA polymerase, can also be found in a promoter region. Eukaryotic promoters will often, but not always, contain “TATA” boxes and “CAT” boxes. Various promoters, including inducible promoters, may be used to drive expression by the various vectors of the present disclosure. [77] The term, “protospacer adjacent motif (PAM),” as used herein, refers to a nucleotide sequence found in a target nucleic acid that directs an effector protein to modify the target nucleic acid at a specific location. In some instances, a PAM is required for a complex of an effector protein and a guide nucleic acid to hybridize to and modify the target nucleic acid. In some instances, the complex does not require a PAM to modify the target nucleic acid. One example of a PAM sequences is NTTN, where N can be any nucleic acid. [78] The term “RNA-dependent DNA polymerase (RDDP),” as used herein, refers to a DNA polymerase that uses a single-stranded RNA as a template for the synthesis of a complementary DNA strand. [79] The term, “RuvC” domain as used herein refers to a region of an effector protein that is capable of cleaving a target nucleic acid, and in certain instances, of processing a pre-crRNA. In some instances, the RuvC domain is located near the C-terminus of the effector protein. A single RuvC domain may comprise RuvC subdomains, for example a RuvCI subdomain, a RuvCII subdomain and a RuvCIII subdomain. The term “RuvC” domain can also refer to a “RuvC-like” domain. Various RuvC-like domains are known in the art and are easily identified using online tools such as InterPro (https://www.ebi.ac.uk/interpro/). For example, a RuvC- like domain may be a domain which shares homology with a region of TnpB proteins of the IS605 and other related families of transposons. [80] The term, “nickase” as used herein refers to an enzyme that possess catalytic activity for single stranded nucleic acid cleavage of a double stranded nucleic acid. A nickase cleaves a phosphodiester bond between two nucleotides of only one strand of dsDNA. [81] The terms, “nuclease” and “endonuclease” are used interchangeably herein to mean an enzyme which possesses catalytic activity for nucleic acid cleavage. [82] The term, “nuclease activity,” is used to refer to catalytic activity that results in nucleic acid cleavage (e.g., ribonuclease activity (ribonucleic acid cleavage), or deoxyribonuclease activity (deoxyribonucleic acid cleavage), etc.). [83] The term "naturally-occurring," "unmodified," or "wild type" as used herein as applied to a nucleic acid, a polypeptide, a cell, or an organism, refers to a nucleic acid, polypeptide, cell, or organism that is found in nature. For example, a polypeptide or polynucleotide sequence that is present in an organism that can be isolated from a source in nature is naturally occurring. [84] The terms, “non-naturally occurring” and “engineered,” as used herein, are used interchangeably and indicate the involvement of the hand of man. The terms, when referring to a nucleic acid, nucleotide, protein, polypeptide, peptide or amino acid, refer to a molecule, such as but not limited to, a nucleic acid, nucleotide, protein, polypeptide, peptide or amino acid refers to a modification of that molecule (e.g., chemical modification, nucleotide sequence, or amino acid sequence) that is not present in the naturally molecule. The terms, when referring to a composition or system described herein, refer to a composition or system having at least one component that is not naturally associated with the other components of the composition or system. By way of a non-limiting example, a composition may include an effector protein and a guide nucleic acid that do not naturally occur together. Conversely, and as a non-limiting further clarifying example, an effector protein or guide nucleic acid that is “natural,” “naturally- occurring,” or “found in nature” includes an effector protein and a guide nucleic acid from a cell or organism that have not been genetically modified by the hand of man. [85] The term, “variant,” is intended to mean a form or version of a protein that differs from the wild-type protein. A variant may have a different function or activity relative to the wild- type protein. [86] The term, “sequence modification,” as used herein refers to a modification of one or more nucleic acid residues of a nucleotide sequence or one or more amino acid residue of an amino acid sequence, such as chemical modification of one or more nucleobases; or chemical modifications to the phosphate backbone, a nucleotide, a nucleobase, or a nucleoside. Such modifications can be made to an effector protein amino acid sequence or guide nucleic acid nucleotide sequence, or any sequence disclosed herein (e.g., a nucleic acid encoding an effector protein or a nucleic acid that, when transcribed, produces a guide nucleic acid). Methods of modifying a nucleic acid or amino acid sequence are known. One of ordinary skill in the art will appreciate that the sequence modification(s) may be located at any position(s) of a nucleic acid such that the function of the nucleic acid, protein, composition or system is not substantially decreased. Nucleic acids provided herein can be prepared according to any available technique including, but not limited to chemical synthesis, enzymatic synthesis, which is generally termed in vitro-transcription, cloning, enzymatic, or chemical cleavage, etc. In some instances, the nucleic acids provided herein are not uniformly modified along the entire length of the molecule. Different nucleotide modifications and/or backbone structures can exist at various positions within the nucleic acid. [87] The term, “nucleic acid expression vector,” as used herein, refers to a plasmid that can be used to express a nucleic acid of interest. [88] The term, “nuclear localization signal (NLS),” as used herein, refers to an entity (e.g., peptide) that facilitates localization of a nucleic acid, protein, or small molecule to the nucleus, when present in a cell that contains a nuclear compartment. [89] A person of ordinary skill in the art would appreciate that referring to a “nucleotide(s)”, and/or “nucleoside(s)”, in the context of a nucleic acid molecule having multiple residues, is interchangeable and describe the sugar and base of the residue contained in the nucleic acid molecule. Similarly, a skilled artisan could understand that linked nucleotides and/or linked nucleosides, as used in the context of a nucleic acid having multiple linked residues, are interchangeable and describe linked sugars and bases of residues contained in a nucleic acid molecule. When referring to a “nucleobase(s)”, or linked nucleobase, as used in the context of a nucleic acid molecule, it can be understood as describing the base of the residue contained in the nucleic acid molecule, for example, the base of a nucleotide, nucleosides, or linked nucleotides or linked nucleosides. A person of ordinary skill in the art when referring to nucleotides, nucleosides, and/or nucleobases would also understand the differences between RNA and DNA (generally the exchange of uridine for thymidine or vice versa) and the presence of nucleoside analogs, such as modified uridines, do not contribute to differences in identity or complementarity among polynucleotides as long as the relevant nucleotides (such as thymidine, uridine, or modified uridine) have the same complement (e.g., adenosine for all of thymidine, uridine, or modified uridine; another example is cytosine and 5-methylcytosine, both of which have guanosine or modified guanosine as a complement). Thus, for example, the sequence 5'-AXG where X is any modified uridine, such as pseudouridine, N1-methyl pseudouridine, or 5-methoxyuridine, is considered 100% identical to AUG in that both are perfectly complementary to the same sequence (5' -CAU). [90] Thus, the term "recombinant" polypeptide does not necessarily refer to a polypeptide whose amino acid sequence does not naturally occur. Instead, a "recombinant" polypeptide is encoded by a recombinant non-naturally occurring DNA sequence, but the amino acid sequence of the polypeptide can be naturally occurring ("wild type") or non-naturally occurring (e.g., a variant, a mutant, etc.). A recombinant polypeptide is the product of a process run by a human or machine. [91] A "vector" or "expression vector" is a replicon, such as plasmid, phage, virus, artificial chromosome, or cosmid, to which another DNA segment, i.e., an "insert", may be attached so as to bring about the replication of the attached segment in a cell. [92] The term “viral vector,” as used herein, refers to a nucleic acid to be delivered into a host cell via a recombinantly produced virus or viral particle. [93] An "expression cassette" comprises a DNA coding sequence operably linked to a promoter. "Operably linked" refers to a juxtaposition wherein the components so described are in a relationship permitting them to function in their intended manner. For instance, a promoter is operably linked to a coding sequence (or the coding sequence can also be said to be operably linked to the promoter) if the promoter affects its transcription or expression. [94] The terms "recombinant expression vector," or '"DNA construct" are used interchangeably herein to refer to a DNA molecule comprising a vector and an insert. Recombinant expression vectors are usually generated for the purpose of expressing and/or propagating the insert(s), or for the construction of other recombinant nucleotide sequences. The insert(s) may or may not be operably linked to a promoter sequence and may or may not be operably linked to DNA regulatory sequences. [95] A cell has been "genetically modified," "transformed," or "transfected" by exogenous DNA or exogenous RNA, e.g., a recombinant expression vector, when such DNA has been introduced inside the cell. The presence of the exogenous DNA results in permanent or transient genetic change. The transforming DNA may or may not be integrated (covalently linked) into the genome of the cell. In prokaryotes, yeast, and mammalian cells for example, the transforming DNA may be maintained on an episomal element such as a plasmid. With respect to eukaryotic cells, a stably transformed cell is one in which the transforming DNA has become integrated into a chromosome so that it is inherited by daughter cells through chromosome replication. This stability is demonstrated by the ability of the eukaryotic cell to establish cell lines or clones that comprise a population of daughter cells containing the transforming DNA. A "clone" is a population of cells derived from a single cell or common ancestor by mitosis. A "cell line" is a clone of a primary cell that is capable of stable growth in vitro for many generations. [96] Suitable methods of genetic modification (also referred to as "transformation") include e.g., viral or bacteriophage infection, transfection, conjugation, protoplast fusion, lipofection, electroporation, calcium phosphate precipitation, polyethyleneimine (PEl)-mediated transfection, DEAE-dextran mediated transfection, liposome-mediated transfection, particle gun technology, calcium phosphate precipitation, direct micro injection, nanoparticle-mediated nucleic acid delivery (see, e.g., Panyam et al. Adv Drug Deliv Rev.2012 Sep 13. pii: S0169- 409X(12)00283-9. doi: 10.1016/j.addr.2012.09.023), and the like. [97] The choice of method of genetic modification is generally dependent on the type of cell being transformed and the circumstances under which the transformation is taking place (e.g., in vitro, ex vivo, or in vivo). A general discussion of these methods can be found in Ausubel, et al., Short Protocols in Molecular Biology, 3rd ed., Wiley & Sons, 1995. [98] "Nuclease" and "endonuclease" are used interchangeably herein to mean an enzyme which possesses catalytic activity for nucleic acid cleavage (e.g., ribonuclease activity (ribonucleic acid cleavage), deoxyribonuclease activity (deoxyribonucleic acid cleavage), etc.). [99] By "cleavage domain," "active domain," or "nuclease domain" of a nuclease it is meant the polypeptide sequence or domain within the nuclease which possesses the catalytic activity for nucleic acid cleavage. A cleavage domain can be contained in a single polypeptide chain or cleavage activity can result from the association of two (or more) polypeptides. A single nuclease domain may consist of more than one isolated stretch of amino acids within a given polypeptide. [100] The terms, “treatment” or “treating,” as used herein, are used in reference to a pharmaceutical or other intervention regimen for obtaining beneficial or desired results in the recipient. Beneficial or desired results include but are not limited to a therapeutic benefit and/or a prophylactic benefit. A therapeutic benefit may refer to eradication or amelioration of symptoms or of an underlying disorder being treated. Also, a therapeutic benefit can be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. A prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying, or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. For prophylactic benefit, a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made. [101] A “syndrome”, as used herein, refers to a group of symptoms which, taken together, characterize a condition. [102] The terms "individual," "subject," "host," and ''patient," used interchangeably herein, refer to an individual organism, e.g., a mammal, including, but not limited to, murines, simians, humans, non-human primates, ungulates, felines, canines, bovines, ovines, mammalian farm animals, mammalian sport animals, and mammalian pets. [103] The term, “subject,” as used herein, refers to an animal. The subject may be a mammal. The subject may be a human. The subject may be diagnosed or at risk for a disease. [104] “Large Serine Recombinase (LSR)” refers to a site-specific recombinase that promotes recombination reactions between recombinase recognition sequences (RRS) located on a donor and target DNA nucleic acid sequences. [105] "Recombinase recognition sequence” or “RRS” refers to the nucleic acid sequences present in donor and target DNA nucleic acids recognized by an LSR described herein. Recombinase recognition sequences may also be referred to in the art as DNA attachment sites. LSR systems were originally described in the context of bacterial and phage integration systems. Therefore, the RRS in the donor nucleic acid is referred to as “attP” (e.g., phage attachment site, used interchangeably with “RRS-1”) and the RRS in the target nucleic acid is referred to as “attB” (e.g., bacterial attachment site, used interchangeably with “RRS-2”). The product of attP × attB recombination is the integration of the donor nucleic acid sequence into the target nucleic acid sequences, in which the donor nucleic acid sequence is flanked by two new recombination sites, attL (used interchangeably with “RRS-L”) and attR (used interchangeably with “RRS-R”), each containing half sites derived from attP and attB. [106] The term “base editing enzyme,” as used herein, refers to a protein, polypeptide, or fragment thereof that is capable of catalyzing the chemical modification of a nucleobase of a deoxyribonucleotide or a ribonucleotide. Such a base editing enzyme, for example, is capable of catalyzing a reaction that modifies a nucleobase that is present in a nucleic acid molecule, such as DNA or RNA (single stranded or double stranded). Non-limiting examples of the type of modification that a base editing enzyme is capable of catalyzing includes converting an existing nucleobase to a different nucleobase, such as converting a cytosine to a guanine or thymine or converting an adenine to a guanine, hydrolytic deamination of an adenine or adenosine, or methylation of cytosine (e.g., CpG, CpA, CpT or CpC). A base editing enzyme itself may or may not bind to the nucleic acid molecule containing the nucleobase. [107] The term “base editor,” as used herein, refers to a fusion protein comprising a base editing enzyme linked to an effector protein. The base editing enzyme may be referred to as a fusion partner. The base editing enzyme can differ from a naturally occurring base editing enzyme. It is understood that any reference to a base editing enzyme herein also refers to a base editing enzyme variant. The base editor is functional when the effector protein is coupled to a guide nucleic acid. The guide nucleic acid imparts sequence specific activity to the base editor. By way of non-limiting example, the effector protein may comprise a catalytically inactive effector protein. Also, by way of non-limiting example, the base editing enzyme may comprise deaminase activity. [108] The term “compatible,” when used to describe two or more recombinase recognition sites, refers to two or more recombinase recognition sites that can be recombined with one another. The term “incompatible” refers to two or more recombinase recognition sites that cannot be recombined with one another. [109] The term “orthogonal,” when used to describe two or more recombinase recognition sites, refers to two or more recombinase recognition sites that cannot react with one another. In some embodiments, the term “orthogonal,” as used herein, can be used interchangeably with the term “incompatible.” [110] Before the present disclosure is further described, it is to be understood that this disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims. [111] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure. [112] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub- combination. All combinations of the embodiments pertaining to the disclosure are specifically embraced by the present disclosure and are disclosed herein just as if each and every combination was individually and explicitly disclosed. In addition, all sub-combinations of the various embodiments and elements thereof are also specifically embraced by the present disclosure and are disclosed herein just as if each and every such sub-combination was individually and explicitly disclosed herein. [113] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior disclosure. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed. I. Recombinase Systems [114] In some embodiments, the present disclosure provides recombinases, compositions comprising the same, and methods of use in gene editing. In some embodiments, the recombinases are large serine recombinases. Non-limiting exemplary LSRs are provided in TABLES 1-3. [115] In general, large serine recombinases (LSRs) catalyze precise rearrangement of DNA through site-specific recombination of small sequences of DNA, referred to herein as recombinase recognition sequences (RRSs) or attachment (att) sites. Recombination mediated by LSRs typically requires only the recombinase protein and the presence of small RRSs in the donor and target nucleic acid sequences. LSR-mediated recombination is also highly directional, reversed in the presence of a single accessory protein called a recombination directionality factor (RDF), and requires no cofactors to bind or bend DNA. LSRs can catalyze recombination between RRS sites on linear or circular DNA substrates and, depending on the position and orientation of the RRS sites, integrate, excise or invert sections of DNA. [116] In the absence of accessory factors, LSRs mediate unidirectional recombination between a first RRS site (RRS-1) in the donor nucleic acid sequence and a second RRS site (RRS-2) in the target nucleic acid sequence, generating RRS-L (left) and RRS-R (right) sites flanking the 5’ and 3’ ends (respectively) of the integrated donor nucleic acid sequence. [117] There are few well-established methods of effectively delivering a circular DNA donor nucleic acid in vivo. AAVs, one of the most commonly used methods of delivering DNA in vivo, does circularize and can be used with an LSR to facilitate donor nucleic acid integration. See e.g., FIG.2A. However, the circularization process of an AAV genome is often inefficient, limiting the availability of the circularized donor DNA available for integration. [118] The present disclosure provides systems and methods wherein recombinases (e.g., LSRs) are used to circularize linear DNA from AAV or other donor vectors in order to enhance (relative to non-circularized AAVs) (1) viral transduction, (2) long-term expression by catalyzing the circularization and stabilization of the donor nucleic acid, (3) integration of a donor nucleic acid sequence in vivo, or any combination thereof. For instance, an LSR can enzymatically drive the formation of a circular DNA from the relatively unstable linear dsDNA of a AAV donor vector. [119] In some embodiments, an AAV donor vector of the present disclosure comprises three LSR recombinase recognition sites (RRS): a pair of RSSs that are compatible with one another (RRS-1a and RRS-1b), and a donor RRS (RRS-2a) that is compatible with an RRS present at a target genomic site (RRS-2b) but is orthogonal to (e.g., incompatible with) the pair of RRS- 1a and RRS-1b. In some embodiments, a recombinase (e.g., LSR) recombines the staggered cuts at RRS-1a and RRS-1b to form a circular nucleic acid (of the donor vector). In other words, the recombinase circularizes the donor vector. An LSR can recombine the RRS-1a and RRS- 1b, circularizing the AAV donor nucleic acid, and then facilitates integration of the donor nucleic acid into a target genomic site via recombination of the RRS-2a and RRS-2b. See e.g., FIG.1 and FIG.2B. In some embodiments, the LSR that mediated circularization of the DNA is the same as the LSR that mediates integration of the DNA into the target nucleic acid sequence. In some embodiments, the LSR that mediates circularization of the DNA is different from the LSR that mediates integration of the DNA into the target nucleic acid sequence. [120] LSR-mediated circularization of DNA can increase the efficiency of AAV (or any delivery vector containing a linear double stranded donor nucleic acid) genome circularization. The circularized AAV genome can then be used either for donor integration or maintained in the cell for years as an episome. Further, the LSR can enhance the production of its own preferred integration substrate, increasing the efficiency of recombinase-based integration. The RRS sites (RRS-1a and RRS-1b) can be positioned within the AAV genome such that circularization will remove unwanted sequences, such as ITRs, that would otherwise be incorporated into the genome. See FIG. 2B. By way of non-limiting example, recombinases may be delivered as an LNP, plasmid, or virus and the donor may be delivered as any virus/donor that has or converts into a double stranded DNA form (AAV/AdV/Lentivirus). [121] Recombinase-based integration exploits the fact that recombinases create a staggered overhang at a pair of compatible recombinase recognition sites (RRS) (e.g., a RRS-1a and a RRS-1b). Exchange and re-ligation of the two staggered cut sites enables recombination. For instance, an LSR can generate staggered cuts at compatible RRS-1a and RRS-1b and recombine RRS-1a and RRS-1b at complementary overhangs. See e.g., FIG. 3A. The same LSR can create staggered cuts at incompatible sites (e.g., a RRS-1a and a RRS-2a, or a RRS- 1b and a RRS-2b) with at least one of the nucleotides of the staggered cuts at RRS-1a and RRS- 1b are different from one of the nucleotides of the staggered cuts at RRS-2a and RRS-2b. In this case, the LSR cannot recombine the two incompatible sites. See e.g., FIG.3B. [122] A self-circularizing AAV contains an RRS pair (e.g., RRS-1a and RRS-1b) with the same internal base pairs. In the correct orientation, a recombinase will react to form a circular template, but only after the cell converts the AAV from a mostly single-stranded genome, to a double stranded genome. See e.g., FIG.2B. The AAV may also contain a recombination site (e.g., RRS-2a) that is orthogonal to (e.g., incompatible with) RRS-1a and RRS1-b. This site can be used for recombination-catalyzed integration in the genome at a recombinase recognition site that is compatible with RRS-2a (e.g., RRS-2b). RRS-2b can be the native recognition sequence of the LSR (i.e. an AttB or AttP site) that has been integrated into the genome (also referred to as a “landing pad”). Alternatively, the RRS-2b can be a pseudosite. A pseudosite is a sequence that is close enough to a native AttB or AttP sequence that it enables LSR-mediated integration. Pseudosites can be computationally predicted or discovered empirically through NGS sequencing after cells are exposed to an LSR and a donor containing RRS-2a. CRISPR/Cas systems, including but not limited to precision editing systems (e.g., RT editing, base editing), may be employed to generate an RRS-2b at a site of interest. In some embodiments, the AAV does not contain an RRS-2a, and the recombinase merely circularizes the donor vector for long-term stability and expression. [123] In some embodiments, the present disclosure provides systems or compositions for the modification of a target nucleic acid comprising a recombinase or a nucleic acid encoding a recombinase; and a donor vector comprising i) a sequence of insertion (SOI); ii) a pair of recombinase recognition sites (RRS-1a and RRS-1b) that are compatible with one another; and iii) optionally, a donor recombinase recognition site (RRS-2a) that is compatible with a target nucleic acid recombinase recognition site (RRS-2b), wherein the donor vector is a linear vector, wherein RRS-1a and RRS-1b are orthogonal to RRS-2a and RRS-2b, and wherein the recombinase recognizes RRS-1a, RRS-1b, RRS-2a and RRS-2b. In some embodiments, the donor vector containing the sequence of insertion (SOI) also comprises the sequence encoding a recombinase. In this instance, the sequence encoding the recombinase can be located 5’ or 3’ of the SOI, RRS-1a, RRS-1b, and RRS-2a. RRS-1a can be located 5’ of the SOI, 5’ of the RRS- 2a, 5’ of the RRS-1b, or any combination thereof. The SOI and RRS-2a can be located between the RRS-1a and RRS-1b. The RRS-1b can be located 3’ of the SOI, 3’ of the RRS-1a, 3’ of the RRS-2a, or any combination thereof. The recombinase can generate staggered cuts at RRS-1a and RRS-1b, wherein the staggered cuts at RRS-1a and RRS-1b are the same. The recombinase can recombine the staggered cuts at RRS-1a and RRS-1b to form a circular nucleic acid that comprises the SOI and RRS-2a. The recombinase can further generate staggered cuts at RRS- 2a and RRS-2b, wherein the staggered cuts at RRS-2a and RRS-2b are the same, and wherein at least one of the nucleotides of the staggered cuts at RRS-1a and RRS-1b are different from one of the nucleotides of the staggered cuts at RRS-2a and RRS-2b. The recombinase can recombine the staggered cuts at RRS-2a and RRS-2b to insert the SOI to the target nucleic acid. [124] A major advantage of LSRs over other emerging technologies is that there is no theoretical upper limit on the size of the donor DNA, with reports demonstrating successful 27-kb integration into mammalian cells with Bxb1 (see, e.g., Duportet et al. Nucleic Acids Res. 42, 13440–13451 (2014)). Although these features make LSRs highly attractive genome editing tools, the practical application of existing recombinases has been limited by several factors, most notably their low integration efficiency. [125] Insertion of transgenes into target nucleic acid sequences using LSRs may offer a number of advantages. By way of non-limiting example, integration may be mediated by one LSR without relying on host factors for DNA integration. In general, LSRs do not degrade DNA or need to be engineered to bind a specific DNA sequence (in contrast to methods that rely on homing endonucleases). Additionally, integration may be targeted to a specific locus known to have minimal positional effects on transgene expression, unlike the use of transposons and retroviruses. Furthermore, transgenes integrated by LSRs though RRS-1:RRS- 2 recombination may not be inverted or remobilized without the presence of a cognate RDF. [126] In some embodiments, the present disclosure provides an LSR, or a nucleic acid encoding the same, wherein the LSR comprises an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% identical to an amino acid sequence selected from SEQ ID NOs: 1-3918 and 9272-9274. In some embodiments, the LSR comprises or consists of an amino acid sequence selected from SEQ ID NOs: 1-3918 and 9272-9274. [127] In some embodiments, the LSR comprises an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% identical to a sequence selected from SEQ ID NOs: 1-2523 and 9272-9274; the RRS- 1 comprises a nucleotide sequence that is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical to a sequence selected from SEQ ID NOs: 6442- 8964 and 9278-9280; and the RRS-2 comprises a nucleotide sequence that is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical to a sequence selected from SEQ ID NOs: 3919-6441 and 9275-9277, wherein the recombinase, RRS-1 and RRS-2 are in the same row of TABLE 1 or TABLE 2. [128] In some embodiments, the target sequence is selected from a nucleotide sequence that is at least 80%, at least 90%, at least 95% or 100% identical to a sequence selected from SEQ ID NOs: 8965-9266, and wherein the target sequence is in the same row of TABLE 1 as the recombinase, RRS-1 and RRS-2. [129] In some embodiments, the LSR or nucleic acid encoding the same, and the donor DNA vector are combined in a single composition. In some embodiments, the nucleic acid encoding the recombinase further comprises the donor DNA or sequence of interest. Recombinase Recognition Sequences [130] In some embodiments, the present disclosure comprises system for the modification of a target nucleic acid comprising (a) a recombinase or a nucleic acid encoding a recombinase; and (b) a donor DNA comprising a first recombinase recognition sequence (RRS-1), and wherein the target nucleic acid comprises a second RRS (RRS-2). [131] In some embodiments, the RRS-1 and/or RRS-2 are less than about 250 nucleotides in length. In some embodiments, the RRS-1 and/or RRS-2 are less than about 250, 200, 150, 100, or 50 nucleotides in length. In some embodiments, the RRS-1 and/or RRS-2 are about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, or 250 nucleotides in length. [132] In some embodiments, the RRS-1 comprises a nucleic acid sequence that is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical to a sequence selected from SEQ ID NOs:6442-8964 and 9278-9280. In some embodiments, the RRS-1 comprises a nucleic acid sequence selected from SEQ ID NOs:6442-8964 and 9278- 9280. In some embodiments, the RRS-1 consists of a nucleic acid sequence selected from SEQ ID NOs:6442-8964 and 9278-9280. [133] In some embodiments, the RRS-2 comprises a nucleotide sequence that is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical to a sequence selected from SEQ ID NOs: 3919-6441 and 9275-9277. In some embodiments, the RRS-2 comprises a nucleic acid sequence selected from SEQ ID NOs: 3919-6441 and 9275- 9277. In some embodiments, the RRS-2 consists of a nucleic acid sequence selected from SEQ ID NOs: 3919-6441 and 9275-9277. [134] In some embodiments, the RRS-1 comprises a nucleic acid sequence that is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical to a sequence selected from SEQ ID NOs:6442-8964 and 9278-9280 and the RRS-2 comprises a nucleotide sequence that is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical to a sequence selected from SEQ ID NOs: 3919-6441 and 9275-9277, wherein the RRS-1 and RRS-2 are in the same row of TABLE 1 or TABLE 2. In some embodiments, the RRS-1 comprises a nucleic acid sequence selected from SEQ ID NOs:6442-8964 and 9278-9280 and the RRS-2 comprises a nucleotide sequence selected from SEQ ID NOs: 3919-6441 and 9275-9277, wherein the RRS-1 and RRS-2 are in the same row of TABLE 1 or TABLE 2. In some embodiments, the RRS-1 consists of a nucleic acid sequence selected from SEQ ID NOs:6442-8964 and 9278-9280 and the RRS-2 consists of a nucleotide sequence selected from SEQ ID NOs: 3919-6441 and 9275-9277, wherein the RRS- 1 and RRS-2 are in the same row of TABLE 1 or TABLE 2. [135] In some embodiments, an RRS is naturally occurring in a target nucleic acid sequence. In some embodiments, an RRS is introduced into a target nucleic acid sequence. In some embodiments, one or more RRSs are introduced into the target nucleic acid sequence. In some embodiments, only one RRS is introduced into a target nucleic acid sequence. In some embodiments, two RRSs are introduced into a target nucleic acid sequence. In some embodiments, the one or more RRSs are introduced into the target nucleic acid sequence using the systems described herein. In some embodiments, the guide nucleic acids described herein comprise one or more RRSs. [136] In some embodiments, an RRS is introduced into a target nucleic acid sequence with a precision editing system described herein. In some embodiments, an RRS is introduced into a target nucleic acid sequence with a method of precision editing described herein. In some embodiments, the precision editing system comprises a retRNA. In some embodiments, the retRNA comprises an RRSs. In some embodiments, the template sequence of the retRNA comprises one or more RRSs. II. Precision Editing Systems [137] Systems, compositions, and methods disclosed herein may comprise components for precision editing. Precision editing systems may be useful for generating an RRS in a target nucleic acid. For example, a target nucleic acid may not initially contain an RRS that can be utilized by a recombinase. However, a