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WO2009097862A1 - Marqueurs génétiques de fertilité - Google Patents

Marqueurs génétiques de fertilité Download PDF

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Publication number
WO2009097862A1
WO2009097862A1 PCT/DK2009/050040 DK2009050040W WO2009097862A1 WO 2009097862 A1 WO2009097862 A1 WO 2009097862A1 DK 2009050040 W DK2009050040 W DK 2009050040W WO 2009097862 A1 WO2009097862 A1 WO 2009097862A1
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ars
bfgl
ngs
bta
markers
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English (en)
Inventor
Mogens Sandø LUND
Bernt Guldbrandtsen
Christian Bendixen
Bo Thomsen
Søren SVENDSEN
Vivi Hunnicke Nielsen
Bente Flügel MAJGREN
Bart Albert Johannes Buitenhuis
Jørn Rind THOMASEN
Johanna HÖGLUNG
Goutam Sahana
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Aarhus Universitet
Kvaegavlsforeningen Dansire
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Aarhus Universitet
Kvaegavlsforeningen Dansire
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the present invention relates to fertility in bovine subjects.
  • the invention relates to genetic markers for the determination of fertility in a bovine subject and a diagnostic kit for detection of genetic markers associated with fertility in a bovine subject.
  • QTL Quantitative trait locus
  • a QTL is not necessarily a gene itself, but rather a DNA region that is closely linked to the genes that underlie the trait in question. Most likely, a QTL is a set of genes that collectively encode a quantitative trait that varies continuously across a population. Thus, the allelic variation of a QTL is associated with variation in a quantitative trait.
  • the presence of QTL is inferred from genetic mapping, in which the genetic location of the QTL is determined relative to known genetic markers.
  • genetic markers that are associated with a particular phenotype, such as fertility traits or to a heritable disease, has been facilitated by the identification of an increasing amount of microsatellite markers as a source of polymorphic markers and single nucleotide polymorphisms associated with a mutation causing a specific phenotype. Markers associated with the mutation or the mutation itself causing a specific phenotype of interest are localised by use of genetic analysis in pedigrees.
  • Non-random association of alleles at different loci is referred to as linkage disequilibrium (LD).
  • LD exists when observed frequencies of haplotypes in a population do not coincide with the haplotype frequencies predicted by multiplying together the frequency of individual genetic markers in each haplotype.
  • haplotype means a set of closely linked genetic markers present on one chromosome which tend to be inherited together.
  • LD is exploited in QTL mapping by associating performance of individuals with the haplotypes they carry.
  • Use of LD mapping within families increases the resolution of mapping.
  • the density of genetic markers needs to be sufficiently high relative to the distance across which LD extends in the given population.
  • LD extends over several tens of centiMorgans for genetic markers (Farnir et al. 2000).
  • Bovine female fertility has been declining for the last decades (Lucy, 2001 ). Improving female fertility is becoming more and more important as the consequences of impaired fertility include additional inseminations, higher veterinary costs, increased culling rate and higher replacement costs.
  • fertility traits are complex, affected by an unknown number of genes and the environment. The heritability for fertility traits usually falls within the range of 2 to 4% for the Holstein population in the Nordic countries (Strudsholm et al., 2007). Traditional selection methods to improve fertility are difficult to use due to this low heritability.
  • Fertility may be measured by a number of different traits.
  • genetic aspects of fertility traits are an important factor to be analysed in order to increase productivity in the future.
  • the use of genetic analysis and genetic selection appears to be a possible method for prediction of these fertility traits. Once mapped, a QTL can be usefully applied in marker assisted selection.
  • One aspect of the present invention relates to a method of determining fertility in a bovine subject, comprising detecting in a sample from said bovine subject the presence or absence of at least one genetic marker that is associated with to at least one trait indicative of fertility of said bovine subject and/or off-spring therefrom, wherein said at least one genetic marker is located on the bovine chromosome BTA1 in a region flanked by and including polymorphic microsatellite markers AGLA17 and URB014, and/or BTA2 in the region flanked by and including polymorphic microsatellite markers TGLA44 and IDVGA-2, and/or BT A4 in the region flanked by and including polymorphic microsatellite markers BMS1788 and MGTG4B, and/or BTA7 in the region flanked by and including polymorphic microsatellite markers BM7160 and BL1043, and/or BTA9 in the region flanked by and including polymorphic microsatellite markers BMS2151 and BMS
  • the present invention relates to a method for selecting bovine subjects for breeding purposes, said method comprising detecting in a sample from said bovine subject the presence or absence of at least one genetic marker as defined in the present invention, wherein said at least one genetic marker is associated with at least one trait indicative of fertility of said bovine subject and/or off-spring therefrom.