precision editing system described herein could be used to generate an RRS in the target nucleic acid, thereby making it possible to insert a donor nucleic acid at that site with a recombinase. [138] In some embodiments, precision editing alters a nucleotide within a target nucleic acid thereby converting it to a recombinase recognition sequence. In some embodiments, the recombinase recognition sequence is a sequence selected from SEQ ID NOs: 3919-8964. RT Editors [139] In some embodiments, precision editing systems comprise an RNA-dependent DNA polymerase (RDDP), an effector protein (e.g., a CRISPR associated (Cas) protein), a guide RNA, and a template RNA. The RDDP and effector protein may be collectively referred to as an “RT editor.” In some embodiments, the RDDP is a reverse transcriptase (RT). In some embodiments, the RDDP and the effector protein are covalently linked. In some embodiments, the guide RNA and template RNA (retRNA) are fused or linked as an extended guide RNA (e.g., rtgRNA). In some embodiments, the present disclosure provides methods of modifying target nucleic acids utilizing precision editing systems. [140] In some embodiments, precision editing systems comprise: (a) an effector protein or a nucleic acid encoding the effector protein; (b) an RNA-directed DNA polymerase (RDDP) or a nucleic acid encoding the RDDP; (c) a guide RNA or nucleic acid encoding the guide RNA, wherein the guide RNA comprises (i) a first region comprising a protein binding sequence, and (ii) a second region comprising a spacer sequence that hybridizes to a target sequence of a first strand of a double stranded DNA (dsDNA) target nucleic acid, wherein the first region is located 5’ of the second region; and (d) a template RNA (retRNA) or nucleic acid encoding the retRNA, wherein the retRNA comprises (i) a primer binding sequence (PBS), and (ii) a template sequence that hybridizes to the target sequence of a second strand of the dsDNA target nucleic acid. In some embodiments, the guide RNA is linked to the retRNA. In some embodiments, the template sequence is located 5’ of the PBS, optionally wherein the 3’ end of the PBS is linked to the 5’ end of the template sequence. In some embodiments, the retRNA is circularized. In some embodiments, the template sequence comprises an RRS sequence or a sequence that is reverse complementary to an RRS. The RRS may be an RRS that is recognized by an LSR described herein. In some instances, the one or more RRSs is linked to a primer binding sequence. The guide nucleic acid may interact with an effector protein and target the effector protein to the desired location in the cell genome. The effector protein may nick a strand of the cell genome and the RDDP may incorporate the one or more RRSs of the guide nucleic acid into the nicked site. This provides an RRS site at the desired location of the cell genome. [141] In some embodiments, the RDDP is not fused to the effector protein. In some embodiments, the RDDP is fused to an aptamer binding protein, and the guide RNA and/or retRNA comprises an aptamer that is capable of being bound by the aptamer binding protein. A non-limiting example of an aptamer is an MS2 aptamer and a non-limiting example of a corresponding aptamer binding protein is an MS2 coat protein. Additional examples of such localizing systems are described by Chen et al., FEBS J. (2013) 280:3734-3754. Base Editors [142] In some embodiments, precision editing systems comprise a base editor, wherein the base editor comprises an effector protein and a base editing enzyme. By way of non-limiting example, the base editing enzyme may comprise deaminase activity. In some embodiments, a base editor may be a fusion protein comprising a base editing enzyme linked to an effector protein. The base editor may be functional when the effector protein is coupled to a guide nucleic acid. The guide nucleic acid imparts sequence specific activity to the base editor. By way of non-limiting example, the effector protein may comprise a catalytically inactive effector protein (e.g., a catalytically inactive variant of an effector protein described herein). [143] In some embodiments, base editors are capable of catalyzing editing (e.g., a chemical modification) of a nucleobase of a nucleic acid molecule, such as DNA or RNA (single stranded or double stranded). In some embodiments, a base editing enzyme, and therefore a base editor, is capable of converting an existing nucleobase to a different nucleobase, such as: an adenine (A) to guanine (G); cytosine (C) to thymine (T); cytosine (C) to guanine (G); uracil (U) to cytosine (C); guanine (G) to adenine (A); hydrolytic deamination of an adenine or adenosine, or methylation of cytosine (e.g., CpG, CpA, CpT or CpC). In some embodiments, base editors edit a nucleobase on a ssDNA. In some embodiments, base editors edit a nucleobase on both strands of dsDNA. In some embodiments, base editors edit a nucleobase of an RNA. [144] In some embodiments, a base editing enzyme comprises a deaminase enzyme. Exemplary deaminases are described in US20210198330, WO2021041945, WO2021050571A1, and WO2020123887, all of which are incorporated herein by reference in their entirety. Exemplary deaminase domains are described WO 2018027078 and WO2017070632, and each are hereby incorporated in its entirety by reference. Also, additional exemplary deaminase domains are described in Komor et al., Nature, 533, 420-424 (2016); Gaudelli et al., Nature, 551, 464-471 (2017); Komor et al., Science Advances, 3:eaao4774 (2017), and Rees et al., Nat Rev Genet.2018 Dec;19(12):770-788. doi: 10.1038/s41576-018- 0059-l, which are hereby incorporated by reference in their entirety. In some embodiments, the deaminase functions as a monomer. In some embodiments, the deaminase functions as heterodimer with an additional protein. In some embodiments, base editors comprise a DNA glycosylase inhibitor (e.g., an uracil glycosylase inhibitor (UGI) or uracil N-glycosylase (UNG)). In some embodiments, the fusion partner is a deaminase, e.g., ADAR1/2, ADAR-2, AID, or any function variant thereof. [145] In some embodiments, a base editor is a cytosine base editor (CBE). In some embodiments, the CBE may convert a cytosine to a thymine. In some embodiments, a cytosine base editing enzyme may accept ssDNA as a substrate but may not be capable of cleaving dsDNA, as linked to a catalytically inactive effector protein. In some embodiments, when bound to its cognate DNA, the catalytically inactive effector protein of the CBE may perform local denaturation of the DNA duplex to generate an R-loop in which the DNA strand not paired with a guide nucleic acid exists as a disordered single-stranded bubble. In some embodiments, the catalytically inactive effector protein generated ssDNA R-loop may enable the CBE to perform efficient and localized cytosine deamination in vitro. In some embodiments, deamination activity is exhibited in a window of about 4 to about 10 base pairs. In some embodiments, fusion to the catalytically inactive effector protein presents a target site to the cytosine base editing enzyme in high effective molarity, which may enable the CBE to deaminate cytosines located in a variety of different sequence motifs, with differing efficacies. In some embodiments, the CBE is capable of mediating RNA-programmed deamination of target cytosines in vitro or in vivo. In some embodiments, the cytosine base editing enzyme is a cytidine deaminase. In some embodiments, the cytosine base editing enzyme is a cytosine base editing enzyme described by Koblan et al. (2018) Nature Biotechnology 36:848-846; Komor et al. (2016) Nature 533:420-424; Koblan et al. (2021) “Efficient C•G-to-G•C base editors developed using CRISPRi screens, target-library analysis, and machine learning,” Nature Biotechnology; Kurt et al. (2021) Nature Biotechnology 39:41-46; Zhao et al. (2021) Nature Biotechnology 39:35-40; and Chen et al. (2021) Nature Communications 12:1384, all incorporated herein by reference. In some embodiments, a base editor is a cytosine to guanine base editor (CGBE). A CGBE may convert a cytosine to a guanine. [146] In some embodiments, a base editor is an adenine base editor (ABE). An ABE may convert an adenine to a guanine. In some embodiments, an ABE converts an A•T base pair to a G•C base pair. In some embodiments, the ABE converts a target A•T base pair to G•C in vivo or in vitro. In some embodiments, ABEs provided herein reverse spontaneous cytosine deamination, which has been linked to pathogenic point mutations. In some embodiments, ABEs provided herein enable correction of pathogenic SNPs (~47% of disease-associated point mutations). In some embodiments, the adenine comprises exocyclic amine that has been deaminated (e.g., resulting in altering its base pairing preferences). In some embodiments, deamination of adenosine yields inosine. In some embodiments, inosine exhibits the base- pairing preference of guanine in the context of a polymerase active site, although inosine in the third position of a tRNA anticodon is capable of pairing with A, U, or C in mRNA during translation. Non-limiting exemplary adenine base editing enzymes suitable for use with effector proteins described herein include: ABE8e, ABE8.20m, APOBEC3A, Anc APOBEC (a.k.a. AncBE4Max), and BtAPOBEC2. Non-limiting exemplary ABEs suitable for use herein include: ABE7, ABE8.1m, ABE8.2m, ABE8.3m, ABE8.4m, ABE8.5m, ABE8.6m, ABE8.7m, ABE8.8m, ABE8.9m, ABE8.10m, ABE8.11m, ABE8.12m, ABE8.13m, ABE8.14m, ABE8.15m, ABE8.16m, ABE8.17m, ABE8.18m, ABE8.19m, ABE8.20m, ABE8.21m, ABE8.22m, ABE8.23m, ABE8.24m, ABE8.1d, ABE8.2d, ABE8.3d, ABE8.4d, ABE8.5d, ABE8.6d, ABE8.7d, ABE8.8d, ABE8.9d, ABE8.10d, ABE8.11d, ABE8.12d, ABE8.13d, ABE8.14d, ABE8.15d, ABE8.16d, ABE8.17d, ABE8.18d, ABE8.19d, ABE8.20d, ABE8.21d, ABE8.22d, ABE8.23d, and ABE8.24d. In some embodiments, the adenine base editing enzyme is an adenine base editing enzyme described in Chu et al., (2021) The CRISPR Journal 4:2:169- 177, incorporated herein by reference. In some embodiments, the adenine deaminase is an adenine deaminase described by Koblan et al. (2018) Nature Biotechnology 36:848-846, incorporated herein by reference. In some embodiments, the adenine base editing enzyme is an adenine base editing enzyme described by Tran et al. (2020) Nature Communications 11:4871. Effector Proteins [147] Provided herein, are compositions, systems, and methods comprising an effector protein and uses thereof. By way of non-limiting example, the effector protein may be utilized in a precision editing system in order to generate an RRS in a target nucleic acid. In general, the effector protein comprises a CRISPR associated (Cas) protein. In some instances, the Cas protein comprises a Type II Cas protein. In some instances, the Cas protein does not comprise a Type II Cas protein. In some instances, the effector protein does not comprise a Cas9 protein. In some instances, the Cas protein comprises a Type V Cas protein. In some embodiments, the Type V Cas protein comprises an RuvC domain and does not comprise an HNH domain. In some instances, the Cas protein comprises a Type VU-3 Cas protein. In some instances, the Cas protein comprises a Type VU-4 protein. In some instances, the Cas protein comprises a CasPhi (CasФ, Cas12J) protein. In some instances, the Cas protein comprises a Cas14 protein. In some instances, the Cas14 protein is a Cas14a protein. In some embodiments, the Cas14a protein is Cas14a.1 (also known as Cas12f1). In some instances, the Cas14 protein is a Cas14b protein. In some embodiments, the Cas protein is engineered from a naturally occurring Cas protein (including but not limited to those described herein and throughout). In some embodiments, the engineered Cas protein 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 98%, at least 99% identical to the naturally occurring Cas protein. Effector proteins of the present disclosure, dimers thereof, and multimeric complexes thereof, may cleave or nick a target nucleic acid within or near a protospacer adjacent motif (PAM) sequence of the target nucleic acid. [148] TABLE 4 provides illustrative amino acid sequences of effector proteins, guide sequences, and PAM sequences that are useful in the compositions, systems and methods described herein. With regards to the PAM sequences: N is any nucleotide; Y is C or T; R is A or G; and S is G or C. In certain embodiments, compositions, systems, and methods provided herein comprise an effector protein and an engineered guide nucleic acid, wherein the effector protein comprises an amino acid sequence that is at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to any one of the sequences as set forth in TABLE 4. In some instances, effector proteins differ from a sequence in TABLE 4 by one or more amino acids. Exemplary amino acid substitutions for effector proteins in TABLE 4 are provided in WO 2023/220570 and WO 2023/141590, both of which are incorporated herein by reference in their entirety. In some embodiments the modifications are conservative substitutions relative to the effector protein sequence in TABLE 4. In some embodiments, the amino acids that differ from the effector proteins are non-conservative substitutions relative to the effector protein sequence in TABLE 4. In some embodiments, a mutation may affect the catalytic activity of the effector protein and results in a catalytically reduced or catalytically inactive mutant. In some embodiments, a mutation can result in the effector protein having nickase activity or increased nickase activity. In some embodiments, a mutation can result in the effector protein having reduced or no nuclease activity but gaining nickase activity. Guide Nucleic Acids [149] Compositions, systems, and methods for precision editing may comprise a guide nucleic acid or a use thereof. Unless otherwise indicated, compositions, systems and methods comprising guide nucleic acids or uses thereof, as described herein and throughout, include DNA molecules, such as expression vectors, that encode a guide nucleic acid. Accordingly, compositions, systems, and methods of the present disclosure comprise a guide nucleic acid or a nucleotide sequence encoding the guide nucleic acid. In general, a guide nucleic acid is a nucleic acid molecule, at least a portion of which may be bound by an effector protein, thereby forming a ribonucleoprotein complex (RNP). Another portion of the guide nucleic acid molecule can comprise a spacer region which is complementary to at least a portion of the target nucleic acid sequence. In some embodiments, the guide nucleic acid imparts activity or sequence selectivity to the effector protein. When complexed with an effector protein, guide nucleic acids can bring the effector protein into proximity of a target nucleic acid. The guide nucleic acid spacer region may hybridize to a target nucleic acid or a portion thereof. In some embodiments, when a guide nucleic acid and an effector protein form an RNP, at least a portion of the RNP binds spacer region, recognizes, and/or hybridizes to a target nucleic acid. Those skilled in the art in reading the below specific examples of guide nucleic acids as used in RNPs described herein, will understand that in some embodiments, a RNP can hybridize, via the spacer region, to one or more target sequences in a target nucleic acid, thereby allowing the RNP to modify and/or recognize a target nucleic acid or sequence contained therein. [150] A guide nucleic acid, as well as any components thereof (e.g., spacer region, repeat region, linker) may comprise one or more deoxyribonucleotides, ribonucleotides, biochemically or chemically modified nucleotides (e.g., one or more sequence modifications as described herein), and any combinations thereof. A guide nucleic acid may comprise a naturally occurring sequence. A guide nucleic acid may comprise a non-naturally occurring sequence, wherein the sequence of the guide nucleic acid, or any portion thereof, may be different from the sequence of a naturally occurring nucleic acid. The guide nucleic acid may be chemically synthesized or recombinantly produced. Guide nucleic acids, while often being referred to as a guide RNA, may include deoxyribonucleosides, ribonucleosides, chemically modified nucleosides, or any combination thereof. In some embodiments, uridines can be exchanged for pseudouridines (e.g., 1N-Methyl-Pseudouridine). In some embodiments, all uridines can be exchanged for 1N-Methyl-Pseudouridine. In this application, U can represent uracil or 1N-Methyl-Pseudouridine. [151] Guide nucleic acids described herein may comprise one or more repeat sequences. In some embodiments, a repeat sequence comprises a nucleotide sequence that is not complementary to a target sequence of a target nucleic acid. In some embodiments, a repeat sequence comprises a nucleotide sequence that may interact with an effector protein. In some embodiments, a repeat sequence includes a nucleotide sequence that is capable of forming a guide nucleic acid-effector protein complex (e.g., a RNP complex). In some embodiments, the repeat sequence may also be referred to as a “protein-binding segment.” TABLE 4 provides exemplary repeat sequences. In some embodiments, the repeat sequence comprises a nucleic acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NOs: 9269-9270. [152] In some embodiments, the present disclosure provides guide nucleic acids for use in combination with the effector proteins and fusion proteins thereof described herein for precision editing of a target nucleic acids sequence. In some embodiments, guide nucleic acids for use in precision editing comprise a spacer sequence, a repeat sequence, a primer binding sequence, and a template sequence. In some instances, compositions, systems, and methods described herein comprise a template RNA (retRNA), wherein the template RNA (retRNA) comprises a primer binding sequence and a template sequence. In some embodiments, the template RNA (retRNA) is an extension of a guide RNA. In some embodiments, the retRNA, the spacer sequence, and the repeat sequence are comprised in the same polynucleotide. In some embodiments, the spacer sequence and repeat sequence are comprised in a first polynucleotide and the retRNA is comprised in a second polynucleotide (e.g., a split RNA system). The template sequence may comprise one or more nucleotides having a different nucleobase than that of a nucleotide at the corresponding position in the target nucleic acid when a spacer sequence of the guide RNA and the target sequence are aligned for maximum identity. The one or more nucleotides may be contiguous. The one or more nucleotides may not be contiguous. The one or more nucleotides may each independently be selected from guanine, adenine, cytosine and thymine. [153] In some instances, the primer binding sequence hybridizes to a primer sequence on the non-target strand of the target dsDNA molecule. In some instances, the primer binding sequence hybridizes to a primer sequence on the target strand of the target dsDNA molecule. In some embodiments, the spacer sequence is complementary to the target sequence on the target strand of the dsDNA molecule, and the primer binding sequence and/or the template sequence is complementary to a primer sequence on the non-target strand of the target dsDNA molecule. In some embodiments, the spacer sequence is complementary to the target sequence on the non-target strand of the dsDNA molecule, and the primer binding sequence and/or the template sequence is complementary to a primer sequence on the target strand of the target dsDNA molecule. III. Donor Nucleic Acids [154] Compositions, systems, and methods may comprise a donor nucleic acid or use thereof. Methods may comprise incorporating a donor nucleic acid into a target nucleic acid. In some embodiments, the donor nucleic acid is incorporated into a target nucleic acid by recombinase mediated insertion. In reference to a viral vector, the term donor nucleic acid refers to a sequence of nucleotides (also referred to as a sequence of insertion (SOI)) that will be or has been introduced into a cell following transfection of the viral vector. The donor nucleic acid may be introduced into the cell by any mechanism of the viral vector, including, but not limited to, integration into the genome of the cell or introduction of an episomal plasmid or viral genome via an integration sequence and a recombinase. [155] Donor nucleic acids of any suitable size may be integrated into a target nucleic acid or genome. In some embodiments, the donor nucleic acid is about 500 bp to about 5kb in length. In some embodiments, the donor nucleic acid comprises a nucleotide sequence encoding a protein. In some embodiments, the donor nucleic acid comprises a gene or a portion thereof. In some embodiments, the donor nucleic acid comprises an exon of a gene. [156] In some embodiments, the donor nucleic acid is useful for treating a loss of function disease. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the SMN protein, or a mutation in the SMN1 gene, in a subject with spinal muscular atrophy (SMA). In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the acid alpha- glucosidase protein, or a mutation in the GAA gene, in a subject with Pompe disease. In some embodiments the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the dystrophin protein, or a mutation in the DMD gene, in a subject with Duchene muscular dystrophy. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the GLUT2 protein, or a mutation in the SLC2A2 gene, in a subject with Fanconi-Bickel syndrome. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the LAMP2 protein, or a mutation in the Mac-3 gene, in a subject with Danon disease. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the glucose-6-phosphatase protein, a mutation in the G6PC gene, a mutation in the glucose-6-phosphate transporter, a mutation in the SLC37A4 gene, a mutation in the SLC17A3 protein, or a mutation in the SLC17A3 gene in a subject with von Gierke’s disease. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the glycogen debranching enzyme, or a mutation in the AGL gene, in a subject with Cori’s disease or Forbes’ disease. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the glycogen phosphorylase protein, or a mutation in the PYGM gene, in a subject with McArdle’s disease. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of the function due to a mutation in the glycogen phosphorylase protein, or a mutation in the PYGL gene, in a subject with Hers’ disease. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the phosphofructokinase protein, or a mutation in the PFKM gene, in a subject with Tarui’s disease. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the GLUT2 protein, or a mutation in the SLC2A2 gene, in a subject with Fanconi-Bickel syndrome. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the fructose- bisphosphate aldolase protein, or a mutation in the ALDOA gene, in a subject with Aldolase A deficiency. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the CFTR protein, or a mutation in the CFTR gene, in a subject with cystic fibrosis. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the factor VIII protein, or a mutation in the F8 gene, in a subject with hemophilia A. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the factor IX protein, or a mutation in the F9 gene, in a subject with hemophilia B. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the sodium chloride cotransporter protein, a mutation in the SLC12A3 gene, a mutation in the chloride voltage-gated channel Kb protein, or a mutation in the CLCNKB gene in a subject with Gitelman syndrome. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the Hexosaminidase A protein, or a mutation in the HEXA gene, in a subject with Tay-Sachs disease. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the hemoglobin subunit beta protein, or a mutation in the HBB gene, in a subject with sickle cell anemia. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the LDL receptor protein, a mutation in the LDLR gene, a mutation in the apolipoprotein B protein, a mutation in the APOB gene, a mutation in the proprotein convertase subtilisin/Kexin type 9 (PCSK9), or a mutation in the PCSK9 gene, in a subject with familial hypercholesterolemia. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the solute carrier family 40 member 1 (SLC40A1) protein, or a mutation in the SLC40A1 gene, in a subject with hemochromatosis. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the Huntingtin protein, or a mutation in the HTT gene, in a subject with Huntington’s disease. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the Vasopressin receptor 2 (V2R), a mutation in the AVPR2 gene, a mutation in the Aquaporin-2 protein, or a mutation in the AQP2 gene, in a subject with nephrogenic diabetes insipidus. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the melanocortin 2 receptor protein, a mutation in the MC2R gene, a mutation in the melanocortin 2 receptor accessory protein, a mutation in the MRAP gene, a mutation in the nicotinamide nucleotide transhydrogenase protein, or a mutation in the NNT gene, in a subject with familial glucocorticoid deficiency. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the KiSS1-derived peptide receptor protein, or a mutation in the KISS1 gene, in a subject with familial hypogonadism. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the prokineticin 2 protein, or a mutation in the PROK2 gene, in a subject with hypogonadism. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the thyrotropin receptor protein, or a mutation in the TSHR gene, in a subject with euthyroid hyperthyroidism. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the immunoglobulin superfamily, member 1 protein, or a mutation in the IGSF1 gene, in a subject with central hypothyroidism. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the collagen type II alpha 1 chain protein, a mutation in the COL2A1 gene, a mutation in the fibroblast growth factor receptor 3 protein, a mutation in the FGFR3 gene, a mutation in the sulfate transporter protein, or a mutation in the SLC26A2 gene, in a subject with chondrodysplasia. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the calcium-sensing receptor protein, or a mutation in the CASR gene, in a subject with benign familial hypocalciuric hypercalcemia or neonatal severe primary hyperparathyroidism. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the rhodopsin protein, or a mutation in the RHO gene, in a subject with retinal degeneration. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the frizzled class receptor 4 protein, a mutation in the FZD4 gene, a mutation in the LDL receptor related protein 5 protein, a mutation in the LRP5 gene, a mutation in the norrin cystine knot growth factor protein, or a mutation in the NDP gene, in a subject with vitreoretinopathy. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the ret proto-oncogene, a mutation in the RET gene, a mutation in the endothelin receptor type B protein, a mutation in the EDNRB gene, a mutation in endothelin 3 protein, or a mutation in the EDN3 gene, in a subject with Hirschsprung disease. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the fragile X mental retardation protein, or a mutation in the FMR1 gene, in a subject with fragile x syndrome. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the glucosylceramidase beta 1 protein, or a mutation in the GBA1 gene, in a subject with Gaucher’s Disease. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the Glucose-6-phosphate dehydrogenase protein, or a mutation in the G6PD gene, in a subject with glucose 6-phosphate dehydrogenase deficiency. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the Glucose-6-phosphate dehydrogenase protein, or a mutation in the G6PD gene, in a subject with glucose 6-phosphate dehydrogenase deficiency. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the SIX homeobox 3 protein, or a mutation in the SIX3 gene, in a subject with holoprosencephaly. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the phenylalanine hydroxylase protein, or a mutation in the PAH gene, in a subject with phenylketonuria. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the frataxin protein, or a mutation in the FXN gene, in a subject with Friedreich’s ataxia. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the serpin family A member 1 protein, or a mutation in the SERPINA1 gene, in a subject with alpha-1 antitrypsin deficiency. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the sphingomyelin phosphodiesterase 1 protein, a mutation in the SMPD1 gene, a mutation in the NPC intracellular cholesterol transporter 1 protein, a mutation in the NPC1 gene, a mutation in the NPC intracellular cholesterol transporter 2 protein, or a mutation in the NPC2 gene, in a subject with Niemann Pick’s disease. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the ubiquitin protein ligase E3A protein, or a mutation in the UBE3A gene, in a subject with Angelman syndrome. In some embodiments, the donor nucleic acid replaces a nucleic acid that causes a loss of function due to a mutation in the polycystin 1 protein, a mutation in the PKD1 gene, a mutation in the polycystin 2 protein, a mutation in the PKD2 gene, a mutation in the PKHD1 ciliary IPT domain containing fibrocystin/polyductin protein, or a mutation in the PKHD1 gene, in a subject with polycystic kidney disease. IV. Methods of Treating a Disorder [157] Compositions, systems and methods disclosed herein may be useful for treating a disease in a subject. Methods may comprise inserting a donor nucleic acid (transgene) into the genome utilizing system or composition described herein, wherein the insertion results in production of a functional protein. Thus, compositions, systems and methods disclosed herein are especially useful for treating loss of function (LOF) diseases. Non-limiting examples of LOF diseases are spinal muscular atrophy (SMA), Pompe disease, Duchene muscular dystrophy, Fanconi-Bickel syndrome, Danon disease, von Gierke's disease, Cori's disease, Forbes' disease, McArdle's disease, Hers' disease, Tarui's disease, Fanconi-Bickel syndrome, Aldolase A deficiency, cystic fibrosis, hemophilia A, hemophilia B, Gitelman syndrome, Tay- Sachs disease, sickle cell anemia, familial hypercholesterolemia, hemochromatosis, Huntington’s disease, nephrogenic diabetes insipidus, familial glucocorticoid deficiency, familial hypogonadism, hypogonadism, euthyroid hyperthyroidism, central hypothyroidism, chondrodysplasia, benign familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, retinal degeneration, vitreoretinopathy, Hirschsprung disease, fragile X syndrome, Gaucher’s Disease, glucose 6-phosphate dehydrogenase deficiency, holoprosencephaly, phenylketonuria, Friedreich’s ataxia, alpha-1 antitrypsin deficiency, Niemann Pick’s disease, Angelman syndrome, and polycystic kidney disease. [158] In some embodiments, the methods comprise administration of an LSR system, or nucleic acid encoding the same, or composition comprising the same to a subject in need thereof. In some embodiments, methods comprise administering a cell that has been modified by a system described herein to a subject. By way of non-limiting example, the disease may be a cancer, an ophthalmological disorder, a neurological disorder, a neurodegenerative disease, a blood disorder, or a metabolic disorder, or a combination thereof. The disease may be an inherited disorder, also referred to as a genetic disorder. V. Methods of Editing [159] Disclosed herein, in some aspects, are methods of modifying a target nucleic acid. In some embodiments, methods comprise contacting a target nucleic acid with a recombinase and inserting a donor nucleic acid into the target nucleic acid. Methods may comprise contacting a cell or a subject with a recombinase, an effector protein, a partner protein, or a combination thereof. Methods may comprise contacting a cell with a nucleic acid encoding a recombinase, an effector protein, a partner protein, or a combination thereof. The nucleic acid may be an expression vector. [160] Methods of the disclosure may be performed in a subject. Compositions of the disclosure may be administered to a subject. A subject may be a human. A subject may be a mammal (e.g., rat, mouse, cow, dog, pig, sheep, horse). Methods of the disclosure may be performed in a cell. A cell may be in vitro. A cell may be in vivo. A cell may be ex vivo. A cell may be an isolated cell. A cell may be a cell inside of an organism. A cell may be an organism. A cell may be a cell in a cell culture. A cell may be one of a collection of cells. A cell may be a mammalian cell or derived from a mammalian cell. A cell may be a rodent cell or derived from a rodent cell. A cell may be a human cell or derived from a human cell. A cell may be a eukaryotic cell or derived from a eukaryotic cell. A cell may be a plant cell or derived from a plant cell. A cell may be an animal cell or derived from an animal cell. In some embodiments, the cell is a stem cell. Non-limiting examples of stem cells are hematopoietic stem cells, muscle stem cells (also referred to as myoblasts or muscle progenitor cells), and pluripotent stem cells (including induced pluripotent stem cells). In some embodiments, the cell is cell derived or differentiated from a pluripotent stem cell. In some embodiments, the cell is a hepatocyte. In some instances, the cell is an immune cell. Non-limiting examples of immune cells are lymphocytes (T cells, B cells, and NK cells), neutrophils, and monocytes/ macrophages. [161] A cell may be from a specific organ or tissue. Non-limiting examples of organs and tissues from which a cell may be obtained or in which a cell may be located include: muscle, adipose, bone, adrenal gland, pituitary gland, thyroid gland, pancreas, testes, ovaries, uterus, heart, lung, aorta, smooth vasculature, endometrium, brain, neurons, spinal cord, kidney, liver, esophagus, stomach, intestine, colon, bladder, and spleen. The tissue may be the subject’s blood, bone marrow, or cord blood. The tissue may be heterologous donor blood, cord blood, or bone marrow. The tissue may be allogeneic blood, cord blood, or bone marrow. Target Nucleic Acids [162] Described herein are compositions, systems and methods for modifying a target nucleic acid, wherein the target nucleic acid is a gene, a portion thereof, a transcript thereof. In some embodiments, systems, compositions and methods described herein are used to insert a donor nucleic acid sequence encoding a wildtype or functional protein (or functional domain thereof) into a target nucleic acid. In some embodiments, the target nucleic acid is a double stranded nucleic acid. In some embodiments, the double stranded nucleic acid is DNA. In some embodiments, the target nucleic acid comprises a eukaryotic gene. In some embodiments, the target nucleic acid comprises a human gene. In some embodiments, the target nucleic acid comprises an intron of a gene. In some embodiments, the target nucleic acid comprises a sequence that does not encode a protein (also referred to as a non-coding region). [163] In some embodiments, the target nucleic acid comprises a safe harbor locus. A “safe harbor locus” refers to a region of the genome that can maintain transgene expression without detrimentally altering the function of host cells. Safe harbor loci are known in the art and include, but are not limited to AAVS1 (PPPIR12C) gene, an ALB gene, an ANGPTL3 gene, an APOC3 gene, an ASGR2 gene, a CCR5 gene, a FIX (F9) gene, a G6PC gene, a GYS2 gene, an HGD gene, a Lp(a) gene, a PCSK9 gene, a SERPINA1 gene, a TF gene, a TTR gene, ROGI1, ROGI2, and an intron thereof (See e.g., Sadelain, M., Papapetrou, E.P., and Bushman, F.D. (2012). Safe harbours for the integration of new DNA in the human genome. Nat. Rev. Cancer 12, 51–58; and Aznauryan et al., 2022, Cell Reports Methods 2, 100154). A description of identifying safe harbor loci in the human genome are also known in the art. See Fig. 1A of Aznauryan et al., 2022, Cell Reports Methods 2, 100154. VI. Vectors & Additional Delivery Systems [164] In some embodiments, compositions and systems provided herein comprise a vector system encoding a polypeptide (e.g., a recombinase) described herein. In some embodiments, a vector can comprise or encode one or more regulatory elements. Regulatory elements can refer to transcriptional and translational control sequences, such as promoters, enhancers, polyadenylation signals, terminators, protein degradation signals, and the like, that provide for and/or regulate transcription of a non-coding sequence or a coding sequence and/or regulate translation of an encoded polypeptide. In some embodiments, a vector can comprise or encode for one or more additional elements, such as, for example, replication origins, antibiotic resistance (or a nucleic acid encoding the same), a tag (or a nucleic acid encoding the same), selectable markers, and the like. [165] Vectors described herein can encode a promoter - a regulatory region on a nucleic acid, such as a DNA sequence, capable of initiating transcription of a downstream (3′ direction) coding or non-coding sequence. As used herein, a promoter can be bound at its 3′ terminus to a nucleic acid the expression or transcription of which is desired, and extends upstream (5′ direction) to include bases or elements necessary to initiate transcription or induce expression, which could be measured at a detectable level. A promoter can comprise a nucleotide sequence, referred to herein as a “promoter sequence”. A promoter sequence can include a transcription initiation site, and one or more protein binding domains responsible for the binding of transcription machinery, such as RNA polymerase. When eukaryotic promoters are used, such promoters can contain “TATA” boxes and “CAT” boxes. Various promoters, including inducible promoters, may be used to drive expression, i.e., transcriptional activation, of the nucleic acid of interest. Accordingly, in some embodiments, the nucleic acid of interest can be operably linked to a promoter. [166] Promotors can be any suitable type of promoter envisioned for the compositions, systems, and methods described herein. Examples include constitutively active promoters (e.g., CMV promoter), inducible promoters (e.g., heat shock promoter, tetracycline-regulated promoter, steroid-regulated promoter, metal-regulated promoter, estrogen receptor-regulated promoter, etc.), spatially restricted and/or temporally restricted promoters (e.g., a tissue specific promoter, a cell type specific promoter, etc.), etc. Suitable promoters include, but are not limited to: SV40 early promoter, mouse mammary tumor virus long terminal repeat (LTR) promoter; adenovirus major late promoter (Ad MLP); a herpes simplex virus (HSV) promoter, a cytomegalovirus (CMV) promoter such as the CMV immediate early promoter region (CMVIE), a rous sarcoma virus (RSV) promoter, a human U6 small nuclear promoter (U6), an enhanced U6 promoter, and a human Hl promoter (Hl). By transcriptional activation, it is intended that transcription will be increased above basal levels in the target cell by 10 fold, by 100 fold, or by 1000 fold, or more. In addition, vectors used for providing a nucleic acid that, when transcribed, produces a guide nucleic acid and/or a nucleic acid that encodes an effector protein to a cell may include nucleic acid sequences that encode for selectable markers in the target cells, so as to identify cells that have taken up the guide nucleic acid and/or an effector protein. [167] In general, vectors provided herein comprise at least one promotor or a combination of promoters driving expression or transcription of one or more genome editing tools described herein. In some embodiments, the viral vector comprises a nucleotide sequence of a promoter. In some embodiments, the viral vector comprises two promoters. In some embodiments, the viral vector comprises three promoters. In some embodiments, the length of the promoter is less than about 500, less than about 400, or less than about 300 linked nucleotides. In some embodiments, the length of the promoter is at least 100 linked nucleotides. Non-limiting examples of promoters include CMV, 7SK, EF1a, RPBSA, hPGK, EFS, SV40, PGK1, Ubc, human beta actin promoter, CAG, TRE, UAS, Ac5, Polyhedrin, CaMKIIa, GAL1, H1, TEF1, GDS, ADH1, CaMV35S, Ubi, U6, MNDU3, MSCV, MND and CAG. [168] In some embodiments, the promoter is an inducible promoter that only drives expression of its corresponding gene when a signal is present, e.g., a hormone, a small molecule, a peptide. Non-limiting examples of inducible promoters are the T7 RNA polymerase promoter, the T3 RNA polymerase promoter, the Isopropyl-beta-D- thiogalactopyranoside (IPTG)-regulated promoter, a lactose induced promoter, a heat shock promoter, a tetracycline-regulated promoter (tetracycline-inducible or tetracycline- repressible), a steroid regulated promoter, a metal-regulated promoter, and an estrogen receptor-regulated promoter. In some embodiments, the promoter is an activation-inducible promoter, such as a CD69 promoter, as described further in Kulemzin et al., (2019), BMC Med Genomics, 12:44. In some embodiments, the promoter for expressing effector protein is a muscle-specific promoter. In some embodiments, the muscle-specific promoter comprises Ck8e, SPC5-12, or Desmin promoter sequence. In some embodiments, the promoter for expressing effector protein is a ubiquitous promoter. In some embodiments, the ubiquitous promoter comprises MND or CAG promoter sequence. [169] In some embodiments, an effector protein, LSR, or RDDP (or a nucleic acid encoding same) and/or a guide nucleic acid (or a nucleic acid that, when transcribed, produces same) are co-administered with a donor nucleic acid. Coadministration can be contact with a target nucleic acid, administered to a cell, such as a host cell, or administered as method of nucleic acid detection, editing, and/or treatment as described herein, in a single vehicle, such as a single expression vector. In certain embodiments, an effector protein, LSR, or RDDP (or a nucleic acid encoding same) and/or a guide nucleic acid (or a nucleic acid that, when transcribed, produces same) are not co-administered with donor nucleic acid in a single vehicle. In certain embodiments, an effector protein (or a nucleic acid encoding same), a guide nucleic acid (or a nucleic acid that, when transcribed, produces same), and/or donor nucleic acid are administered in one or more or two or more vehicles, such as one or more, or two or more expression vectors. Viral Vectors [170] An expression vector can be a viral vector. In some embodiments, a viral vector comprises a nucleic acid to be delivered into a host cell via a recombinantly produced virus or viral particle. The nucleic acid may be single-stranded or double stranded, linear or circular, segmented or non-segmented. The nucleic acid may comprise DNA, RNA, or a combination thereof. In some embodiments, the expression vector is an adeno-associated viral vector. There are a variety of viral vectors that are associated with various types of viruses, including but not limited to retroviruses (e.g., lentiviruses and γ-retroviruses), adenoviruses, arenaviruses, alphaviruses, adeno-associated viruses (AAVs), baculoviruses, vaccinia viruses, herpes simplex viruses and poxviruses. A viral vector provided herein can be derived from or based on any such virus. Often the viral vectors provided herein are an adeno-associated viral vector (AAV vector). Generally, an AAV vector has two inverted terminal repeats (ITRs). According, in some embodiments, the viral vector provided herein comprises two inverted terminal repeats of AAV. The DNA sequence in between the ITRs of an AAV vector provided herein may be referred to herein as the sequence encoding the genome editing tools or a transgene. These genome editing tools can include, but are not limited to, an effector protein, effector protein modifications (e.g., nuclear localization signal (NLS), polyA tail), guide nucleic acid(s), respective promoter(s), and a donor nucleic acid, or combinations thereof. In some embodiments, a nuclear localization signal comprises an entity (e.g., peptide) that facilitates localization of a nucleic acid, protein, or small molecule to the nucleus, when present in a cell that contains a nuclear compartment. [171] In some embodiments, the present disclosure provides AAV vectors comprising a sequence encoding a recombinase and a donor nucleic acid. In some embodiments, the recombinase is a large serine recombinase. In some embodiments, the sequence encoding the recombinase is operably linked to a promoter. In some embodiments, the promoter is a mammalian promoter (e.g., a CMV promoter). In some embodiments, the donor nucleic acid comprises a sequence of insertion (SOI); a pair of recombinase recognition sites (referred to as “RRS-1a/RRS-1b” or “circularization attB/circularization attP”) that are compatible with one another; and a donor recombinase recognition site (referred to as “RRS-2a” or “integration attB”) that is compatible with a target nucleic acid recombinase recognition site (referred to as “RRS-2b”), wherein RRS-1a and RRS-1b are orthogonal to RRS-2a and RRS-2b, and wherein the recombinase recognizes RRS-1a, RRS-1b, RRS-2a and RRS-2b. In some embodiments, the SOI, the donor recombinase recognition site, and the promoter that is operably linked to the sequence encoding the recombinase are placed between the two recombinase recognition sites (i.e., RRS-1a and RRS-1b). In some embodiments, the sequence encoding the recombinase is placed outside of the three recombinase recognition sites (i.e., circularization attB, circularization attP, and integration attB). In some embodiments, the sequence encoding the recombinase and the donor nucleic acid are flanked by a 5’ ITR sequence and a 3’ ITR sequence on the 5’ and 3’ ends. See FIG.7. [172] When placed outside of the three recombinase recognition sites, the recombinase- encoding sequence may be removed from the circular template prior to episome formation and/or integration. In such a scheme, production of the AAV may rely on coexpression of a recombinase directionality factor (RDF) or siRNA/antisense RNA to limit recombinase activity during plasmid propagation and/or viral production. In some embodiments, the present disclosure provides AAV transfer plasmids comprising a) a 5’ ITR sequence; b) a donor nucleic acid, wherein the donor nucleic acid comprises a sequence of insertion (SOI), a pair of recombinase recognition sites (RRS-1a and RRS-1b) that are compatible with one another, and optionally a donor recombinase recognition site (RRS-2a) that is compatible with a target nucleic acid recombinase recognition site (RRS-2b); c) a sequence encoding a recombinase (e.g., LSR) that is operably linked to a promoter (e.g., a CMV promoter), wherein the recombinase recognizes RRS-1a, RRS-1b, RRS-2a and RRS-2b and wherein the opposite strand of the sequence encoding the recombinase is operably linked to a bacterial promoter (e.g., J23119 promoter) that expresses an antisense RNA of the recombinase; d) a 3’ ITR sequence; e) a sequence encoding an shRNA that targets the recombinase; and e) a sequence encoding a RDF. See FIG. 7. During plasmid propagation in bacteria, the antisense RNA of the recombinase can be used to silence the expression of mRNA of the recombinase via RNaseIII or other RNases. In some embodiments, the sequence encoding the shRNA is operably linked to a Pol III promoter (e.g., a hU6 promoter). In such embodiments, the shRNA is only expressed in mammalian cells during viral production. In some embodiments, the sequence encoding the RDF is operably linked to a mammalian promoter (e.g., a CMV or SFFV promoter) followed by a bacterial promoter (e.g., J23104 promoter). In such embodiments, RDF can be expressed in both mammalian cells during viral production and bacterial cells during plasmid propagation. In some embodiments, the sequence encoding the recombinase and the donor nucleic acid are flanked by the 5’ ITR sequence and the 3’ ITR sequence. In some embodiments, the sequence encoding the shRNA and the sequence encoding the RDF are placed outside of the 5’ ITR sequence and the 3’ ITR sequence. In such embodiments, the shRNA and RDF are excluded from the AAV vector during viral production as the AAV vector only includes the genetic payload between ITRs. In such embodiments, the recombinase (e.g., LSR) can be expressed normally in transduced cells and can circularize and integrate the SOI. [173] In some embodiments, the coding region of the AAV vector forms an intramolecular double-stranded DNA template thereby generating an AAV vector that is a self-complementary AAV (scAAV) vector. In general, the sequence encoding the genome editing tools of an scAAV vector has a length of about 2 kb to about 3 kb. The scAAV vector can comprise nucleotide sequences encoding an effector protein, providing guide nucleic acids described herein, and a donor nucleic acid described herein. In some embodiments, the AAV vector provided herein is a self-inactivating AAV vector. [174] In some embodiments, the viral particle that delivers the viral vector described herein is an AAV. AAVs are characterized by their serotype. Non-limiting examples of AAV serotypes are AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, scAAV, AAV-rh10, chimeric or hybrid AAV, or any combination, derivative, or variant thereof. Producing AAV Particles [175] The AAV particles described herein can be referred to as recombinant AAV (rAAV). Often, rAAV particles are generated by transfecting AAV producing cells with an AAV- containing plasmid carrying the sequence encoding the genome editing tools, a plasmid that carries viral encoding regions, i.e., Rep and Cap gene regions; and a plasmid that provides the helper genes such as E1A, E1B, E2A, E4ORF6 and VA. In some embodiments, the AAV producing cells are mammalian cells. In some embodiments, host cells for rAAV viral particle production are mammalian cells. In some embodiments, a mammalian cell for rAAV viral particle production is a COS cell, a HEK293T cell, a HeLa cell, a KB cell, a derivative thereof, or a combination thereof. In some embodiments, rAAV virus particles can be produced in the mammalian cell culture system by providing the rAAV plasmid to the mammalian cell. In some embodiments, producing rAAV virus particles in a mammalian cell can comprise transfecting vectors that express the rep protein, the capsid protein, and the gene-of-interest expression construct flanked by the ITR sequence on the 5’ and 3’ ends. Methods of such processes are provided in, for example, Naso et al., BioDrugs, 2017 Aug;31(4):317-334 and Benskey et al., (2019), Methods Mol Biol., 1937:3-26, each of which is incorporated by reference in their entireties. [176] In some embodiments, rAAV is produced in a non-mammalian cell. In some embodiments, rAAV is produced in an insect cell. In some embodiments, an insect cell for producing rAAV viral particles comprises a Sf9 cell. In some embodiments, production of rAAV virus particles in insect cells can comprise baculovirus. In some embodiments, production of rAAV virus particles in insect cells can comprise infecting the insect cells with three recombinant baculoviruses, one carrying the cap gene, one carrying the rep gene, and one carrying the gene-of-interest expression construct enclosed by an ITR on both the 5’ and 3’ end. In some embodiments, rAAV virus particles are produced by the One Bac system. In some embodiments, rAAV virus particles can be produced by the Two Bac system. In some embodiments, in the Two Bac system, the rep gene and the cap gene of the AAV is integrated into one baculovirus virus genome, and the ITR sequence and the gene-of-interest expression construct is integrated into another baculovirus virus genome. In some embodiments, in the One Bac system, an insect cell line that expresses both the rep protein and the capsid protein is established and infected with a baculovirus virus integrated with the ITR sequence and the gene-of-interest expression construct. Details of such processes are provided in, for example, Smith et. al., (1983), Mol. Cell. Biol., 3(12):2156-65; Urabe et al., (2002), Hum. Gene. Ther., 1;13(16):1935-43; and Benskey et al., (2019), Methods Mol Biol., 1937:3-26, each of which is incorporated by Reference in its entirety. [177] The AAV may be any AAV known in the art. In some embodiments, the viral vector corresponds to a virus of a specific serotype. In some examples, the serotype is selected from an AAV1 serotype, an AAV2 serotype, AAV3 serotype, an AAV4 serotype, AAV5 serotype, an AAV6 serotype, AAV7 serotype, an AAV8 serotype, an AAV9 serotype, an AAV10 serotype, an AAV11 serotype, and an AAV12 serotype. In some embodiments the AAV vector is a recombinant vector, a hybrid AAV vector, a chimeric AAV vector, a self- complementary AAV (scAAV) vector, a single-stranded AAV or any combination thereof. scAAV genomes are generally known in the art and contain both DNA strands which can anneal together to form double-stranded DNA. [178] In some embodiments, methods of producing delivery vectors herein comprise packaging a nucleic acid, or transgene, encoding an effector protein and a nucleic acid that, when transcribed, produces a guide nucleic acid, or a combination thereof, into an AAV vector. In some embodiments, methods of producing the delivery vector comprises, (a) contacting a cell with at least one nucleic acid, or transgene that, when transcribed, produces a guide nucleic acid; at least one nucleic acid that encodes: (i) a Replication (Rep) gene; and (ii) a Capsid (Cap) gene that encodes an AAV capsid protein; (b) expressing the AAV capsid protein in the cell; (c) assembling an AAV particle; and (d) packaging a protein encoding nucleic acid into the AAV particle, thereby generating an AAV delivery vector. In some embodiments, promoters, stuffer sequences, and any combination thereof may be packaged in the AAV vector. In some embodiments, the AAV vector comprises inverted terminal repeats, e.g., a 5’ inverted terminal repeat and a 3’ inverted terminal repeat. In some embodiments, the inverted terminal repeat comprises inverted terminal repeats from AAV. In some embodiments, the inverted terminal repeat comprises inverted terminal repeats of ssAAV vector or scAAV vector. In some embodiments, the AAV vector comprises a mutated inverted terminal repeat that lacks a terminal resolution site. [179] In some embodiments, a hybrid AAV vector is produced by transcapsidation, e.g., packaging an inverted terminal repeat (ITR) from a first serotype into a capsid of a second serotype, wherein the first and second serotypes may be not the same. In some examples, the Rep gene and ITR from a first AAV serotype (e.g., AAV2) may be used in a capsid from a second AAV serotype (e.g., AAV9), wherein the first and second AAV serotypes may be not the same. As a non-limiting example, a hybrid AAV serotype comprising the AAV2 ITRs and AAV9 capsid protein may be indicated AAV2/9. In some examples, the hybrid AAV delivery vector comprises an AAV2/1, AAV2/2, AAV 2/4, AAV2/5, AAV2/8, or AAV2/9 vector. [180] In some embodiments, the AAV vector may be a chimeric AAV vector. In some embodiments, the chimeric AAV vector comprises an exogenous amino acid or an amino acid substitution, or capsid proteins from two or more serotypes. In some examples, a chimeric AAV vector may be genetically engineered to increase transduction efficiency, selectivity, or a combination thereof. Lipid particles [181] In some embodiments, compositions and systems provided herein comprise a lipid particle. In some embodiments, a lipid particle is a lipid nanoparticle (LNP). In some embodiments, a lipid or a lipid nanoparticle can encapsulate an mRNA encoding a recombinase. LNPs are effective for delivery of nucleic acids. Beneficial properties of LNP include ease of manufacture, low cytotoxicity and immunogenicity, high efficiency of nucleic acid encapsulation and cell transfection, multi-dosing capabilities and flexibility of design (Kulkarni et al., (2018) Nucleic Acid Therapeutics, 28(3):146-157). In some embodiments, a method can comprise contacting a cell with an expression vector. In some embodiments, contacting can comprise electroporation, lipofection, or lipid nanoparticle (LNP) delivery of an expression vector. Engineered Proteins [182] Any of the nucleic acid sequences that encode the protein sequences disclosed herein may be codon optimized. In some embodiments, effector proteins described herein are encoded by a codon optimized nucleic acid. This type of optimization can entail a mutation of an effector protein encoding nucleotide sequence to mimic the codon preferences of the intended host organism or cell while encoding the same polypeptide. Thus, the codons can be changed, but the encoded protein remains unchanged. For example, if the intended target cell was a human cell, a human codon-optimized effector protein-encoding nucleotide sequence could be used. As another non-limiting example, if the intended host cell were a mouse cell, then a mouse codon-optimized effector protein-encoding nucleotide sequence could be generated. As another non-limiting example, if the intended host cell were a eukaryotic cell, then a eukaryote codon-optimized effector protein nucleotide sequence could be generated. As another non-limiting example, if the intended host cell were a prokaryotic cell, then a prokaryote codon-optimized effector protein-encoding nucleotide sequence could be generated. Codon usage tables are readily available, for example, at the “Codon Usage Database” available at www.kazusa.or.jp/codon. Accordingly, in some embodiments, effector proteins described herein may be codon optimized for expression in a specific cell, for example, a bacterial cell, a plant cell, a eukaryotic cell, an animal cell, a mammalian cell, or a human cell. In some embodiments, the effector protein is codon optimized for a human cell. [183] It is understood that when describing coding sequences of polypeptides described herein, said coding sequences do not necessarily require a codon encoding a N-terminal Methionine (M) or a Valine (V) as described for the effector proteins described herein. One skilled in the art would understand that a start codon could be replaced or substituted with a start codon that encodes for an amino acid residue sufficient for initiating translation in a host cell. In some embodiments, when a modifying heterologous peptide, such as a fusion partner protein, protein tag or NLS, is located at the N terminus of the effector protein, a start codon for the heterologous peptide serves as a start codon for the effector protein as well. Thus, the natural start codon encoding an amino acid residue sufficient for initiating translation (e.g., Methionine (M) or a Valine (V)) of the effector protein may be removed or absent. [184] In some embodiments, proteins described herein comprise one or more amino acid substitutions as compared to a naturally occurring protein. In some embodiments, the amino acid substitution is a conservative amino acid substitution. In general, a conservative amino acid substitution is the substitution of an amino acid residue for another amino acid residue with similar chemical properties (e.g., size, charge, or polarity). Conservative substitutions may be made by exchanging an amino acid from one of the groups listed below (group 1 to 6) for another amino acid of the same group. Amino acid residues may be divided into groups based on common side chain properties, as follows: (group 1) hydrophobic: norleucine (Nle), methionine (Met), Alanine (Ala), Valine (Val), Leucine (Leu), Isoleucine (Ile); (group 2) neutral hydrophilic: Cysteine (Cys), Serine (Ser), Threonine (Thr), Asparagine (Asn), Glutamine (Gln); (group 3) acidic: Aspartic acid (Asp), Glutamic acid (Glu); (group 4) basic: Histidine (His), Lysine (Lys), Arginine (Arg); (group 5) residues that influence chain orientation: Glycine (Gly), Proline (Pro); and (group 6) aromatic: Tryptophan (Trp), Tyrosine (Tyr), Phenylalanine (Phe). The substitution of one amino acid with another amino acid in a same group listed above may be considered a conservative amino acid substitution. The substitution of one amino acid with another amino acid in a different group listed above may be considered a non-conservative amino acid substitution. Chemical Modifications [185] Polypeptides and nucleic acids described herein may comprise one or more chemical modifications. Examples are modifications of interest that do not alter primary sequence, including chemical derivatization of polypeptides, e.g., acylation, acetylation, carboxylation, amidation, etc. Also included are modifications of glycosylation, e.g. those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps; e.g. by exposing the polypeptide to enzymes which affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes. Also embraced are sequences that have phosphorylated amino acid residues, e.g. phosphotyrosine, phosphoserine, or phosphothreonine. [186] Modifications disclosed herein can also include modification of described polypeptides and/or engineered guide nucleic acids through any suitable method, such as molecular biological techniques and/or synthetic chemistry, to improve their resistance to proteolytic degradation, to change the target sequence specificity, to optimize solubility properties, to alter protein activity (e.g., transcription modulatory activity, enzymatic activity, etc.) or to render them more suitable. Analogs of such polypeptides include those containing residues other than naturally occurring L-amino acids, e.g. D-amino acids or non-naturally occurring synthetic amino acids. D-amino acids may be substituted for some or all of the amino acid residues. Modifications can also include modifications with non-naturally occurring unnatural amino acids. The particular sequence and the manner of preparation will be determined by convenience, economics, purity required, and the like. [187] Modifications can further include the introduction of various groups to polypeptides and/or engineered guide nucleic acids described herein. For example, groups can be introduced during synthesis or during expression of a polypeptide, which allow for linking to other molecules or to a surface. Thus, e.g., cysteines can be used to make thioethers, histidines for linking to a metal ion complex, carboxyl groups for forming amides or esters, amino groups for forming amides, and the like. [188] Modifications can further include modification of nucleic acids described herein (e.g., engineered guide nucleic acids) to provide the nucleic acid with a new or enhanced feature, such as improved stability. Such modifications of a nucleic acid include a base modification, a backbone modification, a sugar modification, or combinations thereof, of one or more nucleotides, nucleosides, or nucleobases in a nucleic acid. [189] In some embodiments, nucleic acids (e.g., engineered guide nucleic acids) described herein comprise one or more modifications comprising: 2’O-methyl modified nucleotides, 2’ Fluoro modified nucleotides; locked nucleic acid (LNA) modified nucleotides; peptide nucleic acid (PNA) modified nucleotides; nucleotides with phosphorothioate linkages; a 5’ cap (e.g., a 7-methylguanylate cap (m7G)), phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates including 3'-alkylene phosphonates, 5'-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3'-amino phosphoramidate and aminoalkyl phosphoramidates, phosphorodiamidates, thionophosphor amidates, thionoalkylphosphonates , thionoalkylphosphotriesters, selenophosphates and boranophosphates having normal 3'-5' linkages, 2'-5' linked analogs of these, and those having inverted polarity wherein one or more internucleotide linkages is a 3' to 3', 5' to 5' or 2' to 2' linkage; phosphorothioate and/or heteroatom internucleoside linkages, such as -CH₂-NH-O- CH₂-, -CH₂-N(CH₃₎-O-CH₂- (known as a methylene (methylimino) or MMI backbone), -CH₂- O-N(CH₃)-CH₂-, -CH₂-N(CH₃)- N(CH₃)-CH₂- and -O-N(CH₃)-CH₂-CH₂- (wherein the native phosphodiester internucleotide linkage is represented as -O-P(=O)(OH)-O-CH₂-); morpholino linkages (formed in part from the sugar portion of a nucleoside); morpholino backbones; phosphorodiamidate or other non-phosphodiester internucleoside linkages; siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methylene formacetyl and thioformacetyl backbones; riboacetyl backbones; alkene containing backbones; sulfamate backbones; methyleneimino and methylenehydrazino backbones; sulfonate and sulfonamide backbones; amide backbones; other backbone modifications having mixed N, O, S and CH₂ component parts; and combinations thereof. VII. Pharmaceutical Compositions and Modes of Administration [190] Disclosed herein, in some aspects, are pharmaceutical compositions for modifying a target nucleic acid in a cell or a subject, comprising any one of the recombinases, effector proteins, RDDPs, fusion proteins thereof, or guide nucleic acids as described herein and any combination thereof. Also disclosed herein, in some aspects, are pharmaceutical compositions comprising a nucleic acid encoding any one of the proteins described herein. Pharmaceutical compositions may be used to modify a target nucleic acid or the expression thereof in a cell in vitro, in vivo or ex vivo. [191] In some embodiments, pharmaceutical compositions comprise one or more nucleic acids; and a pharmaceutically acceptable carrier or diluent. Pharmaceutical compositions described herein may comprise a salt. In some embodiments, the salt is a sodium salt. In some embodiments, the salt is a potassium salt. In some embodiments, the salt is a magnesium salt. In some embodiments, the salt is NaCl. In some embodiments, the salt is KNO₃. In some embodiments, the salt is Mg²⁺ SO₄ ²⁻. [192] Non-limiting examples of pharmaceutically acceptable carriers and diluents suitable for the pharmaceutical compositions disclosed herein include buffers (e.g., neutral buffered saline, phosphate buffered saline); carbohydrates (e.g., glucose, mannose, sucrose, dextran, mannitol); polypeptides or amino acids (e.g., glycine); antioxidants; chelating agents (e.g., EDTA, glutathione); adjuvants (e.g., aluminum hydroxide); surfactants (Polysorbate 80, Polysorbate 20, or Pluronic F68); glycerol; sorbitol; mannitol; polyethyleneglycol; and preservatives. [193] In some embodiments, pharmaceutical compositions are in the form of a solution (e.g., a liquid). The solution may be formulated for injection, e.g., intravenous or subcutaneous injection. In some embodiments, the pH of the solution is about 7, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5, about 8.6, about 8.7, about 8.8, about 8.9, or about 9. In some embodiments, the pH is 7 to 7.5, 7.5 to 8, 8 to 8.5, 8.5 to 9, or 7 to 8.5. In some embodiments, the pH of the solution is less than 7. In some embodiments, the pH is greater than 7.