  • the present invention relates to a diagnostic kit for detecting the presence or absence in a bovine subject of at least one genetic marker as defined in the present invention.
  • the present invention relates to a method of determining fertility in a bovine subject, comprising detecting in a sample from said bovine subject the presence or absence of two or more genetic marker alleles that are associated with at least one trait indicative of fertility of said bovine subject and/or off-spring therefrom, wherein said two or more genetic marker alleles are single nucleotide polymorphisms selected from the group consisting of Hapmap60827-rs29019866, ARS-BFGL-NGS-40979,
  • ARS-BFGL-NGS-1 18182 Hapmap27428-BTA-151920, BTB-01 182684, BTB- 01 182684, BTB-01347067, UA-IFASA-2717, ARS-BFGL-BAC-15431 , BTB-01064770, Hapmap43361 -BTA-80384, BTB-01984646, BTA-122483-no-rs, ARS-BFGL-NGS- 32233, BTA-74241 -no-rs, BTB-01984646, ARS-BFGL-NGS-1 12793, ARS-BFGL-NGS- 57955, ARS-BFGL-NGS-35771 , BTA-321 1 1 -no-rs, ARS-BFGL-BAC-13827, ARS- BFGL-NGS-1 10387, ARS-BFGL-BAC-12582, Hapmap57166-rs29020401 , ARS-BFGL- NGS-1 10104,
  • the genetic marker allele which is genetically coupled to any of said single nucleotide polymorphisms, is preferably located within 5 cM, such as 2 or 1 cM upstream or downstream of said single nucleotide polymorphism.
  • the method preferably comprise detecting two or more single nucleotide polymorphisms, such as at least 3, 4, 5, 6, 7, 8, 9, at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, or at least 70 single nucleotide polymorphisms.
  • Another aspect of the present invention relates to a method of determining fertility in a bovine subject, comprising detecting in a sample from said bovine subject the presence or absence of at least one genetic marker that is associated with at least one trait indicative of fertility of said bovine subject and/or off-spring therefrom, wherein said at least one genetic marker is located on the bovine chromosome
  • BTA1 in a region flanked by and including polymorphic microsatellite markers AGLA17 and URB014, and/or in the region flanked by and including the SNP markers Hapmap38806-BTA-1 10152 and U A- 1 FAS A-2167, and/or flanked by and including the SNP markers Hapmap41527-BTA-38460 and Hapmap60827-rs29019866, and/or flanked by and including the SNP markers BTA-53322-no-rs and ARS-BFGL-NGS- 1 10293, and/or
  • BTA2 in the region flanked by and including polymorphic microsatellite markers TGLA44 and IDVGA-2, and/or BTA3 in the region flanked by and including the SNP markers Hapmap38375-BTA- 108207 and ARS-BFGL-NGS-106599, and/or flanked by and including the SNP markers BTB-01933332 and BTB-00140470, and/or flanked by and including the SNP markers BTB-01326963 and Hapmap47380-BTA-69661 , and/or BTA4 in the region flanked by and including polymorphic microsatellite markers BMS1788 and MGTG4B, and/or in the region flanked by and including the SNP markers BTB-01308655 and BTB-00186089, and/or flanked by and including the SNP markers Hapmap27404-BTA-142249 and Hapmap50451 -BTA-70851 , and/or flanked by and including the SNP markers B
  • BTA6 in the region flanked by and including the SNP markers Hapmap23860-BTC- 065677 and ARS-BFGL-NGS-1 12982, and/or flanked by and including the SNP markers ARS-BFGL-NGS-86825 and ARS-BFGL-NGS-17376, and/or BTA7 in the region flanked by and including polymorphic microsatellite markers BM7160 and BL1043, and/or in the region flanked by and including the SNP markers ARS-BFGL-NGS-3967 and BTB-00313229, and/or flanked by and including the SNP markers Hapmap27428-BTA-151920 and ARS-BFGL-NGS-5139, and/or BTA9 in the region flanked by and including polymorphic microsatellite markers BMS2151 and BMS1967, and/or BTA10 in the region flanked by and including polymorphic microsatellite markers
  • DIK2503 and BMS2614 and/or in the region flanked by and including the SNP markers Hapmap60219-rs29009655 and BTB-01400807, and/or flanked by and including the SNP markers ARS-BFGL-NGS-1 17446 and BTB-00424298, and/or flanked by and including the SNP markers ARS-BFGL-NGS-54030 and ARS-BFGL-NGS-84473, and/or flanked by and including the SNP markers ARS-BFGL-BAC-14182 and ARS- BFGL-NGS-1 17202, and/or flanked by and including the SNP markers BTA- 106513- no-rs and BTB-01970848, and/or