SEQUENCES AND TABLES TABLE 1: LSRs, RRS-1/RRS-2 sites, and safe harbor target sequences Recombinase Protein SEQ RRS-2 SEQ RRS-1 SEQ ID Target Seq ID Protein ID ID ID 3145307 1 3919 6442 8965 3198187 2 3920 6443 8966 3564078 3 3921 6444 8967 3174533 4 3922 6445 8968 3211714 5 3923 6446 8969 3448859 6 3924 6447 8970 3132173 7 3925 6448 8971 3449078 8 3926 6449 8972 3484609 9 3927 6450 8973 3579114 10 3928 6451 8974 2956268 11 3929 6452 8975 3440856 12 3930 6453 8976 3485199 13 3931 6454 8977 3566355 14 3932 6455 8978 2955487 15 3933 6456 8979 2955954 16 3934 6457 8980 3247394 17 3935 6458 8981 3577396 18 3936 6459 8982 3175675 19 3937 6460 8983 3530952 20 3938 6461 8984 3423927 21 3939 6462 8985 3429513 22 3940 6463 8986 3397621 23 3941 6464 8987 3396861 24 3942 6465 8988 3402453 25 3943 6466 8989 3417629 26 3944 6467 8990 3416931 27 3945 6468 8991 3424337 28 3946 6469 8992 3409847 29 3947 6470 8993 3390697 30 3948 6471 8994 3141052 31 3949 6472 8995 3268583 32 3950 6473 8996 3598539 33 3951 6474 8997 3233689 34 3952 6475 8998 3252787 35 3953 6476 8999 3598500 36 3954 6477 9000 3136292 37 3955 6478 9001 3598514 38 3956 6479 9002 2955485 39 3957 6480 9003 Recombinase Protein SEQ RRS-2 SEQ RRS-1 SEQ ID Target Seq ID Protein ID ID ID 3178283 40 3958 6481 9004 3122694 41 3959 6482 9005 3564577 42 3960 6483 9006 3143849 43 3961 6484 9007 3292366 44 3962 6485 9008 3380551 45 3963 6486 9009 3443138 46 3964 6487 9010 3380517 47 3965 6488 9011 3380635 48 3966 6489 9012 3381413 49 3967 6490 9013 3381489 50 3968 6491 9014 3382309 51 3969 6492 9015 3382355 52 3970 6493 9016 3381057 53 3971 6494 9017 3381155 54 3972 6495 9018 3381307 55 3973 6496 9019 3381333 56 3974 6497 9020 3381353 57 3975 6498 9021 3382135 58 3976 6499 9022 3381313 59 3977 6500 9023 3385723 60 3978 6501 9024 3402691 61 3979 6502 9025 3405581 62 3980 6503 9026 3407551 63 3981 6504 9027 3423503 64 3982 6505 9028 3394031 65 3983 6506 9029 3401561 66 3984 6507 9030 3406159 67 3985 6508 9031 3411781 68 3986 6509 9032 3426539 69 3987 6510 9033 3431977 70 3988 6511 9034 3403633 71 3989 6512 9035 3404391 72 3990 6513 9036 3405931 73 3991 6514 9037 3408155 74 3992 6515 9038 3415249 75 3993 6516 9039 3426607 76 3994 6517 9040 3383009 77 3995 6518 9041 3393841 78 3996 6519 9042 3412275 79 3997 6520 9043 3418417 80 3998 6521 9044 3432513 81 3999 6522 9045 3394997 82 4000 6523 9046 Recombinase Protein SEQ RRS-2 SEQ RRS-1 SEQ ID Target Seq ID Protein ID ID ID 3403449 83 4001 6524 9047 3405939 84 4002 6525 9048 3411463 85 4003 6526 9049 3430909 86 4004 6527 9050 3403597 87 4005 6528 9051 3404423 88 4006 6529 9052 3415043 89 4007 6530 9053 3418949 90 4008 6531 9054 3422367 91 4009 6532 9055 3383511 92 4010 6533 9056 3393797 93 4011 6534 9057 3407133 94 4012 6535 9058 3413465 95 4013 6536 9059 3422463 96 4014 6537 9060 3386167 97 4015 6538 9061 3391811 98 4016 6539 9062 3397581 99 4017 6540 9063 3406277 100 4018 6541 9064 3408057 101 4019 6542 9065 3393595 102 4020 6543 9066 3405677 103 4021 6544 9067 3409545 104 4022 6545 9068 3428447 105 4023 6546 9069 3428719 106 4024 6547 9070 3390913 107 4025 6548 9071 3391743 108 4026 6549 9072 3392045 109 4027 6550 9073 3402525 110 4028 6551 9074 3417393 111 4029 6552 9075 3384603 112 4030 6553 9076 3400241 113 4031 6554 9077 3423685 114 4032 6555 9078 3429591 115 4033 6556 9079 3390251 116 4034 6557 9080 3408421 117 4035 6558 9081 3410747 118 4036 6559 9082 3426053 119 4037 6560 9083 3427437 120 4038 6561 9084 3398147 121 4039 6562 9085 3418347 122 4040 6563 9086 3423971 123 4041 6564 9087 3427439 124 4042 6565 9088 3430537 125 4043 6566 9089 Recombinase Protein SEQ RRS-2 SEQ RRS-1 SEQ ID Target Seq ID Protein ID ID ID 3392739 126 4044 6567 9090 3393355 127 4045 6568 9091 3422029 128 4046 6569 9092 3423155 129 4047 6570 9093 3428763 130 4048 6571 9094 3385355 131 4049 6572 9095 3388525 132 4050 6573 9096 3390919 133 4051 6574 9097 3394457 134 4052 6575 9098 3420391 135 4053 6576 9099 3400681 136 4054 6577 9100 3411247 137 4055 6578 9101 3429089 138 4056 6579 9102 3431077 139 4057 6580 9103 3389185 140 4058 6581 9104 3397851 141 4059 6582 9105 3401111 142 4060 6583 9106 3423159 143 4061 6584 9107 3425943 144 4062 6585 9108 3386467 145 4063 6586 9109 3418725 146 4064 6587 9110 3419513 147 4065 6588 9111 3425247 148 4066 6589 9112 3401277 149 4067 6590 9113 3401419 150 4068 6591 9114 3411317 151 4069 6592 9115 3412935 152 4070 6593 9116 3427875 153 4071 6594 9117 3384245 154 4072 6595 9118 3422535 155 4073 6596 9119 3425437 156 4074 6597 9120 3426395 157 4075 6598 9121 3427255 158 4076 6599 9122 3393805 159 4077 6600 9123 3407923 160 4078 6601 9124 3430753 161 4079 6602 9125 3432953 162 4080 6603 9126 3385333 163 4081 6604 9127 3395803 164 4082 6605 9128 3419381 165 4083 6606 9129 3422373 166 4084 6607 9130 3429633 167 4085 6608 9131 3382707 168 4086 6609 9132 Recombinase Protein SEQ RRS-2 SEQ RRS-1 SEQ ID Target Seq ID Protein ID ID ID 3412143 169 4087 6610 9133 3429705 170 4088 6611 9134 3433747 171 4089 6612 9135 3397573 172 4090 6613 9136 3410735 173 4091 6614 9137 3415059 174 4092 6615 9138 3431647 175 4093 6616 9139 3433243 176 4094 6617 9140 3383391 177 4095 6618 9141 3394155 178 4096 6619 9142 3396131 179 4097 6620 9143 3412497 180 4098 6621 9144 3415277 181 4099 6622 9145 3395081 182 4100 6623 9146 3396413 183 4101 6624 9147 3414507 184 4102 6625 9148 3415599 185 4103 6626 9149 3425949 186 4104 6627 9150 3390971 187 4105 6628 9151 3397917 188 4106 6629 9152 3405625 189 4107 6630 9153 3415283 190 4108 6631 9154 3415755 191 4109 6632 9155 3384351 192 4110 6633 9156 3407927 193 4111 6634 9157 3412529 194 4112 6635 9158 3421449 195 4113 6636 9159 3392227 196 4114 6637 9160 3397003 197 4115 6638 9161 3406729 198 4116 6639 9162 3413361 199 4117 6640 9163 3418447 200 4118 6641 9164 3384483 201 4119 6642 9165 3384961 202 4120 6643 9166 3406499 203 4121 6644 9167 3414653 204 4122 6645 9168 3432437 205 4123 6646 9169 3403151 206 4124 6647 9170 3410937 207 4125 6648 9171 3422709 208 4126 6649 9172 3429557 209 4127 6650 9173 3431699 210 4128 6651 9174 3385745 211 4129 6652 9175 Recombinase Protein SEQ RRS-2 SEQ RRS-1 SEQ ID Target Seq ID Protein ID ID ID 3389457 212 4130 6653 9176 3414655 213 4131 6654 9177 3421451 214 4132 6655 9178 3384109 215 4133 6656 9179 3388615 216 4134 6657 9180 3408517 217 4135 6658 9181 3419311 218 4136 6659 9182 3423287 219 4137 6660 9183 3398715 220 4138 6661 9184 3398853 221 4139 6662 9185 3402467 222 4140 6663 9186 3413171 223 4141 6664 9187 3430435 224 4142 6665 9188 3411249 225 4143 6666 9189 3417569 226 4144 6667 9190 3422737 227 4145 6668 9191 3430903 228 4146 6669 9192 3431723 229 4147 6670 9193 3408073 230 4148 6671 9194 3415097 231 4149 6672 9195 3415311 232 4150 6673 9196 3431737 233 4151 6674 9197 3433385 234 4152 6675 9198 3388805 235 4153 6676 9199 3402659 236 4154 6677 9200 3408525 237 4155 6678 9201 3412525 238 4156 6679 9202 3432829 239 4157 6680 9203 3397365 240 4158 6681 9204 3397759 241 4159 6682 9205 3405637 242 4160 6683 9206 3419519 243 4161 6684 9207 3430151 244 4162 6685 9208 3397367 245 4163 6686 9209 3404201 246 4164 6687 9210 3423601 247 4165 6688 9211 3427111 248 4166 6689 9212 3430895 249 4167 6690 9213 3401211 250 4168 6691 9214 3401983 251 4169 6692 9215 3404197 252 4170 6693 9216 3413061 253 4171 6694 9217 3414893 254 4172 6695 9218 Recombinase Protein SEQ RRS-2 SEQ RRS-1 SEQ ID Target Seq ID Protein ID ID ID 3385449 255 4173 6696 9219 3388677 256 4174 6697 9220 3409057 257 4175 6698 9221 3426199 258 4176 6699 9222 3384837 259 4177 6700 9223 3386011 260 4178 6701 9224 3388437 261 4179 6702 9225 3393755 262 4180 6703 9226 3432101 263 4181 6704 9227 3394657 264 4182 6705 9228 3404191 265 4183 6706 9229 3405089 266 4184 6707 9230 3423543 267 4185 6708 9231 3432631 268 4186 6709 9232 3385465 269 4187 6710 9233 3394331 270 4188 6711 9234 3420339 271 4189 6712 9235 3425265 272 4190 6713 9236 3430311 273 4191 6714 9237 3394595 274 4192 6715 9238 3412803 275 4193 6716 9239 3415881 276 4194 6717 9240 3427431 277 4195 6718 9241 3432103 278 4196 6719 9242 3384911 279 4197 6720 9243 3385471 280 4198 6721 9244 3400927 281 4199 6722 9245 3409193 282 4200 6723 9246 3384839 283 4201 6724 9247 3397185 284 4202 6725 9248 3408873 285 4203 6726 9249 3420445 286 4204 6727 9250 3428275 287 4205 6728 9251 3382863 288 4206 6729 9252 3401347 289 4207 6730 9253 3406331 290 4208 6731 9254 3420523 291 4209 6732 9255 3433337 292 4210 6733 9256 3383901 293 4211 6734 9257 3391397 294 4212 6735 9258 3397303 295 4213 6736 9259 3413035 296 4214 6737 9260 3427515 297 4215 6738 9261 Recombinase Protein SEQ RRS-2 SEQ RRS-1 SEQ ID Target Seq ID Protein ID ID ID 3384303 298 4216 6739 9262 3396617 299 4217 6740 9263 3404161 300 4218 6741 9264 3407607 301 4219 6742 9265 3431287 302 4220 6743 9266 TABLE 2: LSRs, RRS-1/RRS-2 sites Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3180902 303 4221 6744 3296093 304 4222 6745 3433962 305 4223 6746 3442781 306 4224 6747 3447107 307 4225 6748 3451870 308 4226 6749 3459733 309 4227 6750 3465007 310 4228 6751 3465500 311 4229 6752 3469311 312 4230 6753 3480835 313 4231 6754 3485455 314 4232 6755 3487658 315 4233 6756 3503432 316 4234 6757 3504448 317 4235 6758 3504901 318 4236 6759 3508488 319 4237 6760 3515021 320 4238 6761 3530090 321 4239 6762 3532821 322 4240 6763 3535442 323 4241 6764 3543955 324 4242 6765 3544473 325 4243 6766 3561831 326 4244 6767 3565941 327 4245 6768 3570103 328 4246 6769 3573383 329 4247 6770 3576133 330 4248 6771 3576806 331 4249 6772 3578419 332 4250 6773 3582976 333 4251 6774 3587941 334 4252 6775 3592600 335 4253 6776 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3120406 336 4254 6777 3180114 337 4255 6778 3185483 338 4256 6779 3192844 339 4257 6780 3257162 340 4258 6781 3454441 341 4259 6782 3458272 342 4260 6783 3478384 343 4261 6784 3482008 344 4262 6785 3483508 345 4263 6786 3486969 346 4264 6787 3493453 347 4265 6788 3517549 348 4266 6789 3520214 349 4267 6790 3531245 350 4268 6791 3539559 351 4269 6792 3539670 352 4270 6793 3540871 353 4271 6794 3547396 354 4272 6795 3552728 355 4273 6796 3553944 356 4274 6797 3558494 357 4275 6798 3563569 358 4276 6799 3570574 359 4277 6800 3571120 360 4278 6801 3578275 361 4279 6802 3590860 362 4280 6803 3591441 363 4281 6804 3598437 364 4282 6805 3598438 365 4283 6806 3598439 366 4284 6807 3598456 367 4285 6808 3128533 368 4286 6809 3129168 369 4287 6810 3168690 370 4288 6811 3179623 371 4289 6812 3183040 372 4290 6813 3209274 373 4291 6814 3234257 374 4292 6815 3235078 375 4293 6816 3249154 376 4294 6817 3436387 377 4295 6818 3439024 378 4296 6819 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3447694 379 4297 6820 3449845 380 4298 6821 3458698 381 4299 6822 3468696 382 4300 6823 3470080 383 4301 6824 3479293 384 4302 6825 3481982 385 4303 6826 3483041 386 4304 6827 3488055 387 4305 6828 3495371 388 4306 6829 3499170 389 4307 6830 3516476 390 4308 6831 3518933 391 4309 6832 3540584 392 4310 6833 3541595 393 4311 6834 3548974 394 4312 6835 3554453 395 4313 6836 3567808 396 4314 6837 3577801 397 4315 6838 3581575 398 4316 6839 3584688 399 4317 6840 3596826 400 4318 6841 2924226 401 4319 6842 2946808 402 4320 6843 2950661 403 4321 6844 3132825 404 4322 6845 3135435 405 4323 6846 3140582 406 4324 6847 3142391 407 4325 6848 3169809 408 4326 6849 3175377 409 4327 6850 3175639 410 4328 6851 3177625 411 4329 6852 3178121 412 4330 6853 3202478 413 4331 6854 3210919 414 4332 6855 3211954 415 4333 6856 3224494 416 4334 6857 3225336 417 4335 6858 3226308 418 4336 6859 3238194 419 4337 6860 3250526 420 4338 6861 3253830 421 4339 6862 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3255195 422 4340 6863 3471183 423 4341 6864 3474443 424 4342 6865 3481308 425 4343 6866 3496559 426 4344 6867 3511858 427 4345 6868 3512325 428 4346 6869 3518420 429 4347 6870 3531410 430 4348 6871 3535110 431 4349 6872 3595953 432 4350 6873 3598368 433 4351 6874 3199652 434 4352 6875 3455288 435 4353 6876 3455933 436 4354 6877 3456449 437 4355 6878 3459109 438 4356 6879 3476422 439 4357 6880 3488854 440 4358 6881 3507550 441 4359 6882 3511473 442 4360 6883 3523907 443 4361 6884 3524942 444 4362 6885 3525147 445 4363 6886 3527490 446 4364 6887 3532268 447 4365 6888 3534381 448 4366 6889 3537612 449 4367 6890 3538758 450 4368 6891 3541853 451 4369 6892 3544265 452 4370 6893 3549653 453 4371 6894 3550343 454 4372 6895 3551216 455 4373 6896 3556157 456 4374 6897 3558795 457 4375 6898 3565881 458 4376 6899 3567820 459 4377 6900 3569828 460 4378 6901 3570903 461 4379 6902 3577600 462 4380 6903 3583716 463 4381 6904 3585194 464 4382 6905 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3594314 465 4383 6906 2943150 466 4384 6907 3120116 467 4385 6908 3121255 468 4386 6909 3122334 469 4387 6910 3148112 470 4388 6911 3158643 471 4389 6912 3159981 472 4390 6913 3183264 473 4391 6914 3186315 474 4392 6915 3216765 475 4393 6916 3246394 476 4394 6917 3250051 477 4395 6918 3439539 478 4396 6919 3446178 479 4397 6920 3447406 480 4398 6921 3452525 481 4399 6922 3455433 482 4400 6923 3480868 483 4401 6924 3482378 484 4402 6925 3484471 485 4403 6926 3490863 486 4404 6927 3491695 487 4405 6928 3495103 488 4406 6929 3497706 489 4407 6930 3519340 490 4408 6931 3519424 491 4409 6932 3522489 492 4410 6933 3527796 493 4411 6934 3557288 494 4412 6935 3579256 495 4413 6936 3582172 496 4414 6937 3598393 497 4415 6938 3598395 498 4416 6939 2955593 499 4417 6940 2955659 500 4418 6941 3116733 501 4419 6942 3116945 502 4420 6943 3124747 503 4421 6944 3128426 504 4422 6945 3130315 505 4423 6946 3135796 506 4424 6947 3137622 507 4425 6948 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3160092 508 4426 6949 3165740 509 4427 6950 3169098 510 4428 6951 3171590 511 4429 6952 3177881 512 4430 6953 3184097 513 4431 6954 3220906 514 4432 6955 3231862 515 4433 6956 3237954 516 4434 6957 3241503 517 4435 6958 3460987 518 4436 6959 3468192 519 4437 6960 3473037 520 4438 6961 3495852 521 4439 6962 3500078 522 4440 6963 3524674 523 4441 6964 3536579 524 4442 6965 3536640 525 4443 6966 3555238 526 4444 6967 3576378 527 4445 6968 3594201 528 4446 6969 3598424 529 4447 6970 3598425 530 4448 6971 3598426 531 4449 6972 3127262 532 4450 6973 3146083 533 4451 6974 3174829 534 4452 6975 3200067 535 4453 6976 3202597 536 4454 6977 3208797 537 4455 6978 3245201 538 4456 6979 3248502 539 4457 6980 3250718 540 4458 6981 3443550 541 4459 6982 3458500 542 4460 6983 3461512 543 4461 6984 3473966 544 4462 6985 3489408 545 4463 6986 3492212 546 4464 6987 3501537 547 4465 6988 3528900 548 4466 6989 3529341 549 4467 6990 3530200 550 4468 6991 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3533924 551 4469 6992 3534519 552 4470 6993 3544330 553 4471 6994 3547753 554 4472 6995 3548601 555 4473 6996 3559172 556 4474 6997 3564872 557 4475 6998 3571042 558 4476 6999 3580242 559 4477 7000 3580795 560 4478 7001 3584099 561 4479 7002 3584593 562 4480 7003 3588646 563 4481 7004 3598430 564 4482 7005 2926717 565 4483 7006 3146624 566 4484 7007 3152893 567 4485 7008 3164750 568 4486 7009 3170531 569 4487 7010 3198045 570 4488 7011 3219184 571 4489 7012 3228071 572 4490 7013 3253426 573 4491 7014 3257156 574 4492 7015 3440336 575 4493 7016 3451587 576 4494 7017 3454052 577 4495 7018 3459856 578 4496 7019 3460171 579 4497 7020 3464115 580 4498 7021 3468204 581 4499 7022 3476550 582 4500 7023 3477917 583 4501 7024 3480654 584 4502 7025 3486647 585 4503 7026 3504914 586 4504 7027 3510647 587 4505 7028 3521786 588 4506 7029 3522291 589 4507 7030 3532882 590 4508 7031 3537784 591 4509 7032 3540940 592 4510 7033 3560378 593 4511 7034 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3567252 594 4512 7035 3567668 595 4513 7036 3598431 596 4514 7037 2955902 597 4515 7038 3142580 598 4516 7039 3159695 599 4517 7040 3165141 600 4518 7041 3195588 601 4519 7042 3222139 602 4520 7043 3227132 603 4521 7044 3239561 604 4522 7045 3252967 605 4523 7046 3434045 606 4524 7047 3441784 607 4525 7048 3445899 608 4526 7049 3461191 609 4527 7050 3485601 610 4528 7051 3485823 611 4529 7052 3487448 612 4530 7053 3498523 613 4531 7054 3499774 614 4532 7055 3536965 615 4533 7056 3547483 616 4534 7057 3551485 617 4535 7058 3563504 618 4536 7059 3563954 619 4537 7060 3568126 620 4538 7061 3569316 621 4539 7062 3579388 622 4540 7063 3579558 623 4541 7064 3580717 624 4542 7065 3582530 625 4543 7066 3595700 626 4544 7067 3597184 627 4545 7068 3598432 628 4546 7069 2955523 629 4547 7070 2955547 630 4548 7071 2955621 631 4549 7072 2956302 632 4550 7073 3142775 633 4551 7074 3170893 634 4552 7075 3175836 635 4553 7076 3201287 636 4554 7077 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3204084 637 4555 7078 3217881 638 4556 7079 3218845 639 4557 7080 3231598 640 4558 7081 3446969 641 4559 7082 3448188 642 4560 7083 3453640 643 4561 7084 3461654 644 4562 7085 3466078 645 4563 7086 3466238 646 4564 7087 3469004 647 4565 7088 3472809 648 4566 7089 3476734 649 4567 7090 3487352 650 4568 7091 3492164 651 4569 7092 3514134 652 4570 7093 3526081 653 4571 7094 3537693 654 4572 7095 3546517 655 4573 7096 3553703 656 4574 7097 3564456 657 4575 7098 3576955 658 4576 7099 3586746 659 4577 7100 3598433 660 4578 7101 3598434 661 4579 7102 3113473 662 4580 7103 3115349 663 4581 7104 3120234 664 4582 7105 3126677 665 4583 7106 3155503 666 4584 7107 3157056 667 4585 7108 3166518 668 4586 7109 3168822 669 4587 7110 3172099 670 4588 7111 3182617 671 4589 7112 3200508 672 4590 7113 3238535 673 4591 7114 3434288 674 4592 7115 3436976 675 4593 7116 3453820 676 4594 7117 3476065 677 4595 7118 3482759 678 4596 7119 3485351 679 4597 7120 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3486910 680 4598 7121 3513328 681 4599 7122 3514918 682 4600 7123 3524413 683 4601 7124 3526019 684 4602 7125 3534374 685 4603 7126 3541981 686 4604 7127 3552519 687 4605 7128 3576057 688 4606 7129 3583918 689 4607 7130 3589041 690 4608 7131 3597647 691 4609 7132 3598435 692 4610 7133 3598436 693 4611 7134 3598440 694 4612 7135 3130651 695 4613 7136 3157974 696 4614 7137 3163555 697 4615 7138 3179325 698 4616 7139 3196889 699 4617 7140 3197943 700 4618 7141 3216528 701 4619 7142 3227913 702 4620 7143 3231759 703 4621 7144 3237762 704 4622 7145 3238049 705 4623 7146 3249476 706 4624 7147 3256570 707 4625 7148 3279029 708 4626 7149 3279936 709 4627 7150 3280143 710 4628 7151 3434546 711 4629 7152 3444370 712 4630 7153 3448221 713 4631 7154 3455719 714 4632 7155 3463066 715 4633 7156 3478549 716 4634 7157 3479445 717 4635 7158 3522272 718 4636 7159 3530869 719 4637 7160 3535140 720 4638 7161 3563037 721 4639 7162 3566514 722 4640 7163 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3591462 723 4641 7164 3598441 724 4642 7165 3598442 725 4643 7166 3598443 726 4644 7167 3138000 727 4645 7168 3139433 728 4646 7169 3154059 729 4647 7170 3198148 730 4648 7171 3198570 731 4649 7172 3241922 732 4650 7173 3252316 733 4651 7174 3253119 734 4652 7175 3435558 735 4653 7176 3439366 736 4654 7177 3445604 737 4655 7178 3447467 738 4656 7179 3464661 739 4657 7180 3478098 740 4658 7181 3481161 741 4659 7182 3490412 742 4660 7183 3492879 743 4661 7184 3493777 744 4662 7185 3496917 745 4663 7186 3502075 746 4664 7187 3518004 747 4665 7188 3522160 748 4666 7189 3523094 749 4667 7190 3525530 750 4668 7191 3530681 751 4669 7192 3542334 752 4670 7193 3557950 753 4671 7194 3562318 754 4672 7195 3562739 755 4673 7196 3577379 756 4674 7197 3589449 757 4675 7198 3596450 758 4676 7199 3598444 759 4677 7200 3136584 760 4678 7201 3147107 761 4679 7202 3156813 762 4680 7203 3164292 763 4681 7204 3182143 764 4682 7205 3188213 765 4683 7206 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3218668 766 4684 7207 3229701 767 4685 7208 3230869 768 4686 7209 3234530 769 4687 7210 3238466 770 4688 7211 3244385 771 4689 7212 3251468 772 4690 7213 3291678 773 4691 7214 3435519 774 4692 7215 3449736 775 4693 7216 3481783 776 4694 7217 3483185 777 4695 7218 3498027 778 4696 7219 3508808 779 4697 7220 3523301 780 4698 7221 3527013 781 4699 7222 3527197 782 4700 7223 3535488 783 4701 7224 3542751 784 4702 7225 3558886 785 4703 7226 3560187 786 4704 7227 3562602 787 4705 7228 3578798 788 4706 7229 3585227 789 4707 7230 3598445 790 4708 7231 3598538 791 4709 7232 3118951 792 4710 7233 3172361 793 4711 7234 3173502 794 4712 7235 3192339 795 4713 7236 3203095 796 4714 7237 3213117 797 4715 7238 3229035 798 4716 7239 3235789 799 4717 7240 3244669 800 4718 7241 3289519 801 4719 7242 3466047 802 4720 7243 3469549 803 4721 7244 3472288 804 4722 7245 3472298 805 4723 7246 3472614 806 4724 7247 3472762 807 4725 7248 3484885 808 4726 7249 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3489123 809 4727 7250 3498956 810 4728 7251 3508875 811 4729 7252 3512159 812 4730 7253 3513739 813 4731 7254 3520486 814 4732 7255 3541537 815 4733 7256 3556665 816 4734 7257 3561917 817 4735 7258 3576632 818 4736 7259 3598446 819 4737 7260 3598447 820 4738 7261 3598448 821 4739 7262 3598449 822 4740 7263 3598450 823 4741 7264 3129475 824 4742 7265 3139477 825 4743 7266 3141786 826 4744 7267 3163020 827 4745 7268 3167411 828 4746 7269 3181935 829 4747 7270 3187928 830 4748 7271 3198398 831 4749 7272 3210221 832 4750 7273 3221115 833 4751 7274 3228006 834 4752 7275 3228541 835 4753 7276 3239774 836 4754 7277 3246353 837 4755 7278 3291915 838 4756 7279 3296091 839 4757 7280 3443974 840 4758 7281 3457240 841 4759 7282 3471604 842 4760 7283 3475495 843 4761 7284 3476605 844 4762 7285 3500975 845 4763 7286 3503250 846 4764 7287 3507812 847 4765 7288 3518683 848 4766 7289 3521198 849 4767 7290 3526840 850 4768 7291 3547269 851 4769 7292 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3552376 852 4770 7293 3564339 853 4771 7294 3598451 854 4772 7295 3598452 855 4773 7296 3125702 856 4774 7297 3144916 857 4775 7298 3151587 858 4776 7299 3167444 859 4777 7300 3178055 860 4778 7301 3185815 861 4779 7302 3197286 862 4780 7303 3202198 863 4781 7304 3209432 864 4782 7305 3241995 865 4783 7306 3278042 866 4784 7307 3438910 867 4785 7308 3457800 868 4786 7309 3465529 869 4787 7310 3471088 870 4788 7311 3499528 871 4789 7312 3500179 872 4790 7313 3506847 873 4791 7314 3516758 874 4792 7315 3523505 875 4793 7316 3523694 876 4794 7317 3528086 877 4795 7318 3532360 878 4796 7319 3532759 879 4797 7320 3535042 880 4798 7321 3538968 881 4799 7322 3541864 882 4800 7323 3572178 883 4801 7324 3575925 884 4802 7325 3591699 885 4803 7326 3598159 886 4804 7327 3598453 887 4805 7328 3598454 888 4806 7329 3118031 889 4807 7330 3138263 890 4808 7331 3159007 891 4809 7332 3180407 892 4810 7333 3181575 893 4811 7334 3240957 894 4812 7335 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3248842 895 4813 7336 3441060 896 4814 7337 3445507 897 4815 7338 3454851 898 4816 7339 3459179 899 4817 7340 3462661 900 4818 7341 3474601 901 4819 7342 3474930 902 4820 7343 3484198 903 4821 7344 3509341 904 4822 7345 3541786 905 4823 7346 3543731 906 4824 7347 3546401 907 4825 7348 3553213 908 4826 7349 3560473 909 4827 7350 3560768 910 4828 7351 3565679 911 4829 7352 3574053 912 4830 7353 3575467 913 4831 7354 3576011 914 4832 7355 3577961 915 4833 7356 3579480 916 4834 7357 3587142 917 4835 7358 3592827 918 4836 7359 3596643 919 4837 7360 3598455 920 4838 7361 3120853 921 4839 7362 3122600 922 4840 7363 3131159 923 4841 7364 3136908 924 4842 7365 3143760 925 4843 7366 3168637 926 4844 7367 3177134 927 4845 7368 3182881 928 4846 7369 3204319 929 4847 7370 3225594 930 4848 7371 3442135 931 4849 7372 3450997 932 4850 7373 3454918 933 4851 7374 3472183 934 4852 7375 3474149 935 4853 7376 3479206 936 4854 7377 3498390 937 4855 7378 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3500492 938 4856 7379 3506579 939 4857 7380 3506789 940 4858 7381 3509735 941 4859 7382 3512461 942 4860 7383 3517465 943 4861 7384 3524811 944 4862 7385 3548272 945 4863 7386 3551382 946 4864 7387 3554894 947 4865 7388 3555696 948 4866 7389 3582383 949 4867 7390 3583285 950 4868 7391 3586218 951 4869 7392 3598457 952 4870 7393 3598458 953 4871 7394 2921892 954 4872 7395 2926811 955 4873 7396 2927972 956 4874 7397 2945271 957 4875 7398 2955137 958 4876 7399 2955159 959 4877 7400 2955317 960 4878 7401 2955323 961 4879 7402 2955361 962 4880 7403 2955379 963 4881 7404 2955651 964 4882 7405 2955984 965 4883 7406 2956166 966 4884 7407 2956172 967 4885 7408 2956238 968 4886 7409 2956258 969 4887 7410 2961326 970 4888 7411 2961829 971 4889 7412 2961918 972 4890 7413 3114036 973 4891 7414 3122252 974 4892 7415 3126929 975 4893 7416 3452305 976 4894 7417 3456078 977 4895 7418 3537273 978 4896 7419 3562149 979 4897 7420 3584213 980 4898 7421 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3584919 981 4899 7422 3585918 982 4900 7423 3586483 983 4901 7424 3598459 984 4902 7425 3598460 985 4903 7426 3598461 986 4904 7427 3157696 987 4905 7428 3162399 988 4906 7429 3162832 989 4907 7430 3163648 990 4908 7431 3164426 991 4909 7432 3165431 992 4910 7433 3168330 993 4911 7434 3176855 994 4912 7435 3181817 995 4913 7436 3183862 996 4914 7437 3187587 997 4915 7438 3188292 998 4916 7439 3212100 999 4917 7440 3213594 1000 4918 7441 3227674 1001 4919 7442 3233209 1002 4920 7443 3243257 1003 4921 7444 3243497 1004 4922 7445 3243838 1005 4923 7446 3245807 1006 4924 7447 3253250 1007 4925 7448 3452826 1008 4926 7449 3458468 1009 4927 7450 3488571 1010 4928 7451 3495070 1011 4929 7452 3525140 1012 4930 7453 3529536 1013 4931 7454 3569551 1014 4932 7455 3589407 1015 4933 7456 3598462 1016 4934 7457 3598463 1017 4935 7458 3137542 1018 4936 7459 3149132 1019 4937 7460 3155303 1020 4938 7461 3158543 1021 4939 7462 3171746 1022 4940 7463 3182535 1023 4941 7464 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3208269 1024 4942 7465 3250400 1025 4943 7466 3290520 1026 4944 7467 3435110 1027 4945 7468 3440526 1028 4946 7469 3448375 1029 4947 7470 3449322 1030 4948 7471 3464849 1031 4949 7472 3465124 1032 4950 7473 3467472 1033 4951 7474 3467751 1034 4952 7475 3468460 1035 4953 7476 3476829 1036 4954 7477 3502188 1037 4955 7478 3508736 1038 4956 7479 3512602 1039 4957 7480 3517091 1040 4958 7481 3520546 1041 4959 7482 3525364 1042 4960 7483 3528138 1043 4961 7484 3538603 1044 4962 7485 3543121 1045 4963 7486 3548151 1046 4964 7487 3553476 1047 4965 7488 3570569 1048 4966 7489 3574954 1049 4967 7490 3580635 1050 4968 7491 2924894 1051 4969 7492 2926634 1052 4970 7493 2928753 1053 4971 7494 2930732 1054 4972 7495 2942044 1055 4973 7496 2952796 1056 4974 7497 2955103 1057 4975 7498 2955221 1058 4976 7499 2955253 1059 4977 7500 2955279 1060 4978 7501 2955297 1061 4979 7502 2955373 1062 4980 7503 2955425 1063 4981 7504 2955435 1064 4982 7505 2955509 1065 4983 7506 2955511 1066 4984 7507 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 2955517 1067 4985 7508 2955549 1068 4986 7509 2955559 1069 4987 7510 2955633 1070 4988 7511 2955717 1071 4989 7512 2955734 1072 4990 7513 2955736 1073 4991 7514 2955764 1074 4992 7515 3183496 1075 4993 7516 3435368 1076 4994 7517 3491153 1077 4995 7518 3516934 1078 4996 7519 3535849 1079 4997 7520 3549948 1080 4998 7521 3580318 1081 4999 7522 3586852 1082 5000 7523 3596513 1083 5001 7524 2955782 1084 5002 7525 2955784 1085 5003 7526 2955802 1086 5004 7527 2956018 1087 5005 7528 2956058 1088 5006 7529 2956134 1089 5007 7530 2956142 1090 5008 7531 2956152 1091 5009 7532 2956188 1092 5010 7533 2956198 1093 5011 7534 2956262 1094 5012 7535 2956292 1095 5013 7536 2956328 1096 5014 7537 2956352 1097 5015 7538 2961789 1098 5016 7539 3179143 1099 5017 7540 3196089 1100 5018 7541 3436020 1101 5019 7542 3438903 1102 5020 7543 3443462 1103 5021 7544 3473166 1104 5022 7545 3474531 1105 5023 7546 3486690 1106 5024 7547 3489639 1107 5025 7548 3496095 1108 5026 7549 3505869 1109 5027 7550 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3523626 1110 5028 7551 3543263 1111 5029 7552 3567541 1112 5030 7553 3598207 1113 5031 7554 3598464 1114 5032 7555 3120643 1115 5033 7556 3146749 1116 5034 7557 3148690 1117 5035 7558 3185122 1118 5036 7559 3227306 1119 5037 7560 3229784 1120 5038 7561 3230980 1121 5039 7562 3438044 1122 5040 7563 3463214 1123 5041 7564 3467360 1124 5042 7565 3475807 1125 5043 7566 3489683 1126 5044 7567 3495628 1127 5045 7568 3496639 1128 5046 7569 3501730 1129 5047 7570 3516859 1130 5048 7571 3521442 1131 5049 7572 3528569 1132 5050 7573 3533567 1133 5051 7574 3538361 1134 5052 7575 3550166 1135 5053 7576 3558691 1136 5054 7577 3558988 1137 5055 7578 3567196 1138 5056 7579 3570205 1139 5057 7580 3577239 1140 5058 7581 3584878 1141 5059 7582 3585545 1142 5060 7583 3589853 1143 5061 7584 3593112 1144 5062 7585 3594435 1145 5063 7586 3595275 1146 5064 7587 3598346 1147 5065 7588 2956026 1148 5066 7589 2961304 1149 5067 7590 3118665 1150 5068 7591 3123093 1151 5069 7592 3137741 1152 5070 7593 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3149182 1153 5071 7594 3153707 1154 5072 7595 3180076 1155 5073 7596 3189191 1156 5074 7597 3189475 1157 5075 7598 3196343 1158 5076 7599 3202903 1159 5077 7600 3243464 1160 5078 7601 3290650 1161 5079 7602 3445527 1162 5080 7603 3451483 1163 5081 7604 3452107 1164 5082 7605 3495770 1165 5083 7606 3498447 1166 5084 7607 3502161 1167 5085 7608 3509050 1168 5086 7609 3518637 1169 5087 7610 3533681 1170 5088 7611 3546851 1171 5089 7612 3553845 1172 5090 7613 3556055 1173 5091 7614 3558864 1174 5092 7615 3562781 1175 5093 7616 3573496 1176 5094 7617 3583550 1177 5095 7618 3594720 1178 5096 7619 3598347 1179 5097 7620 3129121 1180 5098 7621 3133112 1181 5099 7622 3134166 1182 5100 7623 3142469 1183 5101 7624 3192408 1184 5102 7625 3196537 1185 5103 7626 3212008 1186 5104 7627 3220332 1187 5105 7628 3222853 1188 5106 7629 3230119 1189 5107 7630 3230204 1190 5108 7631 3243052 1191 5109 7632 3244691 1192 5110 7633 3278140 1193 5111 7634 3284788 1194 5112 7635 3448668 1195 5113 7636 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3470998 1196 5114 7637 3475292 1197 5115 7638 3475677 1198 5116 7639 3484488 1199 5117 7640 3493535 1200 5118 7641 3501220 1201 5119 7642 3511754 1202 5120 7643 3529968 1203 5121 7644 3548002 1204 5122 7645 3561734 1205 5123 7646 3574579 1206 5124 7647 3579029 1207 5125 7648 3586558 1208 5126 7649 3598348 1209 5127 7650 3598349 1210 5128 7651 3598350 1211 5129 7652 2950447 1212 5130 7653 3115011 1213 5131 7654 3121091 1214 5132 7655 3150716 1215 5133 7656 3176994 1216 5134 7657 3183968 1217 5135 7658 3185661 1218 5136 7659 3203875 1219 5137 7660 3208541 1220 5138 7661 3209364 1221 5139 7662 3227861 1222 5140 7663 3247322 1223 5141 7664 3249539 1224 5142 7665 3250075 1225 5143 7666 3282226 1226 5144 7667 3434955 1227 5145 7668 3442052 1228 5146 7669 3444939 1229 5147 7670 3450524 1230 5148 7671 3455859 1231 5149 7672 3456822 1232 5150 7673 3466695 1233 5151 7674 3472065 1234 5152 7675 3521049 1235 5153 7676 3532480 1236 5154 7677 3564709 1237 5155 7678 3566156 1238 5156 7679 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3587186 1239 5157 7680 3587434 1240 5158 7681 3594954 1241 5159 7682 3598351 1242 5160 7683 3598352 1243 5161 7684 3117230 1244 5162 7685 3119428 1245 5163 7686 3148822 1246 5164 7687 3155768 1247 5165 7688 3157429 1248 5166 7689 3158907 1249 5167 7690 3170277 1250 5168 7691 3181310 1251 5169 7692 3212141 1252 5170 7693 3225015 1253 5171 7694 3234293 1254 5172 7695 3248018 1255 5173 7696 3460614 1256 5174 7697 3464110 1257 5175 7698 3464473 1258 5176 7699 3492620 1259 5177 7700 3497418 1260 5178 7701 3514074 1261 5179 7702 3533812 1262 5180 7703 3534257 1263 5181 7704 3548719 1264 5182 7705 3551710 1265 5183 7706 3557568 1266 5184 7707 3559526 1267 5185 7708 3565208 1268 5186 7709 3575158 1269 5187 7710 3586468 1270 5188 7711 3589201 1271 5189 7712 3598353 1272 5190 7713 3598354 1273 5191 7714 3598355 1274 5192 7715 3598356 1275 5193 7716 3169576 1276 5194 7717 3176222 1277 5195 7718 3224242 1278 5196 7719 3232153 1279 5197 7720 3296096 1280 5198 7721 3435201 1281 5199 7722 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3441462 1282 5200 7723 3451323 1283 5201 7724 3459206 1284 5202 7725 3462843 1285 5203 7726 3480411 1286 5204 7727 3486388 1287 5205 7728 3493761 1288 5206 7729 3497033 1289 5207 7730 3505294 1290 5208 7731 3506958 1291 5209 7732 3518135 1292 5210 7733 3529123 1293 5211 7734 3531498 1294 5212 7735 3545436 1295 5213 7736 3550891 1296 5214 7737 3553402 1297 5215 7738 3556799 1298 5216 7739 3598357 1299 5217 7740 3598358 1300 5218 7741 3598359 1301 5219 7742 3598360 1302 5220 7743 3598361 1303 5221 7744 3598362 1304 5222 7745 3598363 1305 5223 7746 3598364 1306 5224 7747 3598365 1307 5225 7748 3598531 1308 5226 7749 2955499 1309 5227 7750 2956220 1310 5228 7751 3135938 1311 5229 7752 3177331 1312 5230 7753 3177542 1313 5231 7754 3183100 1314 5232 7755 3201603 1315 5233 7756 3218768 1316 5234 7757 3242169 1317 5235 7758 3243329 1318 5236 7759 3249940 1319 5237 7760 3439604 1320 5238 7761 3443295 1321 5239 7762 3443478 1322 5240 7763 3446036 1323 5241 7764 3448963 1324 5242 7765 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3520876 1325 5243 7766 3528822 1326 5244 7767 3529479 1327 5245 7768 3544209 1328 5246 7769 3547767 1329 5247 7770 3577758 1330 5248 7771 3588243 1331 5249 7772 3593816 1332 5250 7773 3598366 1333 5251 7774 3598367 1334 5252 7775 3598369 1335 5253 7776 3598370 1336 5254 7777 3598371 1337 5255 7778 3598372 1338 5256 7779 3598373 1339 5257 7780 3598532 1340 5258 7781 3598533 1341 5259 7782 2936751 1342 5260 7783 2956130 1343 5261 7784 2961330 1344 5262 7785 2961346 1345 5263 7786 2961703 1346 5264 7787 3141198 1347 5265 7788 3160701 1348 5266 7789 3164216 1349 5267 7790 3166384 1350 5268 7791 3169901 1351 5269 7792 3180767 1352 5270 7793 3207655 1353 5271 7794 3210634 1354 5272 7795 3240831 1355 5273 7796 3241850 1356 5274 7797 3244042 1357 5275 7798 3255371 1358 5276 7799 3296094 1359 5277 7800 3440247 1360 5278 7801 3454777 1361 5279 7802 3473759 1362 5280 7803 3483575 1363 5281 7804 3510173 1364 5282 7805 3518230 1365 5283 7806 3523573 1366 5284 7807 3532569 1367 5285 7808 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3579899 1368 5286 7809 3580640 1369 5287 7810 3587720 1370 5288 7811 3596892 1371 5289 7812 3598374 1372 5290 7813 3598375 1373 5291 7814 3598376 1374 5292 7815 2953449 1375 5293 7816 2955267 1376 5294 7817 3114200 1377 5295 7818 3144416 1378 5296 7819 3172278 1379 5297 7820 3179993 1380 5298 7821 3190582 1381 5299 7822 3204699 1382 5300 7823 3224025 1383 5301 7824 3232431 1384 5302 7825 3249087 1385 5303 7826 3434651 1386 5304 7827 3443796 1387 5305 7828 3445097 1388 5306 7829 3461432 1389 5307 7830 3481788 1390 5308 7831 3505477 1391 5309 7832 3510032 1392 5310 7833 3514755 1393 5311 7834 3524760 1394 5312 7835 3536854 1395 5313 7836 3552646 1396 5314 7837 3555894 1397 5315 7838 3557138 1398 5316 7839 3561380 1399 5317 7840 3572078 1400 5318 7841 3583859 1401 5319 7842 3597248 1402 5320 7843 3598377 1403 5321 7844 3598378 1404 5322 7845 3598379 1405 5323 7846 2919382 1406 5324 7847 2961787 1407 5325 7848 3133221 1408 5326 7849 3140436 1409 5327 7850 3148516 1410 5328 7851 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3156205 1411 5329 7852 3197371 1412 5330 7853 3223072 1413 5331 7854 3237885 1414 5332 7855 3290282 1415 5333 7856 3436263 1416 5334 7857 3448028 1417 5335 7858 3479612 1418 5336 7859 3481542 1419 5337 7860 3484066 1420 5338 7861 3487857 1421 5339 7862 3494267 1422 5340 7863 3496136 1423 5341 7864 3499123 1424 5342 7865 3522540 1425 5343 7866 3526411 1426 5344 7867 3536886 1427 5345 7868 3539236 1428 5346 7869 3548891 1429 5347 7870 3567501 1430 5348 7871 3573723 1431 5349 7872 3575610 1432 5350 7873 3588390 1433 5351 7874 3598380 1434 5352 7875 3598381 1435 5353 7876 3598382 1436 5354 7877 2933648 1437 5355 7878 2933679 1438 5356 7879 2936609 1439 5357 7880 2946275 1440 5358 7881 2950275 1441 5359 7882 2952962 1442 5360 7883 2955097 1443 5361 7884 2955143 1444 5362 7885 2955169 1445 5363 7886 2955207 1446 5364 7887 2955273 1447 5365 7888 2955331 1448 5366 7889 2955383 1449 5367 7890 2955419 1450 5368 7891 2955513 1451 5369 7892 2955577 1452 5370 7893 2955683 1453 5371 7894 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 2955792 1454 5372 7895 2955870 1455 5373 7896 2955912 1456 5374 7897 2956036 1457 5375 7898 2956282 1458 5376 7899 2956290 1459 5377 7900 2956364 1460 5378 7901 2961123 1461 5379 7902 2961316 1462 5380 7903 3125506 1463 5381 7904 3133194 1464 5382 7905 3137188 1465 5383 7906 3150280 1466 5384 7907 3155846 1467 5385 7908 3176776 1468 5386 7909 3149612 1469 5387 7910 3173809 1470 5388 7911 3188647 1471 5389 7912 3197485 1472 5390 7913 3198782 1473 5391 7914 3216592 1474 5392 7915 3226176 1475 5393 7916 3231488 1476 5394 7917 3241363 1477 5395 7918 3251479 1478 5396 7919 3284210 1479 5397 7920 3436542 1480 5398 7921 3444590 1481 5399 7922 3446776 1482 5400 7923 3447265 1483 5401 7924 3449571 1484 5402 7925 3457326 1485 5403 7926 3461928 1486 5404 7927 3477978 1487 5405 7928 3480380 1488 5406 7929 3490053 1489 5407 7930 3493127 1490 5408 7931 3505668 1491 5409 7932 3530829 1492 5410 7933 3536329 1493 5411 7934 3539834 1494 5412 7935 3572172 1495 5413 7936 3593401 1496 5414 7937 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3598209 1497 5415 7938 3598383 1498 5416 7939 3598384 1499 5417 7940 3598385 1500 5418 7941 3598386 1501 5419 7942 2948754 1502 5420 7943 2955780 1503 5421 7944 2955818 1504 5422 7945 2955986 1505 5423 7946 2955994 1506 5424 7947 2955998 1507 5425 7948 2956156 1508 5426 7949 2956180 1509 5427 7950 2961300 1510 5428 7951 2961876 1511 5429 7952 3125005 1512 5430 7953 3126659 1513 5431 7954 3140902 1514 5432 7955 3281115 1515 5433 7956 3437877 1516 5434 7957 3454536 1517 5435 7958 3471751 1518 5436 7959 3473337 1519 5437 7960 3491221 1520 5438 7961 3500773 1521 5439 7962 3504692 1522 5440 7963 3513800 1523 5441 7964 3529237 1524 5442 7965 3531684 1525 5443 7966 3533309 1526 5444 7967 3543021 1527 5445 7968 3547020 1528 5446 7969 3551933 1529 5447 7970 3565130 1530 5448 7971 3581130 1531 5449 7972 3585297 1532 5450 7973 3598387 1533 5451 7974 2953202 1534 5452 7975 3125230 1535 5453 7976 3135052 1536 5454 7977 3142251 1537 5455 7978 3168080 1538 5456 7979 3197133 1539 5457 7980 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3199564 1540 5458 7981 3203807 1541 5459 7982 3207919 1542 5460 7983 3230456 1543 5461 7984 3244993 1544 5462 7985 3439723 1545 5463 7986 3440645 1546 5464 7987 3451636 1547 5465 7988 3470342 1548 5466 7989 3470665 1549 5467 7990 3470841 1550 5468 7991 3475217 1551 5469 7992 3482448 1552 5470 7993 3492632 1553 5471 7994 3501095 1554 5472 7995 3503932 1555 5473 7996 3511424 1556 5474 7997 3550573 1557 5475 7998 3552189 1558 5476 7999 3555012 1559 5477 8000 3575802 1560 5478 8001 3585077 1561 5479 8002 3598388 1562 5480 8003 3598389 1563 5481 8004 3598390 1564 5482 8005 3598391 1565 5483 8006 3598392 1566 5484 8007 3116513 1567 5485 8008 3126066 1568 5486 8009 3126403 1569 5487 8010 3131007 1570 5488 8011 3159820 1571 5489 8012 3172166 1572 5490 8013 3179825 1573 5491 8014 3180347 1574 5492 8015 3232024 1575 5493 8016 3285508 1576 5494 8017 3289332 1577 5495 8018 3451722 1578 5496 8019 3453387 1579 5497 8020 3469759 1580 5498 8021 3472959 1581 5499 8022 3491837 1582 5500 8023 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3493103 1583 5501 8024 3496314 1584 5502 8025 3498728 1585 5503 8026 3501436 1586 5504 8027 3506090 1587 5505 8028 3507254 1588 5506 8029 3513489 1589 5507 8030 3521801 1590 5508 8031 3525270 1591 5509 8032 3533457 1592 5510 8033 3555773 1593 5511 8034 3562279 1594 5512 8035 3569702 1595 5513 8036 3571640 1596 5514 8037 3571771 1597 5515 8038 3598394 1598 5516 8039 3598534 1599 5517 8040 2955243 1600 5518 8041 3116381 1601 5519 8042 3124096 1602 5520 8043 3192659 1603 5521 8044 3201848 1604 5522 8045 3208782 1605 5523 8046 3224858 1606 5524 8047 3239590 1607 5525 8048 3243672 1608 5526 8049 3251797 1609 5527 8050 3277637 1610 5528 8051 3277927 1611 5529 8052 3284434 1612 5530 8053 3284979 1613 5531 8054 3453462 1614 5532 8055 3463680 1615 5533 8056 3464489 1616 5534 8057 