  • BTA1 1 in the region flanked by and including polymorphic microsatellite markers BM716 and HEL13, and/or BTA12 in the region flanked by and including polymorphic microsatellite markers BMS410 and BMS2724, and/or
  • BTA13 in the region flanked by and including polymorphic microsatellite markers BMS1742 and AGLA232, and/or in the region flanked by and including the SNP markers BTA-33924-no-rs and BTA-33932-no-rs, and/or flanked by and including the SNP markers ARS-BFGL-NGS-1 10285 and ARS-BFGL-NGS-18039, and/or flanked by and including the SNP markers Hapmap58773-rs29015694 and ARS-BFGL-NGS- 4795, and/or flanked by and including the SNP markers ARS-BFGL-NGS-109563and ARS-BFGL-NGS-1 14957, and/or
  • BTA14 in the region flanked by and including polymorphic microsatellite markers RM180 and BL1036, and/or
  • BTA15 in the region flanked by and including polymorphic microsatellite markers BR3510 and BMS429, and/or
  • BTA17 in the region flanked by and including polymorphic microsatellite markers RM156 and BM1233, and/or in the region flanked by and including the SNP markers ARS-BFGL-NGS-40557 and Hapmap56175-rs29013219, and/or flanked by and including the SNP markers Hapmap48324-BTA-41405 and UA-IFASA-5513, and/or BTA20 in the region flanked by and including polymorphic microsatellite markers BM3517 and UWCA26, and/or n the region flanked by and including the SNP markers BTA-1 15956-no-rs and Hapmap41280-BTA-50090, and/or flanked by and including the SNP markers Hapmap39724-BTA-122305 and Hapmap52690-ss46526609, and/or flanked by and including the SNP markers BTB-01263022 and BTB-00788976, and/or flanked
  • BTA24 in the region flanked by and including polymorphic microsatellite markers BMS917 and BMS3024, and/or in the region flanked by and including the SNP markers BTB-01485274 and BTB-00884791 , and/or flanked by and including the SNP markers BTB-00886719 and ARS-BFGL-NGS-1 1 1285, and/or flanked by and including the SNP markers Hapmap56316-rs29025240 and ARS-BFGL-NGS-18151 and/or
  • BTA25 in the region flanked by and including polymorphic microsatellite markers ILSTS102 and AF5, and/or
  • BTA26 in the region flanked by and including polymorphic microsatellite markers BMS651 and BM7237, and/or BTA29 in the region flanked by and including the SNP markers ARS-BFGL-NGS-
  • the genetic marker is preferably a microsatellite marker allele and/or a single nucleotide polymorphism (SNP) allele.
  • the bovine sample is preferably selected from the group consisting of blood, semen (sperm), urine, liver tissue, muscle, skin, hair, follicles, ear, tail, fat, testicular tissue, lung tissue, saliva, spinal cord biopsy, and any other tissue, and the bovine subject is preferably a member of the Holstein breed According to the present invention fertility may be observed by determining traits indicative of fertility, examples of fertility traits are Number of inseminations cows (AISC), Number of inseminations heifers (AISH), Fertility treatment 1 st lactation (FERT1 ), Fertility treatment 2nd lactation (FERT2), Fertility treatments 3rd lactation (FERT3), Heat strength cows (HSTC), Heat strength heifers (HSTH), Calving to first insemination (ICF), First to last insemination cows (IFLC), First to last insemination heifers (IFLH), 56 day Non-return rate cows (NRRC), 56 day Non-return rate
  • Embodiments of the present invention comprise the methods above, wherein the at least one genetic marker is detected by microsatellite genotyping using at least one oligonucleotide selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 432 and/or or by SNP genotyping using at least one oligonucleotide selected from the group consisting of selected from the group consisting of SEQ ID NO: 433 to SEQ ID NO: 740.
  • the present invention relates to a method for selecting bovine subjects for breeding purposes, said method comprising detecting in a sample from said bovine subject the presence or absence of at least one genetic marker, or a combination thereof, as defined in any of the preceding claims, wherein said at least one genetic marker is associated with at least one trait indicative of fertility of said bovine subject and/or off-spring therefrom.