3477114 1617 5535 8058 3478270 1618 5536 8059 3495270 1619 5537 8060 3529051 1620 5538 8061 3530278 1621 5539 8062 3539141 1622 5540 8063 3546589 1623 5541 8064 3548425 1624 5542 8065 3555293 1625 5543 8066 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3558607 1626 5544 8067 3565270 1627 5545 8068 3597452 1628 5546 8069 3598396 1629 5547 8070 3598397 1630 5548 8071 3598465 1631 5549 8072 3598535 1632 5550 8073 2952670 1633 5551 8074 3146001 1634 5552 8075 3146758 1635 5553 8076 3165785 1636 5554 8077 3169113 1637 5555 8078 3220410 1638 5556 8079 3224099 1639 5557 8080 3225797 1640 5558 8081 3231962 1641 5559 8082 3241624 1642 5560 8083 3247577 1643 5561 8084 3250176 1644 5562 8085 3253384 1645 5563 8086 3437458 1646 5564 8087 3441352 1647 5565 8088 3449600 1648 5566 8089 3453730 1649 5567 8090 3466900 1650 5568 8091 3468066 1651 5569 8092 3470756 1652 5570 8093 3491907 1653 5571 8094 3497130 1654 5572 8095 3544685 1655 5573 8096 3552919 1656 5574 8097 3559737 1657 5575 8098 3563936 1658 5576 8099 3572971 1659 5577 8100 3573590 1660 5578 8101 3574775 1661 5579 8102 3592230 1662 5580 8103 3598466 1663 5581 8104 3598467 1664 5582 8105 3598468 1665 5583 8106 3119953 1666 5584 8107 3123578 1667 5585 8108 3125681 1668 5586 8109 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3143059 1669 5587 8110 3144822 1670 5588 8111 3146470 1671 5589 8112 3165822 1672 5590 8113 3166853 1673 5591 8114 3168147 1674 5592 8115 3180681 1675 5593 8116 3188514 1676 5594 8117 3192022 1677 5595 8118 3204448 1678 5596 8119 3216222 1679 5597 8120 3221425 1680 5598 8121 3224508 1681 5599 8122 3229879 1682 5600 8123 3241642 1683 5601 8124 3438694 1684 5602 8125 3460347 1685 5603 8126 3499624 1686 5604 8127 3501318 1687 5605 8128 3534935 1688 5606 8129 3555458 1689 5607 8130 3576435 1690 5608 8131 3590568 1691 5609 8132 3595183 1692 5610 8133 3598398 1693 5611 8134 3598399 1694 5612 8135 3598469 1695 5613 8136 3598470 1696 5614 8137 3598471 1697 5615 8138 3598472 1698 5616 8139 3119649 1699 5617 8140 3152125 1700 5618 8141 3154644 1701 5619 8142 3167233 1702 5620 8143 3184415 1703 5621 8144 3189369 1704 5622 8145 3202971 1705 5623 8146 3206106 1706 5624 8147 3222234 1707 5625 8148 3243763 1708 5626 8149 3246924 1709 5627 8150 3278369 1710 5628 8151 3283805 1711 5629 8152 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3284129 1712 5630 8153 3293891 1713 5631 8154 3479032 1714 5632 8155 3482586 1715 5633 8156 3489569 1716 5634 8157 3503013 1717 5635 8158 3536045 1718 5636 8159 3542567 1719 5637 8160 3544098 1720 5638 8161 3568012 1721 5639 8162 3572714 1722 5640 8163 3575325 1723 5641 8164 3590268 1724 5642 8165 3594040 1725 5643 8166 3598473 1726 5644 8167 3598474 1727 5645 8168 3598475 1728 5646 8169 3598476 1729 5647 8170 3598477 1730 5648 8171 3598540 1731 5649 8172 3114924 1732 5650 8173 3132417 1733 5651 8174 3135482 1734 5652 8175 3139148 1735 5653 8176 3158194 1736 5654 8177 3169547 1737 5655 8178 3174218 1738 5656 8179 3182045 1739 5657 8180 3191392 1740 5658 8181 3234634 1741 5659 8182 3246990 1742 5660 8183 3282604 1743 5661 8184 3435394 1744 5662 8185 3438332 1745 5663 8186 3442249 1746 5664 8187 3466548 1747 5665 8188 3469866 1748 5666 8189 3493943 1749 5667 8190 3494052 1750 5668 8191 3500685 1751 5669 8192 3504057 1752 5670 8193 3513561 1753 5671 8194 3519026 1754 5672 8195 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3533278 1755 5673 8196 3540281 1756 5674 8197 3546198 1757 5675 8198 3552996 1758 5676 8199 3587730 1759 5677 8200 3598478 1760 5678 8201 3598479 1761 5679 8202 3598480 1762 5680 8203 3598541 1763 5681 8204 3128631 1764 5682 8205 3133982 1765 5683 8206 3144295 1766 5684 8207 3147112 1767 5685 8208 3150556 1768 5686 8209 3157234 1769 5687 8210 3159527 1770 5688 8211 3171940 1771 5689 8212 3182451 1772 5690 8213 3191812 1773 5691 8214 3200310 1774 5692 8215 3211085 1775 5693 8216 3222655 1776 5694 8217 3235980 1777 5695 8218 3243193 1778 5696 8219 3252027 1779 5697 8220 3257160 1780 5698 8221 3285384 1781 5699 8222 3459332 1782 5700 8223 3510129 1783 5701 8224 3511648 1784 5702 8225 3514502 1785 5703 8226 3549470 1786 5704 8227 3554788 1787 5705 8228 3578768 1788 5706 8229 3598400 1789 5707 8230 3598401 1790 5708 8231 3598402 1791 5709 8232 3598481 1792 5710 8233 3598482 1793 5711 8234 3598483 1794 5712 8235 3598484 1795 5713 8236 3598485 1796 5714 8237 3113322 1797 5715 8238 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3115156 1798 5716 8239 3160287 1799 5717 8240 3185368 1800 5718 8241 3216491 1801 5719 8242 3227687 1802 5720 8243 3228192 1803 5721 8244 3235666 1804 5722 8245 3245054 1805 5723 8246 3251626 1806 5724 8247 3438612 1807 5725 8248 3454358 1808 5726 8249 3457206 1809 5727 8250 3457952 1810 5728 8251 3460060 1811 5729 8252 3497558 1812 5730 8253 3518797 1813 5731 8254 3529796 1814 5732 8255 3534223 1815 5733 8256 3545203 1816 5734 8257 3551617 1817 5735 8258 3556361 1818 5736 8259 3581480 1819 5737 8260 3597011 1820 5738 8261 3598486 1821 5739 8262 3598487 1822 5740 8263 3598488 1823 5741 8264 3598489 1824 5742 8265 3598490 1825 5743 8266 3598491 1826 5744 8267 3598492 1827 5745 8268 3598493 1828 5746 8269 3598542 1829 5747 8270 3124066 1830 5748 8271 3124419 1831 5749 8272 3140113 1832 5750 8273 3164993 1833 5751 8274 3175344 1834 5752 8275 3190702 1835 5753 8276 3211396 1836 5754 8277 3214552 1837 5755 8278 3221025 1838 5756 8279 3224701 1839 5757 8280 3226572 1840 5758 8281 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3230064 1841 5759 8282 3232879 1842 5760 8283 3233840 1843 5761 8284 3238600 1844 5762 8285 3278710 1845 5763 8286 3283560 1846 5764 8287 3450035 1847 5765 8288 3482266 1848 5766 8289 3483324 1849 5767 8290 3491320 1850 5768 8291 3504484 1851 5769 8292 3515286 1852 5770 8293 3525755 1853 5771 8294 3552886 1854 5772 8295 3598403 1855 5773 8296 3598494 1856 5774 8297 3598495 1857 5775 8298 3598496 1858 5776 8299 3598497 1859 5777 8300 3598498 1860 5778 8301 3598543 1861 5779 8302 2955844 1862 5780 8303 3130202 1863 5781 8304 3139562 1864 5782 8305 3152416 1865 5783 8306 3157358 1866 5784 8307 3163182 1867 5785 8308 3174182 1868 5786 8309 3210418 1869 5787 8310 3210726 1870 5788 8311 3211581 1871 5789 8312 3229620 1872 5790 8313 3252248 1873 5791 8314 3257154 1874 5792 8315 3286196 1875 5793 8316 3288798 1876 5794 8317 3293905 1877 5795 8318 3442628 1878 5796 8319 3455154 1879 5797 8320 3504347 1880 5798 8321 3541131 1881 5799 8322 3559331 1882 5800 8323 3592421 1883 5801 8324 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3598404 1884 5802 8325 3598405 1885 5803 8326 3598406 1886 5804 8327 3598499 1887 5805 8328 3598501 1888 5806 8329 3598502 1889 5807 8330 3598503 1890 5808 8331 3598504 1891 5809 8332 3598544 1892 5810 8333 2955191 1893 5811 8334 3124667 1894 5812 8335 3129863 1895 5813 8336 3139295 1896 5814 8337 3141579 1897 5815 8338 3147287 1898 5816 8339 3151964 1899 5817 8340 3153847 1900 5818 8341 3166012 1901 5819 8342 3171114 1902 5820 8343 3171386 1903 5821 8344 3202119 1904 5822 8345 3219595 1905 5823 8346 3219886 1906 5824 8347 3239149 1907 5825 8348 3248337 1908 5826 8349 3291480 1909 5827 8350 3434739 1910 5828 8351 3441656 1911 5829 8352 3468358 1912 5830 8353 3481667 1913 5831 8354 3506119 1914 5832 8355 3582578 1915 5833 8356 3598407 1916 5834 8357 3598408 1917 5835 8358 3598505 1918 5836 8359 3598506 1919 5837 8360 3598507 1920 5838 8361 3598508 1921 5839 8362 3598509 1922 5840 8363 3598510 1923 5841 8364 3114685 1924 5842 8365 3115822 1925 5843 8366 3118812 1926 5844 8367 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3120134 1927 5845 8368 3125828 1928 5846 8369 3126896 1929 5847 8370 3157854 1930 5848 8371 3163769 1931 5849 8372 3168991 1932 5850 8373 3187516 1933 5851 8374 3199378 1934 5852 8375 3215025 1935 5853 8376 3219460 1936 5854 8377 3221216 1937 5855 8378 3224690 1938 5856 8379 3232546 1939 5857 8380 3233503 1940 5858 8381 3242870 1941 5859 8382 3249324 1942 5860 8383 3254976 1943 5861 8384 3281695 1944 5862 8385 3284494 1945 5863 8386 3446299 1946 5864 8387 3472568 1947 5865 8388 3507153 1948 5866 8389 3545540 1949 5867 8390 3548892 1950 5868 8391 3571935 1951 5869 8392 3592530 1952 5870 8393 3598511 1953 5871 8394 3598512 1954 5872 8395 3598513 1955 5873 8396 2953132 1956 5874 8397 2955229 1957 5875 8398 2955269 1958 5876 8399 2955561 1959 5877 8400 2955579 1960 5878 8401 2955685 1961 5879 8402 2955834 1962 5880 8403 3438572 1963 5881 8404 3450446 1964 5882 8405 3464684 1965 5883 8406 3467144 1966 5884 8407 3469591 1967 5885 8408 3478741 1968 5886 8409 3489880 1969 5887 8410 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3490492 1970 5888 8411 3491037 1971 5889 8412 3494702 1972 5890 8413 3512999 1973 5891 8414 3516608 1974 5892 8415 3520340 1975 5893 8416 3521641 1976 5894 8417 3527915 1977 5895 8418 3538529 1978 5896 8419 3545048 1979 5897 8420 3545336 1980 5898 8421 3549003 1981 5899 8422 3549600 1982 5900 8423 3550409 1983 5901 8424 3574155 1984 5902 8425 3574355 1985 5903 8426 3591235 1986 5904 8427 3595854 1987 5905 8428 2955894 1988 5906 8429 2955928 1989 5907 8430 2956010 1990 5908 8431 2956044 1991 5909 8432 2956048 1992 5910 8433 2956250 1993 5911 8434 2956278 1994 5912 8435 2956338 1995 5913 8436 2956362 1996 5914 8437 2961661 1997 5915 8438 2961673 1998 5916 8439 2961835 1999 5917 8440 3183568 2000 5918 8441 3203476 2001 5919 8442 3212773 2002 5920 8443 3219697 2003 5921 8444 3442442 2004 5922 8445 3490748 2005 5923 8446 3494823 2006 5924 8447 3502898 2007 5925 8448 3519882 2008 5926 8449 3531853 2009 5927 8450 3531935 2010 5928 8451 3531962 2011 5929 8452 3547926 2012 5930 8453 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3573280 2013 5931 8454 3577485 2014 5932 8455 3580054 2015 5933 8456 3598515 2016 5934 8457 3598516 2017 5935 8458 3122502 2018 5936 8459 3133589 2019 5937 8460 3134604 2020 5938 8461 3137290 2021 5939 8462 3153626 2022 5940 8463 3187144 2023 5941 8464 3196749 2024 5942 8465 3200827 2025 5943 8466 3230804 2026 5944 8467 3247493 2027 5945 8468 3280307 2028 5946 8469 3282363 2029 5947 8470 3290432 2030 5948 8471 3436837 2031 5949 8472 3452973 2032 5950 8473 3465401 2033 5951 8474 3473250 2034 5952 8475 3479028 2035 5953 8476 3504764 2036 5954 8477 3535597 2037 5955 8478 3538205 2038 5956 8479 3565477 2039 5957 8480 3569964 2040 5958 8481 3598213 2041 5959 8482 3598409 2042 5960 8483 3598410 2043 5961 8484 3598411 2044 5962 8485 3598412 2045 5963 8486 3598517 2046 5964 8487 3598518 2047 5965 8488 3598519 2048 5966 8489 3598520 2049 5967 8490 2955313 2050 5968 8491 2955699 2051 5969 8492 2955832 2052 5970 8493 2956224 2053 5971 8494 3115678 2054 5972 8495 3127374 2055 5973 8496 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3129623 2056 5974 8497 3174746 2057 5975 8498 3182863 2058 5976 8499 3188050 2059 5977 8500 3192643 2060 5978 8501 3212484 2061 5979 8502 3213842 2062 5980 8503 3222051 2063 5981 8504 3232216 2064 5982 8505 3235109 2065 5983 8506 3285335 2066 5984 8507 3438778 2067 5985 8508 3459461 2068 5986 8509 3463454 2069 5987 8510 3470146 2070 5988 8511 3506603 2071 5989 8512 3509192 2072 5990 8513 3534599 2073 5991 8514 3573897 2074 5992 8515 3576317 2075 5993 8516 3583147 2076 5994 8517 3591764 2077 5995 8518 3598521 2078 5996 8519 3598522 2079 5997 8520 3598523 2080 5998 8521 3142174 2081 5999 8522 3152209 2082 6000 8523 3167655 2083 6001 8524 3230642 2084 6002 8525 3235486 2085 6003 8526 3247764 2086 6004 8527 3440147 2087 6005 8528 3461055 2088 6006 8529 3469214 2089 6007 8530 3484292 2090 6008 8531 3488461 2091 6009 8532 3502719 2092 6010 8533 3508247 2093 6011 8534 3515383 2094 6012 8535 3524351 2095 6013 8536 3551570 2096 6014 8537 3558247 2097 6015 8538 3577672 2098 6016 8539 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3581408 2099 6017 8540 3598413 2100 6018 8541 3598414 2101 6019 8542 3598415 2102 6020 8543 3598416 2103 6021 8544 3598417 2104 6022 8545 3598418 2105 6023 8546 3598419 2106 6024 8547 3598420 2107 6025 8548 3598421 2108 6026 8549 3598524 2109 6027 8550 3598525 2110 6028 8551 3598536 2111 6029 8552 3598537 2112 6030 8553 2944074 2113 6031 8554 2955768 2114 6032 8555 2955962 2115 6033 8556 3116089 2116 6034 8557 3118605 2117 6035 8558 3119150 2118 6036 8559 3139670 2119 6037 8560 3154181 2120 6038 8561 3162226 2121 6039 8562 3166190 2122 6040 8563 3171577 2123 6041 8564 3191050 2124 6042 8565 3199458 2125 6043 8566 3214130 2126 6044 8567 3229964 2127 6045 8568 3231120 2128 6046 8569 3246163 2129 6047 8570 3251877 2130 6048 8571 3255835 2131 6049 8572 3277573 2132 6050 8573 3294418 2133 6051 8574 3463490 2134 6052 8575 3480043 2135 6053 8576 3530508 2136 6054 8577 3591856 2137 6055 8578 3593488 2138 6056 8579 3598422 2139 6057 8580 3598526 2140 6058 8581 3598527 2141 6059 8582 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3598528 2142 6060 8583 3598529 2143 6061 8584 3598530 2144 6062 8585 2953504 2145 6063 8586 2955874 2146 6064 8587 3116308 2147 6065 8588 3118231 2148 6066 8589 3125099 2149 6067 8590 3140344 2150 6068 8591 3144076 2151 6069 8592 3159412 2152 6070 8593 3177489 2153 6071 8594 3178593 2154 6072 8595 3179544 2155 6073 8596 3192210 2156 6074 8597 3200912 2157 6075 8598 3205594 2158 6076 8599 3218439 2159 6077 8600 3222601 2160 6078 8601 3242775 2161 6079 8602 3244488 2162 6080 8603 3245467 2163 6081 8604 3251617 2164 6082 8605 3441247 2165 6083 8606 3467813 2166 6084 8607 3475973 2167 6085 8608 3485069 2168 6086 8609 3492793 2169 6087 8610 3538805 2170 6088 8611 3539080 2171 6089 8612 3580517 2172 6090 8613 3584351 2173 6091 8614 3595468 2174 6092 8615 3596054 2175 6093 8616 3598423 2176 6094 8617 2955553 2177 6095 8618 2956192 2178 6096 8619 3146303 2179 6097 8620 3186532 2180 6098 8621 3191198 2181 6099 8622 3191694 2182 6100 8623 3195910 2183 6101 8624 3202191 2184 6102 8625 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3215295 2185 6103 8626 3232267 2186 6104 8627 3239892 2187 6105 8628 3251003 2188 6106 8629 3439865 2189 6107 8630 3442549 2190 6108 8631 3450697 2191 6109 8632 3462934 2192 6110 8633 3464242 2193 6111 8634 3465650 2194 6112 8635 3474380 2195 6113 8636 3488331 2196 6114 8637 3494316 2197 6115 8638 3503763 2198 6116 8639 3503998 2199 6117 8640 3515545 2200 6118 8641 3516056 2201 6119 8642 3553323 2202 6120 8643 3563467 2203 6121 8644 3566856 2204 6122 8645 3572955 2205 6123 8646 3598427 2206 6124 8647 3598428 2207 6125 8648 3598429 2208 6126 8649 2955325 2209 6127 8650 2961599 2210 6128 8651 3113234 2211 6129 8652 3113568 2212 6130 8653 3113814 2213 6131 8654 3113916 2214 6132 8655 3114500 2215 6133 8656 3115234 2216 6134 8657 3116186 2217 6135 8658 3117192 2218 6136 8659 3117449 2219 6137 8660 3117597 2220 6138 8661 3117830 2221 6139 8662 3118335 2222 6140 8663 3118454 2223 6141 8664 3118992 2224 6142 8665 3119261 2225 6143 8666 3119821 2226 6144 8667 3120509 2227 6145 8668 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3120745 2228 6146 8669 3124838 2229 6147 8670 3135695 2230 6148 8671 3149746 2231 6149 8672 3178200 2232 6150 8673 3179808 2233 6151 8674 3200369 2234 6152 8675 3244157 2235 6153 8676 3255416 2236 6154 8677 3479868 2237 6155 8678 3508938 2238 6156 8679 3582054 2239 6157 8680 3590172 2240 6158 8681 3120980 2241 6159 8682 3121460 2242 6160 8683 3122868 2243 6161 8684 3123391 2244 6162 8685 3123663 2245 6163 8686 3123961 2246 6164 8687 3124240 2247 6165 8688 3124959 2248 6166 8689 3127475 2249 6167 8690 3127622 2250 6168 8691 3127669 2251 6169 8692 3127871 2252 6170 8693 3129263 2253 6171 8694 3130133 2254 6172 8695 3130488 2255 6173 8696 3130801 2256 6174 8697 3131788 2257 6175 8698 3131930 2258 6176 8699 3132023 2259 6177 8700 3132394 2260 6178 8701 3132616 2261 6179 8702 3132684 2262 6180 8703 3132971 2263 6181 8704 3132992 2264 6182 8705 3133362 2265 6183 8706 3133804 2266 6184 8707 3134102 2267 6185 8708 3134928 2268 6186 8709 3135249 2269 6187 8710 3135712 2270 6188 8711 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3136452 2271 6189 8712 3137433 2272 6190 8713 3137831 2273 6191 8714 3138089 2274 6192 8715 3140607 2275 6193 8716 3141150 2276 6194 8717 3141378 2277 6195 8718 3143489 2278 6196 8719 3144062 2279 6197 8720 3144706 2280 6198 8721 3145394 2281 6199 8722 3146135 2282 6200 8723 3146438 2283 6201 8724 3146608 2284 6202 8725 3146980 2285 6203 8726 3147387 2286 6204 8727 3147752 2287 6205 8728 3148047 2288 6206 8729 3148218 2289 6207 8730 3149003 2290 6208 8731 3149254 2291 6209 8732 3149482 2292 6210 8733 3150359 2293 6211 8734 3151200 2294 6212 8735 3151474 2295 6213 8736 3152070 2296 6214 8737 3152577 2297 6215 8738 3152691 2298 6216 8739 3152762 2299 6217 8740 3153016 2300 6218 8741 3156929 2301 6219 8742 3157020 2302 6220 8743 3158321 2303 6221 8744 3158690 2304 6222 8745 3159685 2305 6223 8746 3159913 2306 6224 8747 3160568 2307 6225 8748 3160780 2308 6226 8749 3161184 2309 6227 8750 3161263 2310 6228 8751 3161634 2311 6229 8752 3162509 2312 6230 8753 3162735 2313 6231 8754 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3162944 2314 6232 8755 3163531 2315 6233 8756 3164069 2316 6234 8757 3164348 2317 6235 8758 3164769 2318 6236 8759 3165961 2319 6237 8760 3166633 2320 6238 8761 3166796 2321 6239 8762 3167211 2322 6240 8763 3168012 2323 6241 8764 3168408 2324 6242 8765 3170171 2325 6243 8766 3170538 2326 6244 8767 3170832 2327 6245 8768 3170969 2328 6246 8769 3171270 2329 6247 8770 3171845 2330 6248 8771 3172984 2331 6249 8772 3173895 2332 6250 8773 3174044 2333 6251 8774 3174331 2334 6252 8775 3175247 2335 6253 8776 3175965 2336 6254 8777 3176761 2337 6255 8778 3177128 2338 6256 8779 3177238 2339 6257 8780 3178901 2340 6258 8781 3181472 2341 6259 8782 3182259 2342 6260 8783 3182982 2343 6261 8784 3183382 2344 6262 8785 3183737 2345 6263 8786 3183812 2346 6264 8787 3185075 2347 6265 8788 3185228 2348 6266 8789 3185716 2349 6267 8790 3185754 2350 6268 8791 3185955 2351 6269 8792 3186030 2352 6270 8793 3186956 2353 6271 8794 3187328 2354 6272 8795 3188172 2355 6273 8796 3189124 2356 6274 8797 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3189711 2357 6275 8798 3189785 2358 6276 8799 3189802 2359 6277 8800 3190037 2360 6278 8801 3190191 2361 6279 8802 3190387 2362 6280 8803 3190510 2363 6281 8804 3191487 2364 6282 8805 3191528 2365 6283 8806 3195104 2366 6284 8807 3195766 2367 6285 8808 3195863 2368 6286 8809 3197447 2369 6287 8810 3199295 2370 6288 8811 3199930 2371 6289 8812 3200486 2372 6290 8813 3200744 2373 6291 8814 3200921 2374 6292 8815 3201953 2375 6293 8816 3202335 2376 6294 8817 3202590 2377 6295 8818 3203227 2378 6296 8819 3203399 2379 6297 8820 3203600 2380 6298 8821 3203694 2381 6299 8822 3205143 2382 6300 8823 3205442 2383 6301 8824 3205508 2384 6302 8825 3205738 2385 6303 8826 3207563 2386 6304 8827 3207809 2387 6305 8828 3207891 2388 6306 8829 3208017 2389 6307 8830 3208695 2390 6308 8831 3210187 2391 6309 8832 3210356 2392 6310 8833 3212450 2393 6311 8834 3212555 2394 6312 8835 3213081 2395 6313 8836 3215425 2396 6314 8837 3216906 2397 6315 8838 3217236 2398 6316 8839 3217580 2399 6317 8840 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3218249 2400 6318 8841 3218526 2401 6319 8842 3218613 2402 6320 8843 3219085 2403 6321 8844 3219353 2404 6322 8845 3219765 2405 6323 8846 3220107 2406 6324 8847 3222121 2407 6325 8848 3222476 2408 6326 8849 3225507 2409 6327 8850 3226414 2410 6328 8851 3226481 2411 6329 8852 3226824 2412 6330 8853 3226866 2413 6331 8854 3227492 2414 6332 8855 3228263 2415 6333 8856 3228410 2416 6334 8857 3228592 2417 6335 8858 3229264 2418 6336 8859 3229408 2419 6337 8860 3231382 2420 6338 8861 3232819 2421 6339 8862 3233607 2422 6340 8863 3234074 2423 6341 8864 3234517 2424 6342 8865 3234740 2425 6343 8866 3234771 2426 6344 8867 3234993 2427 6345 8868 3235247 2428 6346 8869 3237040 2429 6347 8870 3239701 2430 6348 8871 3240002 2431 6349 8872 3240608 2432 6350 8873 3241110 2433 6351 8874 3242207 2434 6352 8875 3242511 2435 6353 8876 3242531 2436 6354 8877 3243158 2437 6355 8878 3243945 2438 6356 8879 3244557 2439 6357 8880 3244891 2440 6358 8881 3244953 2441 6359 8882 3245333 2442 6360 8883 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3245491 2443 6361 8884 3246681 2444 6362 8885 3247197 2445 6363 8886 3247949 2446 6364 8887 3249647 2447 6365 8888 3251201 2448 6366 8889 3251412 2449 6367 8890 3253588 2450 6368 8891 3254361 2451 6369 8892 3256107 2452 6370 8893 3256268 2453 6371 8894 3256804 2454 6372 8895 3257164 2455 6373 8896 3258252 2456 6374 8897 3258257 2457 6375 8898 3258967 2458 6376 8899 3259017 2459 6377 8900 3259182 2460 6378 8901 3259914 2461 6379 8902 3261153 2462 6380 8903 3261840 2463 6381 8904 3262382 2464 6382 8905 3262457 2465 6383 8906 3262902 2466 6384 8907 3266329 2467 6385 8908 3266611 2468 6386 8909 3267021 2469 6387 8910 3267091 2470 6388 8911 3267161 2471 6389 8912 3268405 2472 6390 8913 3269039 2473 6391 8914 3269770 2474 6392 8915 3271420 2475 6393 8916 3271664 2476 6394 8917 3272059 2477 6395 8918 3272898 2478 6396 8919 3273228 2479 6397 8920 3274022 2480 6398 8921 3274175 2481 6399 8922 3275769 2482 6400 8923 3276542 2483 6401 8924 3277369 2484 6402 8925 3277498 2485 6403 8926 Recombinase Protein ID Protein SEQ ID RRS-2 SEQ ID RRS-1 SEQ ID 3277741 2486 6404 8927 3277893 2487 6405 8928 3278263 2488 6406 8929 3278509 2489 6407 8930 3278533 2490 6408 8931 3279155 2491 6409 8932 3280391 2492 6410 8933 3281441 2493 6411 8934 3281483 2494 6412 8935 3281631 2495 6413 8936 3281890 2496 6414 8937 3282124 2497 6415 8938 3283231 2498 6416 8939 3283470 2499 6417 8940 3284905 2500 6418 8941 3285168 2501 6419 8942 3285862 2502 6420 8943 3286024 2503 6421 8944 3286102 2504 6422 8945 3287406 2505 6423 8946 3288908 2506 6424 8947 3289248 2507 6425 8948 3289607 2508 6426 8949 3289759 2509 6427 8950 3290196 2510 6428 8951 3293413 2511 6429 8952 3293540 2512 6430 8953 3293718 2513 6431 8954 3293745 2514 6432 8955 3294008 2515 6433 8956 3294242 2516 6434 8957 3294283 2517 6435 8958 3296088 2518 6436 8959 3296089 2519 6437 8960 3296090 2520 6438 8961 3296092 2521 6439 8962 3296095 2522 6440 8963 3296201 2523 6441 8964 BxbI 9272 9275 9278 Pf80 9273 9276 9279 PhiC31 9274 9277 9280 TABLE 3. Exemplary LSRs Recombinase Protein SEQ Recombinase Protein SEQ Protein ID ID Protein ID ID 2919352 2524 2954263 3222 2919361 2525 2954265 3223 2919363 2526 2954267 3224 2919522 2527 2954269 3225 2919527 2528 2954271 3226 2919570 2529 2954295 3227 2919598 2530 2954313 3228 2919602 2531 2954320 3229 2919637 2532 2954353 3230 2919734 2533 2955099 3231 2919746 2534 2955101 3232 2919762 2535 2955107 3233 2919775 2536 2955109 3234 2919782 2537 2955111 3235 2919784 2538 2955113 3236 2919798 2539 2955115 3237 2919862 2540 2955117 3238 2919903 2541 2955119 3239 2919965 2542 2955121 3240 3013037 2543 2955123 3241 3013038 2544 2955125 3242 3013039 2545 2955127 3243 3013040 2546 2955129 3244 2920020 2547 2955131 3245 2920023 2548 2955133 3246 2920042 2549 2955135 3247 2920069 2550 2955139 3248 2920116 2551 2955141 3249 2920126 2552 2955145 3250 2920138 2553 2955147 3251 2920158 2554 2955149 3252 2920188 2555 2955151 3253 2920202 2556 2955153 3254 2920231 2557 2955155 3255 2920312 2558 2955157 3256 2920447 2559 2955161 3257 2920491 2560 2955163 3258 2920524 2561 2955165 3259 2920526 2562 2955167 3260 2920626 2563 2955173 3261 2920843 2564 2955175 3262 2920856 2565 2955177 3263 Recombinase Protein SEQ Recombinase Protein SEQ Protein ID ID Protein ID ID 2920863 2566 2955179 3264 2920920 2567 2955181 3265 2920945 2568 2955183 3266 2920959 2569 2955185 3267 2920973 2570 2955187 3268 2921023 2571 2955189 3269 2921049 2572 2955193 3270 2921068 2573 2955195 3271 2921078 2574 2955197 3272 2921097 2575 2955199 3273 2921197 2576 2955201 3274 2921392 2577 2955203 3275 2921433 2578 2955205 3276 2921447 2579 2955209 3277 2921492 2580 2955211 3278 2921527 2581 2955213 3279 2921936 2582 2955217 3280 2921966 2583 2955219 3281 2921972 2584 2955223 3282 2921978 2585 2955225 3283 2922011 2586 2955227 3284 2922096 2587 2955231 3285 2922144 2588 2955233 3286 2922425 2589 2955235 3287 2922485 2590 2955237 3288 2922525 2591 2955239 3289 2922598 2592 2955241 3290 2922677 2593 2955245 3291 2922772 2594 2955247 3292 2922839 2595 2955249 3293 2922860 2596 2955251 3294 2922874 2597 2955255 3295 2922889 2598 2955257 3296 2922895 2599 2955261 3297 2922959 2600 2955263 3298 2922999 2601 2955265 3299 2923014 2602 2955271 3300 2923027 2603 2955275 3301 2923212 2604 2955277 3302 2923247 2605 2955281 3303 2923295 2606 2955283 3304 2923297 2607 2955285 3305 2923311 2608 2955287 3306 Recombinase Protein SEQ Recombinase Protein SEQ Protein ID ID Protein ID ID 2923318 2609 2955289 3307 2923326 2610 2955291 3308 2923389 2611 2955293 3309 2923403 2612 2955295 3310 2923437 2613 2955299 3311 2923554 2614 2955301 3312 2923567 2615 2955303 3313 2923583 2616 2955305 3314 2923613 2617 2955307 3315 2923659 2618 2955309 3316 2923666 2619 2955311 3317 2923668 2620 2955319 3318 2923670 2621 2955321 3319 2923672 2622 2955327 3320 2923674 2623 2955329 3321 2923676 2624 2955333 3322 2923678 2625 2955335 3323 2923680 2626 2955337 3324 2923684 2627 2955339 3325 2923690 2628 2955341 3326 2923695 2629 2955343 3327 2923760 2630 2955345 3328 2924061 2631 2955347 3329 2924127 2632 2955349 3330 2924162 2633 2955351 3331 2924185 2634 2955353 3332 2924200 2635 2955357 3333 2924251 2636 2955359 3334 2924265 2637 2955363 3335 2924364 2638 2955365 3336 2924497 2639 2955367 3337 2924537 2640 2955369 3338 2924550 2641 2955371 3339 2924554 2642 2955375 3340 2924558 2643 2955377 3341 2924579 2644 2955381 3342 2924611 2645 2955385 3343 2924916 2646 2955387 3344 2925097 2647 2955389 3345 2925161 2648 2955391 3346 2925208 2649 2955393 3347 2925225 2650 2955395 3348 2925230 2651 2955397 3349 Recombinase Protein SEQ Recombinase Protein SEQ Protein ID ID Protein ID ID 2925232 2652 2955399 3350 2925247 2653 2955401 3351 2925351 2654 2955403 3352 2925365 2655 2955407 3353 2925515 2656 2955409 3354 2925824 2657 2955411 3355 2925861 2658 2955413 3356 2925957 2659 2955415 3357 2926133 2660 2955417 3358 2926207 2661 2955421 3359 2926250 2662 2955423 3360 2926293 2663 2955427 3361 2926319 2664 2955431 3362 2926324 2665 2955433 3363 2926327 2666 2955437 3364 2926332 2667 2955439 3365 2926496 2668 2955441 3366 2926540 2669 2955443 3367 2926553 2670 2955445 3368 2926732 2671 2955447 3369 2927198 2672 2955449 3370 2927509 2673 2955451 3371 2927517 2674 2955453 3372 2927522 2675 2955455 3373 2927550 2676 2955457 3374 2927562 2677 2955459 3375 2927594 2678 2955461 3376 2927657 2679 2955463 3377 2927880 2680 2955465 3378 2927906 2681 2955467 3379 2928301 2682 2955469 3380 2928523 2683 2955471 3381 2928551 2684 2955473 3382 2928563 2685 2955475 3383 2928967 2686 2955477 3384 2928977 2687 2955479 3385 2928995 2688 2955481 3386 2929059 2689 2955483 3387 2929097 2690 2955489 3388 2929164 2691 2955491 3389 2929191 2692 2955493 3390 2929197 2693 2955495 3391 2929203 2694 2955497 3392 Recombinase Protein SEQ Recombinase Protein SEQ Protein ID ID Protein ID ID 2929216 2695 2955501 3393 2929218 2696 2955503 3394 2929222 2697 2955505 3395 2929268 2698 2955507 3396 2929271 2699 2955515 3397 2929326 2700 2955519 3398 2929365 2701 2955521 3399 2929383 2702 2955525 3400 2929442 2703 2955527 3401 2929461 2704 2955529 3402 2929499 2705 2955531 3403 2929537 2706 2955533 3404 2929648 2707 2955535 3405 2929680 2708 2955537 3406 2929768 2709 2955539 3407 2929805 2710 2955541 3408 2929869 2711 2955543 3409 2929943 2712 2955545 3410 2930030 2713 2955551 3411 2930086 2714 2955555 3412 2930099 2715 2955557 3413 2930208 2716 2955565 3414 2930256 2717 2955567 3415 2930258 2718 2955569 3416 2930306 2719 2955571 3417 2930384 2720 2955573 3418 2930386 2721 2955575 3419 2930388 2722 2955581 3420 2930390 2723 2955583 3421 2930392 2724 2955585 3422 2930394 2725 2955587 3423 2930410 2726 2955589 3424 2930441 2727 2955591 3425 2930448 2728 2955595 3426 2930678 2729 2955597 3427 2930703 2730 2955599 3428 2930752 2731 2955601 3429 2930757 2732 2955603 3430 2930796 2733 2955605 3431 2930799 2734 2955607 3432 2930854 2735 2955609 3433 2931127 2736 2955611 3434 2931201 2737 2955613 3435 Recombinase Protein SEQ Recombinase Protein SEQ Protein ID ID Protein ID ID 2931284 2738 2955615 3436 2931304 2739 2955617 3437 2931309 2740 2955619 3438 2931373 2741 2955623 3439 2931437 2742 2955625 3440 2931490 2743 2955627 3441 2931493 2744 2955629 3442 2931579 2745 2955631 3443 2931585 2746 2955635 3444 2931671 2747 2955637 3445 2931691 2748 2955639 3446 2931793 2749 2955641 3447 2931796 2750 2955643 3448 2931860 2751 2955645 3449 2931986 2752 2955647 3450 2932051 2753 2955649 3451 2932102 2754 2955653 3452 2932107 2755 2955657 3453 2932176 2756 2955661 3454 2932238 2757 2955663 3455 2932295 2758 2955665 3456 2932365 2759 2955667 3457 2932438 2760 2955669 3458 2932517 2761 2955671 3459 2932555 2762 2955673 3460 2932645 2763 2955675 3461 2932698 2764 2955677 3462 2932726 2765 2955679 3463 2932771 2766 2955681 3464 2932834 2767 2955687 3465 2932939 2768 2955689 3466 2932987 2769 2955691 3467 2933037 2770 2955693 3468 2933110 2771 2955695 3469 2933223 2772 2955697 3470 2933247 2773 2955701 3471 2933297 2774 2955703 3472 2933396 2775 2955705 3473 2933588 2776 2955707 3474 2933597 2777 2955709 3475 2933665 2778 2955711 3476 2933717 2779 2955713 3477 2933745 2780 2955715 3478 Recombinase Protein SEQ Recombinase Protein SEQ Protein ID ID Protein ID ID 2933748 2781 2955719 3479 2933751 2782 2955721 3480 2933760 2783 2955724 3481 2933836 2784 2955726 3482 2933873 2785 2955728 3483 2933891 2786 2955730 3484 2933986 2787 2955732 3485 2933991 2788 2955738 3486 2934000 2789 2955740 3487 2934004 2790 2955742 3488 2934011 2791 2955744 3489 2934014 2792 2955748 3490 2934018 2793 2955750 3491 2934168 2794 2955752 3492 2934233 2795 2955754 3493 2934277 2796 2955756 3494 2934397 2797 2955758 3495 2934402 2798 2955760 3496 2934445 2799 2955762 3497 2934452 2800 2955766 3498 2934525 2801 2955770 3499 2934532 2802 2955772 3500 2934535 2803 2955774 3501 2934540 2804 2955776 3502 2934597 2805 2955778 3503 2934601 2806 2955786 3504 2934629 2807 2955788 3505 2934711 2808 2955794 3506 2934765 2809 2955796 3507 2934845 2810 2955798 3508 2934908 2811 2955804 3509 2934915 2812 2955806 3510 2935031 2813 2955808 3511 2935054 2814 2955810 3512 2935099 2815 2955812 3513 2935134 2816 2955814 3514 2935227 2817 2955816 3515 2935290 2818 2955820 3516 2935332 2819 2955822 3517 2935387 2820 2955824 3518 2935439 2821 2955826 3519 2935496 2822 2955828 3520 2935536 2823 2955830 3521 Recombinase Protein SEQ Recombinase Protein SEQ Protein ID ID Protein ID ID 2935618 2824 2955836 3522 2935621 2825 2955838 3523 2935628 2826 2955840 3524 2935641 2827 2955842 3525 2935914 2828 2955846 3526 2936026 2829 2955848 3527 2936230 2830 2955850 3528 2936258 2831 2955852 3529 2936343 2832 2955854 3530 2936359 2833 2955856 3531 2936392 2834 2955858 3532 2936477 2835 2955860 3533 2936490 2836 2955862 3534 2936495 2837 2955864 3535 2936626 2838 2955866 3536 2936785 2839 2955868 3537 2936792 2840 2955872 3538 2936949 2841 2955876 3539 2936951 2842 2955878 3540 2937049 2843 2955880 3541 2937055 2844 2955882 3542 2937065 2845 2955884 3543 2937074 2846 2955886 3544 2937105 2847 2955888 3545 2937117 2848 2955890 3546 2937140 2849 2955892 3547 2937173 2850 2955896 3548 2937177 2851 2955898 3549 2937189 2852 2955900 3550 2937279 2853 2955904 3551 2937301 2854 2955906 3552 2937312 2855 2955908 3553 2937316 2856 2955910 3554 2937373 2857 2955914 3555 2937428 2858 2955916 3556 2937440 2859 2955918 3557 2937489 2860 2955920 3558 2937534 2861 2955922 3559 2937583 2862 2955924 3560 2937628 2863 2955926 3561 2937661 2864 2955930 3562 2937711 2865 2955932 3563 2937766 2866 2955934 3564 Recombinase Protein SEQ Recombinase Protein SEQ Protein ID ID Protein ID ID 2937811 2867 2955936 3565 2937914 2868 2955938 3566 2937916 2869 2955940 3567 2938021 2870 2955942 3568 2938027 2871 2955944 3569 2938093 2872 2955946 3570 2938203 2873 2955948 3571 2938243 2874 2955950 3572 2938245 2875 2955952 3573 2938285 2876 2955956 3574 2938349 2877 2955958 3575 2938443 2878 2955960 3576 2938493 2879 2955964 3577 2938496 2880 2955966 3578 2938562 2881 2955968 3579 2938604 2882 2955970 3580 2938712 2883 2955972 3581 2938761 2884 2955974 3582 2938764 2885 2955976 3583 2938797 2886 2955978 3584 2938887 2887 2955980 3585 2938945 2888 2955982 3586 2938992 2889 2955988 3587 2939040 2890 2955990 3588 2939088 2891 2955992 3589 2939159 2892 2955996 3590 2939212 2893 2956000 3591 2939216 2894 2956002 3592 2939266 2895 2956006 3593 2939347 2896 2956008 3594 2939405 2897 2956012 3595 2939454 2898 2956014 3596 2939494 2899 2956016 3597 2939543 2900 2956020 3598 2939630 2901 2956022 3599 2939633 2902 2956024 3600 2939683 2903 2956028 3601 2939736 2904 2956030 3602 2939843 2905 2956032 3603 2939896 2906 2956034 3604 2939949 2907 2956038 3605 2940009 2908 2956040 3606 2940064 2909 2956042 3607 Recombinase Protein SEQ Recombinase Protein SEQ Protein ID ID Protein ID ID 2940117 2910 2956046 3608 2940173 2911 2956050 3609 2940175 2912 2956052 3610 2940277 2913 2956054 3611 2940330 2914 2956056 3612 2940334 2915 2956060 3613 2940396 2916 2956062 3614 2940446 2917 2956064 3615 2940481 2918 2956066 3616 2940542 2919 2956068 3617 2940626 2920 2956070 3618 2940628 2921 2956072 3619 2940679 2922 2956074 3620 2940744 2923 2956076 3621 2940799 2924 2956078 3622 2940840 2925 2956080 3623 2940923 2926 2956082 3624 2940965 2927 2956084 3625 2940978 2928 2956086 3626 2940996 2929 2956088 3627 2941067 2930 2956090 3628 2941069 2931 2956092 3629 2941131 2932 2956094 3630 2941211 2933 2956096 3631 2941313 2934 2956098 3632 2941375 2935 2956100 3633 2941432 2936 2956102 3634 2941506 2937 2956106 3635 2941558 2938 2956108 3636 2941661 2939 2956110 3637 2941748 2940 2956112 3638 2941770 2941 2956114 3639 2941862 2942 2956116 3640 2941864 2943 2956118 3641 2941906 2944 2956120 3642 2941948 2945 2956122 3643 2941992 2946 2956124 3644 2942124 2947 2956126 3645 2942129 2948 2956128 3646 2942137 2949 2956132 3647 2942149 2950 2956136 3648 2942155 2951 2956138 3649 2942161 2952 2956140 3650 Recombinase Protein SEQ Recombinase Protein SEQ Protein ID ID Protein ID ID 2942221 2953 2956144 3651 2942233 2954 2956146 3652 2942259 2955 2956148 3653 2942262 2956 2956150 3654 2942267 2957 2956154 3655 2942279 2958 2956158 3656 2942301 2959 2956160 3657 2942309 2960 2956162 3658 2942318 2961 2956164 3659 2942350 2962 2956168 3660 2942429 2963 2956170 3661 2942432 2964 2956174 3662 2942435 2965 2956176 3663 2942437 2966 2956178 3664 2942452 2967 2956182 3665 2942472 2968 2956184 3666 2942532 2969 2956186 3667 2942574 2970 2956190 3668 2942589 2971 2956194 3669 2942597 2972 2956196 3670 2942637 2973 2956200 3671 2942665 2974 2956202 3672 2942688 2975 2956204 3673 2942695 2976 2956206 3674 2942716 2977 2956208 3675 2942760 2978 2956210 3676 2942773 2979 2956212 3677 2942779 2980 2956214 3678 2942817 2981 2956216 3679 2942839 2982 2956218 3680 2942852 2983 2956222 3681 2942866 2984 2956226 3682 2943054 2985 2956228 3683 2943072 2986 2956230 3684 2943112 2987 2956232 3685 2943114 2988 2956234 3686 2943119 2989 2956236 3687 2943200 2990 2956244 3688 2943219 2991 2956246 3689 2943243 2992 2956248 3690 2943269 2993 2956252 3691 2943378 2994 2956254 3692 2943423 2995 2956260 3693 Recombinase Protein SEQ Recombinase Protein SEQ Protein ID ID Protein ID ID 2943456 2996 2956264 3694 2943501 2997 2956266 3695 2943564 2998 2956270 3696 2943574 2999 2956272 3697 2943583 3000 2956276 3698 2943593 3001 2956280 3699 2943614 3002 2956284 3700 2943649 3003 2956286 3701 2943829 3004 2956288 3702 2943878 3005 2956294 3703 2943914 3006 2956296 3704 2943943 3007 2956298 3705 2943961 3008 2956300 3706 2944026 3009 2956304 3707 2944033 3010 2956306 3708 2944044 3011 2956308 3709 2944051 3012 2956310 3710 2944119 3013 2956312 3711 2944144 3014 2956314 3712 2944159 3015 2956316 3713 2944179 3016 2956318 3714 2944191 3017 2956320 3715 2944193 3018 2956322 3716 2944248 3019 2956324 3717 2944399 3020 2956326 3718 2944443 3021 2956330 3719 2944548 3022 2956332 3720 2944582 3023 2956334 3721 2944697 3024 2956336 3722 2944762 3025 2956340 3723 2944775 3026 2956342 3724 2944831 3027 2956344 3725 2944911 3028 2956346 3726 2944913 3029 2956348 3727 2944931 3030 2956350 3728 2944983 3031 2956354 3729 2945085 3032 2956356 3730 2945111 3033 2956358 3731 2945114 3034 2956360 3732 2945161 3035 2956366 3733 2945228 3036 2956368 3734 2945351 3037 2956370 3735 2945361 3038 2956372 3736 Recombinase Protein SEQ Recombinase Protein SEQ Protein ID ID Protein ID ID 2945403 3039 2956374 3737 2945503 3040 2956376 3738 2945686 3041 2956378 3739 2945695 3042 2956380 3740 2945698 3043 2956382 3741 2945721 3044 2961117 3742 2945739 3045 2961119 3743 2945803 3046 2961125 3744 2945811 3047 2961288 3745 2945829 3048 2961290 3746 2945831 3049 2961292 3747 2945836 3050 2961294 3748 2945845 3051 2961296 3749 2945862 3052 2961298 3750 2945888 3053 2961302 3751 2945982 3054 2961306 3752 2946050 3055 2961308 3753 2946066 3056 2961310 3754 2946073 3057 2961312 3755 2946082 3058 2961314 3756 2946089 3059 2961318 3757 2946092 3060 2961320 3758 2946100 3061 2961322 3759 2946117 3062 2961324 3760 2946172 3063 2961328 3761 2946332 3064 2961332 3762 2946394 3065 2961334 3763 2946455 3066 2961336 3764 2946540 3067 2961338 3765 2946586 3068 2961340 3766 2946639 3069 2961342 3767 2946819 3070 2961344 3768 2946848 3071 2961348 3769 2946902 3072 2961350 3770 2946906 3073 2961352 3771 2947001 3074 2961354 3772 2947017 3075 2961356 3773 2947072 3076 2961358 3774 2947116 3077 2961360 3775 2947175 3078 2961362 3776 2947232 3079 2961364 3777 2947321 3080 2961366 3778 2947330 3081 2961368 3779 Recombinase Protein SEQ Recombinase Protein SEQ Protein ID ID Protein ID ID 2947430 3082 2961370 3780 2947432 3083 2961579 3781 2947499 3084 2961581 3782 2947532 3085 2961583 3783 2947562 3086 2961585 3784 2947564 3087 2961587 3785 2947608 3088 2961589 3786 2947706 3089 2961591 3787 2947729 3090 2961593 3788 2947747 3091 2961597 3789 2948078 3092 2961601 3790 2948157 3093 2961603 3791 2948170 3094 2961605 3792 2948229 3095 2961607 3793 2948239 3096 2961609 3794 2948269 3097 2961611 3795 2948282 3098 2961615 3796 2948330 3099 2961619 3797 2948375 3100 2961621 3798 2948507 3101 2961627 3799 2948608 3102 2961629 3800 2948613 3103 2961631 3801 2948637 3104 2961633 3802 2948641 3105 2961635 3803 2948984 3106 2961637 3804 2949005 3107 2961639 3805 2949032 3108 2961643 3806 2949056 3109 2961645 3807 2949074 3110 2961647 3808 2949117 3111 2961649 3809 2949144 3112 2961651 3810 2949159 3113 2961655 3811 2949173 3114 2961657 3812 2949181 3115 2961659 3813 2949195 3116 2961665 3814 2949200 3117 2961669 3815 2949328 3118 2961671 3816 2949445 3119 2961675 3817 2949513 3120 2961677 3818 2949628 3121 2961679 3819 2949648 3122 2961681 3820 2949684 3123 2961683 3821 2949757 3124 2961687 3822 Recombinase Protein SEQ Recombinase Protein SEQ Protein ID ID Protein ID ID 2949957 3125 2961689 3823 2949970 3126 2961691 3824 2949985 3127 2961693 3825 2949997 3128 2961695 3826 2950004 3129 2961697 3827 2950016 3130 2961699 3828 2950027 3131 2961701 3829 2950055 3132 2961705 3830 2950086 3133 2961707 3831 2950108 3134 2961711 3832 2950169 3135 2961713 3833 2950209 3136 2961715 3834 2950355 3137 2961717 3835 2950461 3138 2961719 3836 2950534 3139 2961721 3837 2950619 3140 2961723 3838 2950623 3141 2961727 3839 2950630 3142 2961729 3840 2950633 3143 2961731 3841 2950636 3144 2961733 3842 2950712 3145 2961735 3843 2950815 3146 2961737 3844 2950817 3147 2961739 3845 2950878 3148 2961741 3846 2950936 3149 2961743 3847 2950987 3150 2961745 3848 2951075 3151 2961747 3849 2951133 3152 2961749 3850 2951229 3153 2961751 3851 2951293 3154 2961753 3852 2951317 3155 2961755 3853 2951359 3156 2961757 3854 2951420 3157 2961759 3855 2951491 3158 2961761 3856 2951493 3159 2961763 3857 2951534 3160 2961765 3858 2951623 3161 2961767 3859 2951661 3162 2961769 3860 2951711 3163 2961771 3861 2951761 3164 2961773 3862 2951780 3165 2961775 3863 2951816 3166 2961779 3864 2951853 3167 2961781 3865 Recombinase Protein SEQ Recombinase Protein SEQ Protein ID ID Protein ID ID 2951857 3168 2961783 3866 2951944 3169 2961785 3867 2951960 3170 2961791 3868 2952027 3171 2961793 3869 2952037 3172 2961795 3870 2952047 3173 2961797 3871 2952078 3174 2961799 3872 2952145 3175 2961801 3873 2952149 3176 2961803 3874 2952170 3177 2961807 3875 2952211 3178 2961815 3876 2952214 3179 2961817 3877 2952218 3180 2961819 3878 2952233 3181 2961821 3879 2952268 3182 2961823 3880 2952283 3183 2961825 3881 2952302 3184 2961831 3882 2952306 3185 2961833 3883 2952482 3186 2961837 3884 2952531 3187 2961839 3885 2952596 3188 2961841 3886 2952601 3189 2961843 3887 2952605 3190 2961845 3888 2952629 3191 2961856 3889 2952649 3192 2961858 3890 2952657 3193 2961862 3891 2952688 3194 2961864 3892 2953100 3195 2961866 3893 2953179 3196 2961868 3894 2953186 3197 2961870 3895 2953236 3198 2961872 3896 2953305 3199 2961878 3897 2953323 3200 2961880 3898 2953334 3201 2961882 3899 2953349 3202 2961884 3900 2953355 3203 2961888 3901 2953559 3204 2961890 3902 2953603 3205 2961892 3903 2953749 3206 2961894 3904 2953801 3207 2961896 3905 2953806 3208 2961898 3906 2953832 3209 2961900 3907 2953849 3210 2961902 3908 Recombinase Protein SEQ Recombinase Protein SEQ Protein ID ID Protein ID ID 2953855 3211 2961904 3909 2953903 3212 2961906 3910 2954001 3213 2961908 3911 2954065 3214 2961912 3912 2954144 3215 2961914 3913 2954180 3216 2961916 3914 2954252 3217 2961920 3915 2954255 3218 2961922 3916 2954257 3219 2961924 3917 2954259 3220 2961926 3918 2^{954261 3221}