  • the present invention relates to a diagnostic kit for detecting the presence or absence in a bovine subject of two or more genetic marker alleles as defined herein, said kit comprising at least one detection member.
  • the detection member is for example an oligonucleotide primer or probe.
  • kits, comprsing at least one oligonucleotide is selected from the group consisting of SEQ ID NO.: 1 to SEQ ID NO.: 432 and/or SEQ ID NO.: 433 to SEQ ID NO.: 740 and/or any combination thereof.
  • the kits may also comprise one or more reference sample comprising positive or negative control genetic material, as well as instructions for the performance of the detection method of the kit, and for the interpretation of the results.
  • Figures 1 -10 Genome scan of BTA1 in relation to fertility. Numbers refer to 'herdbook number' and fertility trait, respectively.
  • the abbreviation phe# refers to the following fertility traits: phe4: AISC; phe5: AISH; phe12:ICF; phe13: IFLC; phe14: IFLH; phe15: NRRC; phe16: NRRH; pheSEI O: HSTC; and pheSE1 1 : HSTH, as defined elsewhere herein.
  • the abbreviation "nyafertj4", “nyafertj ⁇ ” and “nyafertj ⁇ ” refers to fertility treatments in first, second and third lactation, respectively.
  • the X- axis represents the distance of the chromosome expressed in Morgan according to the positions employed in this analysis.
  • the Y-axis represents the test-statistics of the QTL analysis expressed in the F-value. High F-values are indicative of genes, which affect the investigated fertility traits.
  • Figures 1 1 -13 Genome scan of BT A2 in relation to fertility. Numbers refer to 'herdbook number' and fertility trait, respectively.
  • the abbreviation phe# refers to the following fertility traits: phe4: AISC; phe5: AISH; phe12:ICF; phe13: IFLC; phe14: IFLH; phe15: NRRC; phe16: NRRH; pheSEI O: HSTC; and pheSE1 1 : HSTH, as defined elsewhere herein.
  • nyafertj4 refers to fertility treatments in first, second and third lactation, respectively.
  • the X- axis represents the distance of the chromosome expressed in Morgan according to the positions employed in this analysis.
  • the Y-axis represents the test-statistics of the QTL analysis expressed in the F-value. High F-values are indicative of genes, which affect the investigated fertility traits.
  • Figures 14-16 Genome scan of BT A4 in relation to fertility. Numbers refer to 'herdbook number' and fertility trait, respectively.
  • the abbreviation phe# refers to the following fertility traits: phe4: AISC; phe5: AISH; phe12:ICF; phe13: IFLC; phe14:
  • nyafertj4 refers to fertility treatments in first, second and third lactation, respectively.
  • the X- axis represents the distance of the chromosome expressed in Morgan according to the positions employed in this analysis.
  • the Y-axis represents the test-statistics of the QTL analysis expressed in the F-value. High F-values are indicative of genes, which affect the investigated fertility traits.
  • Figures 17-22 Genome scan of BT A7 in relation to fertility. Numbers refer to 'herdbook number' and fertility trait, respectively.
  • the abbreviation phe# refers to the following fertility traits: phe4: AISC; phe5: AISH; phe12:ICF; phe13: IFLC; phe14: IFLH; phe15: NRRC; phe16: NRRH; pheSEI O: HSTC; and pheSE1 1 : HSTH, as defined elsewhere herein.
  • the abbreviation "nyafertj4", “nyafertj ⁇ ” and “nyafertj ⁇ ” refers to fertility treatments in first, second and third lactation, respectively.
  • the X- axis represents the distance of the chromosome expressed in Morgan according to the positions employed in this analysis.
  • the Y-axis represents the test-statistics of the QTL analysis expressed in the F-value. High F-values are indicative of genes, which affect the investigated fertility traits.
  • Figures 23-28 Genome scan of BT A9 in relation to fertility. Numbers refer to 'herdbook number' and fertility trait, respectively.
  • the abbreviation phe# refers to the following fertility traits: phe4: AISC; phe5: AISH; phe12:ICF; phe13: IFLC; phe14: IFLH; phe15: NRRC; phe16: NRRH; pheSEI O: HSTC; and pheSE1 1 : HSTH, as defined elsewhere herein.
  • the abbreviation "nyafertj4", “nyafertj ⁇ ” and “nyafertj ⁇ ” refers to fertility treatments in first, second and third lactation, respectively.