TABLE 4. Exemplary Effector Proteins N_ame ^{Amino Acid Sequence} _SEQ Repeat SEQ PAM ID Sequences ID: C_asФ.12 ^{MIKPTVSQFLTPGFKLIRNHSRTAGLKLKNEGEEACKKFVRENEIPKD} ₉₂₆₇ ^{CUUUCAAGACUAAU} 9269; NTYN; NTTN; ECPNFQGGPAIANIIAKSREFTEWEIYQSSLAIQEVIFTLPKDKLPEP AGAUUGCUCCUUAC 9270 TTTS ILKEEWRAQWLSEHGLDTVPYKEAAGLNLIIKNAVNTYKGVQVKVDNK GAGGAGAC; NKNNLAKINRKNEIAKLNGEQEISFEEIKAFDDKGYLLQKPSPNKSIY AUUGCUCCUUACGA CYQSVSPKPFITSKYHNVNLPEEYIGYYRKSNEPIVSPYQFDRLRIPI GGAGAC GEPGYVPKWQYTFLSKKENKRRKLSKRIKNVSPILGIICIKKDWCVFD MRGLLRTNHWKKYHKPTDSINDLFDYFTGDPVIDTKANVVRFRYKMEN GIVNYKPVREKKGKELLENICDQNGSCKLATVDVGQNNPVAIGLFELK KVNGELTKTLISRHPTPIDFCNKITAYRERYDKLESSIKLDAIKQLTS EQKIEVDNYNNNFTPQNTKQIVCSKLNINPNDLPWDKMISGTHFISEK AQVSNKSEIYFTSTDKGKTKDVMKSDYKWFQDYKPKLSKEVRDALSDI EWRLRRESLEFNKLSKSREQDARQLANWISSMCDVIGIENLVKKNNFF GGSGKREPGWDNFYKPKKENRWWINAIHKALTELSQNKGKRVILLPAM RTSITCPKCKYCDSKNRNGEKFNCLKCGIELNADIDVATENLATVAIT AQSMPKPTCERSGDAKKPVRARKAKAPEFHDKLAPSYTVVLREAV CasM.2654 MSVLTRKVQLIPVGDKEERDRVYKYLRDGIEAQNRAMNLYMSGLYFAA ₉₂₆₈ ^{AAGGAUGCCAAAC} _{9271 NNTN; TNTR;} 66 INEASKEDRKELNQLYSRIATSSKGSAYTTDIEFPTGLASTSTLSMAV TNTG RQDFTKSLKDGLMYGRVSLPTYRKDNPLFVDVRFVALRGTKQKYNGLY HEYKSHTEFLDNLYSSDLKVYIKFANDITFQVIFGNPRKSSALRSEFQ NIFEEYYKVCQSSIQFSGTKIILNMAMDIPDKEIELDEDVCVGVDLGI AIPAVCALNKNRYSRVSIGSKEDFLRVRTKIRNQRKRLQTNLKSSNGG HGRKKKMKPMDRFRDYEANWVQNYNHYVSRQVVDFAVKNKAKYINLEN LEGIRDDVKNEWLLSNWSYYQLQQYITYKAKTYGIEVRKINPYHTSQR CSCCGYEDAGNRPKKEKGQAYFKCLKCGEEMNADFNAARNIAMSTEFQ SGKKTKKQKKEQHENK

EXAMPLES [194] The following examples are included for illustrative purposes only and are not intended to limit the scope of the disclosure. Example 1. AAV is circularized by a recombinase in eukaryotic cells [195] Mammalian cells with an integrated promoter (e.g., a PGK promotor) upstream of an LSR RRS-2b site are transfected with a plasmid encoding a large serine recombinase (e.g., PhiC31) and a promoterless linear donor vector carrying a GFP reporter and RRS-2a located between an LSR RRS-1a and RRS-1b (FIG. 4, Step 1). GFP fluorescence is detected if the linear donor vector circularizes (FIG. 4, Step 2) and integrates into a target site of a genome by the LSR (FIG.4, Step 3). Alternatively, the recombinase may be encoded on an AAV or AdV vector that contains the SOI and recombinase recognition sites. The mammalian cells are transduced by the AAV or AdV vector. GFP fluorescence is detected if the double stranded DNA containing the GFP reporter is circularized and integrated into a target site of a genome by the recombinase. Example 2. AAV reporters are circularized by a recombinase in eukaryotic cells [196] Human HEK293T cells stably integrated with an integration landing pad were transfected with various reporter constructs (digested from AAV vectors) as shown in FIG.5 and Bxb1 (SEQ ID NO: 9272) to test the ability of an LSR to improve integration by AAV circularization. Bxb1 is referred to as the cognate LSR. As controls, cells were also transfected with these reporters and an orthogonal LSR, PhiC31 (SEQ ID NO: 9274). [197] The first reporter, referred to as, “integration only,” has an attP site for circularization, but not a corresponding attB site for circularization. Thus, this reporter cannot circularize. However, it does have an integration attB site that is compatible with the attP site in the integration landing pad of the cell line. Thus, it is capable of integrating. [198] The second reporter, referred to as, “circularization only,” has an attB and attP site for circularization, but does not have an integration attB site that is compatible with the integration landing pad. Thus, it is capable of circularizing, but not integrating. [199] The third reporter, referred to as the “full reporter,” has att sites for circularization and an integration attB site that is compatible with the attP site in the integration landing pad of the cell line. Thus, it is capable of circularizing and integrating. [200] As shown in FIG. 6, the full reporter will express BFP under control of a CMV promoter upon circularization (as will the circularization only reporter). As shown in FIG.6, mCherry will be expressed under the control of an EF1a promoter upon integration of the full reporter into the landing pad of the cell line (as will the integration only reporter). [201] To determine if circularization of a reporter by LSR promoted reporter integration into the cell landing pad, fluorescence of mCherry and BFP were quantified in the various transfected cells. Cells transfected with a circularized plasmid comprising an mCherry reporter driven by a constitutive promoter was included as a positive control. [202] TABLE 5 provides results at 15 days post-transfection, including the mCherry and BFP fluorescence of cells (values are an average of triplicates +/- standard deviation), fold change of cognate over orthogonal control (Fold orth.), fold change of full reporter cognate over integration only cognate (Fold, integ.), and fold change of full reporter cognate over circularization cognate (Fold circ.). Results showed that circularization improved integration greater than 5-fold (5.15; compare full reporter cognate to integration only cognate). It was noted that the circularized DNA integrated nearly efficiently as the mCherry positive control. TABLE 5. Post-transfection results %mCherry+ Fold Fold %BFP+ Fold Fold orth. integ. orth. circ. Integration only, o_rthogonal ^{0.18 +/- 0.03 0.50 +/- 0.03} Integration only, c_ognate ^{0.49 +/- 0.02 2.67 0.45 +/- 0.01 0.90} Circularization only, o_rthogonal ^{0.17 +/- 0.02 0.42 +/- 0.01} Circularization only, c_ognate ^{0.26 +/- 0.02 1.56 0.94 +/- 0.04 2.22} Full reporter, o_rthogonal ^{0.15 +/- 0.03 0.44 +/- 0.02} Full reporter, cognate 2.52 +/- 0.09 17.20 5.15 2.79 +/- 0.07 6.29 2.97 mCherry + control 2.96 +/- 0.07 0.02 +/- 0.00 [203] This experiment was repeated with fluorescence analysis performed 10 days post- transfection. Results showed that circularization improved integration greater than 7-fold (7.10; compare full reporter cognate to integration only cognate).

Claims

CLAIMS 1. A system or composition for the modification of a target nucleic acid comprising: a) a recombinase or a nucleic acid encoding a recombinase; and b) a donor vector comprising i) a sequence of insertion (SOI); ii) a pair of recombinase recognition sites (RRS-1a and RRS-1b) that are compatible with one another; and iii) optionally, a donor recombinase recognition site (RRS-2a) that is compatible with a target nucleic acid recombinase recognition site (RRS-2b), wherein the donor vector is a linear vector, wherein RRS-1a and RRS-1b are orthogonal to RRS-2a and RRS-2b, and wherein the recombinase recognizes RRS-1a, RRS-1b, RRS-2a and RRS-2b. 2. A system or composition for the modification of a target nucleic acid comprising a donor vector, wherein the donor vector comprises: i) a sequence encoding a recombinase; ii) a sequence of insertion (SOI); iii) a pair of recombinase recognition sites (RRS-1a and RRS-1b) that are compatible with one another; and iv) optionally, a donor recombinase recognition site (RRS-2a) that is compatible with a target nucleic acid recombinase recognition site (RRS-2b), wherein the donor vector is a linear vector, wherein RRS-1a and RRS-1b are orthogonal to RRS-2a and RRS-2b, and wherein the recombinase recognizes RRS-1a, RRS-1b, RRS-2a and RRS-2b. 3. The system or composition of claim 2, wherein the sequence encoding the recombinase is located 5’ or 3’ of the SOI, RRS-1a, RRS-1b, and RRS-2a. 4. The system or composition of any preceding claim, wherein RRS-1a is located 5’ of the SOI, 5’ of the RRS-2a, 5’ of the RRS-1b, or any combination thereof. 5. The system or composition of any preceding claim, wherein the SOI and RRS-2a are located between the RRS-1a and RRS-1b. 6. The system or composition of any preceding claim, wherein the RRS-1b is located 3’ of the SOI, 3’ of the RRS-1a, 3’ of the RRS-2a, or any combination thereof. 7. The system or composition of any preceding claim, wherein the recombinase generates staggered cuts at RRS-1a and RRS-1b, wherein the staggered cuts at RRS- 1a and RRS-1b are the same. 8. The system or composition of claim 7, wherein the recombinase recombines the staggered cuts at RRS-1a and RRS-1b to form a circular nucleic acid of the donor vector. 9. The system or composition of claim 8, wherein the circular nucleic acid comprises the SOI and RRS-2a. 10. The system or composition of any of claims 7-9, wherein the recombinase generates staggered cuts at RRS-2a and RRS-2b, wherein the staggered cuts at RRS-2a and RRS-2b are the same, and wherein at least one of the nucleotides of the staggered cuts at RRS-1a and RRS-1b are different from one of the nucleotides of the staggered cuts at RRS-2a and RRS-2b. 11. The system or composition of claim 10, wherein the recombinase recombines the staggered cuts at RRS-2a and RRS-2b to insert the SOI to the target nucleic acid. 12. The system or composition of any preceding claim, wherein the donor vector is an adeno-associated viral (AAV) vector. 13. The system or composition of any preceding claim, wherein the donor vector is a self- inactivating AAV vector. 14. The system or composition of any preceding claim, wherein the recombinase is a large serine recombinase. 15. The system or composition of any preceding claim, wherein: a) RRS-1a comprises a first AttB site and RRS-1b comprises a first AttP site or vice versa; and b) RRS-2a comprises a second AttP site and RRS-2b comprises a second AttB site or vice versa, wherein the first AttB site is compatible with the first AttP site, and the second AttP site is compatible with the second AttB site, and wherein the first AttB site is incompatible with the second AttP site, and wherein the second AttB site is incompatible with the first AttP site. 16. The system or composition any preceding claim, wherein the recombinase comprises an amino acid sequence that is at least 35%, 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 95%, at least 97%, at least 98%, at least 99%, or 100% identical to a sequence selected from TABLES 1-3. 17. The system or composition any preceding claim, wherein the recombinase comprises an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% identical to a sequence selected from SEQ ID NOs: 1-2523 and 9272-9274, the RRS-1a and/or RRS-2a comprises a nucleotide sequence that is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical to a sequence selected from SEQ ID NOs: 6442-8964 and 9278-9280, and the RRS-1b and/or RRS-2b comprises a nucleotide sequence that is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical to a sequence selected from SEQ ID NOs: 3919-6441 and 9275-9277, wherein the recombinase, RRS-1 and RRS-2 are in the same row of TABLE 1 or TABLE 2. 18. The system or composition of any preceding claim, wherein the RRS-2b is located in or near a safe harbor locus. 19. The system or composition of claim 18, wherein the safe harbor locus is in or near an AAVS1 (PPPIR12C) gene, an ALB gene, an Angptl3 gene, an ApoC3 gene, an ASGR2 gene, a CCR5 gene, a FIX (F9) gene, a G6PC gene, a Gys2 gene, an HGD gene, a Lp(a) gene, a Pcsk9 gene, a Serpina1 gene, a TF gene, and a TTR gene, and an intron thereof. 20. The system or composition of claim 18, wherein the RRS-2b is located in or near a target sequence of the human albumin gene (ALB) or AAVS1 gene. 21. The system or composition of any preceding claim, wherein the nucleic acid encoding the recombinase and the donor DNA vector are combined in a single composition. 22. The system or composition of any preceding claim, comprising a lipid nanoparticle (LNP), wherein the nucleic acid encoding the recombinase is associated with the LNP, optionally wherein the nucleic acid encoding the recombinase comprises a messenger RNA (mRNA). 23. The system or composition of any preceding claim, wherein the donor vector is linked to or codelivered with the nucleic acid encoding a recombinase in a delivery vector. 24. The system or composition of any preceding claim, comprising: a) an effector protein or a nucleic acid encoding the same, b) an effector partner protein or a nucleic acid encoding the same, c) a guide nucleic acid or a DNA molecule encoding the same, or d) a combination thereof. 25. The system or composition of claim 24, wherein the effector partner protein is selected from an RNA dependent DNA polymerase (RDDP) and a base editing enzyme. 26. The system or composition of claim 24 or 25, wherein the effector protein is a CRISPR associated (Cas) protein. 27. The system or composition of claim 26, wherein the Cas protein is a Type II protein or a Type V Cas protein. 28. The system or composition of claim 26, wherein the Cas protein comprises an amino acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NOs: 9267-9268. 29. The system or composition of any one of claims 26-28, wherein the length of the Cas protein is 350 to 500, 350-600, 350-700, 350-800, 350-900, or 350-1000 amino acids. 30. The system or composition of any one of claims 26-29, wherein the Cas protein comprises nickase activity. 31. The system or composition of any one of claims 24-30, wherein the effector partner protein comprises an RDDP. 32. The system or composition of claim 31, comprising at least one guide nucleic acid, wherein the at least one guide nucleic acid comprises: i) a protein binding sequence, wherein the effector protein is capable of binding the protein binding sequence, ii) a spacer sequence that hybridizes to a first target sequence on a first strand of the target nucleic acid, iii) a primer binding sequence, optionally wherein a portion of the primer binding sequence hybridizes to a first portion of the second strand of the target nucleic acid; and iv) a template sequence that hybridizes to a second portion of the second strand of the target nucleic acid. 33. The system or composition of claim 32, wherein the protein binding sequence comprises a nucleic acid sequence that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NOs: 9269-9271. 34. A method of modifying a target nucleic acid comprising contacting the target nucleic acid with the composition or components of the system of any one of claims 1-32. 35. The method of claim 34, wherein the SOI is inserted into the target nucleic acid at RRS-2b. 36. A method of modifying a target nucleic acid comprising contacting the target nucleic acid with the composition or components of the system of any one of claims 24-33. 37. The method of claim 36, comprising contacting the target nucleic acid with the effector protein, the effector partner protein, and the guide nucleic acid prior to contacting the target nucleic acid with the nucleic acid encoding the recombinase and the donor DNA vector. 38. The method of claim 37, comprising modifying the target nucleic acid to produce the RRS-2b. 39. The method of any one of claims 32-38, comprising contacting a cell with the composition or components of the system. 40. The method of claim 39, wherein the cell is a eukaryotic cell. 41. A recombinant adeno-associated virus (AAV) vector, comprising: a) a 5’ inverted terminal repeat (ITR) sequence; b) a donor nucleic acid comprising: i) a sequence of insertion (SOI), ii) two recombinase recognition sites (RRS-1a and RRS-1b) that are compatible with one another, and iii) optionally, a donor recombinase recognition site (RRS-2a) that is compatible with a target nucleic acid recombinase recognition site (RRS-2b), wherein RRS-1a and RRS-1b are orthogonal to RRS-2a and RRS-2b; c) a sequence encoding a recombinase that is operably linked to a promoter, wherein the recombinase recognizes RRS-1a, RRS-1b, RRS-2a and RRS-2b; and d) a 3’ ITR sequence. 42. The AAV vector of claim 41, wherein the SOI, the donor recombinase recognition site, and the promoter that is operably linked to the sequence encoding the recombinase are placed between RRS1-a and RRS-1b. 43. The AAV vector of claim 41 or 42, wherein the sequence encoding the recombinase is placed outside of RRS1-a, RRS-1b and RRS-2a. 44. The AAV vector of any one of claims 41-43, wherein the recombinase is a large serine recombinase (LSR). 45. The AAV vector of any one of claims 41-44, wherein the promoter is a mammalian promoter. 46. The AAV vector of claim 45, wherein the promoter is a CMV promoter. 47. An AAV transfer plasmid, comprising a) a 5’ inverted terminal repeat (ITR) sequence; b) a donor nucleic acid comprising: i) a sequence of insertion (SOI); ii) two recombinase recognition sites (RRS-1a and RRS-1b) that are compatible with one another; and iii) optionally, a donor recombinase recognition site (RRS-2a) that is compatible with a target nucleic acid recombinase recognition site (RRS-2b), wherein RRS-1a and RRS-1b are orthogonal to RRS-2a and RRS-2b; c) a sequence encoding a recombinase that is operably linked to a promoter, wherein the recombinase recognizes RRS-1a, RRS-1b, RRS-2a and RRS-2b and wherein the opposite strand of the sequence encoding the recombinase is operably linked to a bacterial promoter that expresses an antisense RNA of the recombinase; d) a 3’ ITR sequence; e) a sequence encoding an shRNA that targets the recombinase, wherein the sequence encoding the shRNA is operably linked to a Pol III promoter; and f) a sequence encoding a recombinase directionality factor (RDF) that is operably linked to a mammalian promoter followed by a bacterial promoter. 48. The AAV transfer plasmid of claim 47, wherein the sequence encoding the recombinase and the donor nucleic acid are flanked by the 5’ ITR sequence and the 3’ ITR sequence. 49. The AAV transfer plasmid of claim 47 or 48, wherein the sequence encoding the shRNA and the sequence encoding the RDF are placed outside of the 5’ ITR sequence and the 3’ ITR sequence. 50. The AAV transfer plasmid of any one of claims 47-49, wherein the bacterial promoter that is operably linked to the opposite strand of the sequence encoding the recombinase is a J23119 promoter. 51. The AAV transfer plasmid of any one of claims 47-50, wherein the Pol III promoter is a hU6 promoter. 52. The AAV transfer plasmid of any one of claims 47-51, wherein the bacterial promoter that is operably linked to the sequence encoding the RDF is a J23104 promoter. 53. The AAV transfer plasmid of any one of claims 47-52, wherein the mammalian promoter that is operably linked to the sequence encoding the RDF is a CMV promoter or a SFFV promoter.