  • the X- axis represents the distance of the chromosome expressed in Morgan according to the positions employed in this analysis.
  • the Y-axis represents the test-statistics of the QTL analysis expressed in the F-value. High F-values are indicative of genes, which affect the investigated fertility traits.
  • FIG. 29-38 Genome scan of BTA10 in relation to fertility. Numbers refer to
  • phe# refers to the following fertility traits: phe4: AISC; phe5: AISH; phe12:ICF; phe13: IFLC; phe14: IFLH; phe15: NRRC; phe16: NRRH; pheSEI O: HSTC; and pheSE1 1 : HSTH, as defined elsewhere herein.
  • “nyafertj ⁇ ” refers to fertility treatments in first, second and third lactation, respectively.
  • the X-axis represents the distance of the chromosome expressed in Morgan according to the positions employed in this analysis.
  • the Y-axis represents the test-statistics of the QTL analysis expressed in the F-value. High F-values are indicative of genes, which affect the investigated fertility traits.
  • Figures 39-43 Genome scan of BTA1 1 in relation to fertility. Numbers refer to
  • phe# refers to the following fertility traits: phe4: AISC; phe5: AISH; phe12:ICF; phe13: IFLC; phe14: IFLH; phe15: NRRC; phe16: NRRH; pheSEI O: HSTC; and pheSE1 1 :
  • HSTH as defined elsewhere herein.
  • the abbreviation "nyafertj4", “nyafertj ⁇ ” and “nyafertj ⁇ ” refers to fertility treatments in first, second and third lactation, respectively.
  • the X-axis represents the distance of the chromosome expressed in Morgan according to the positions employed in this analysis.
  • the Y-axis represents the test-statistics of the QTL analysis expressed in the F-value. High
  • F-values are indicative of genes, which affect the investigated fertility traits.
  • FIG. 44-46 Genome scan of BTA12 in relation to fertility. Numbers refer to
  • phe# refers to the following fertility traits: phe4: AISC; phe5: AISH; phe12:ICF; phe13: IFLC; phe14: IFLH; phe15: NRRC; phe16: NRRH; pheSEI O: HSTC; and pheSE1 1 : HSTH, as defined elsewhere herein.
  • the abbreviation "nyafertj4", “nyafertj ⁇ ” and “nyafertj ⁇ ” refers to fertility treatments in first, second and third lactation, respectively.
  • the X-axis represents the distance of the chromosome expressed in Morgan according to the positions employed in this analysis.
  • the Y-axis represents the test-statistics of the QTL analysis expressed in the F-value. High F-values are indicative of genes, which affect the investigated fertility traits.
  • Figures 47-49 Genome scan of BTA13 in relation to fertility. Numbers refer to 'herdbook number' and fertility trait, respectively.
  • the abbreviation phe# refers to the following fertility traits: phe4: AISC; phe5: AISH; phe12:ICF; phe13: IFLC; phe14: IFLH; phe15: NRRC; phe16: NRRH; pheSEI O: HSTC; and pheSE1 1 : HSTH, as defined elsewhere herein.
  • the abbreviation "nyafertj4", “nyafertj ⁇ ” and “nyafertj ⁇ ” refers to fertility treatments in first, second and third lactation, respectively.
  • the X-axis represents the distance of the chromosome expressed in
  • phe# refers to the following fertility traits: phe4: AISC; phe5: AISH; phe12:ICF; phe13: IFLC; phe14: IFLH; phe15: NRRC; phe16: NRRH; pheSEI O: HSTC; and pheSE1 1 : HSTH, as defined elsewhere herein.
  • “nyafertj ⁇ ” refers to fertility treatments in first, second and third lactation, respectively.
  • the X-axis represents the distance of the chromosome expressed in Morgan according to the positions employed in this analysis.
  • the Y-axis represents the test-statistics of the QTL analysis expressed in the F-value. High F-values are indicative of genes, which affect the investigated fertility traits.
  • FIG. 53-55 Genome scan of BTA17 in relation to fertility. Numbers refer to
  • phe# refers to the following fertility traits: phe4: AISC; phe5: AISH; phe12:ICF; phe13: IFLC; phe14: IFLH; phe15: NRRC; phe16: NRRH; pheSEI O: HSTC; and pheSE1 1 :
  • HSTH as defined elsewhere herein.
  • the abbreviation "nyafertj4", “nyafertj ⁇ ” and “nyafertj ⁇ ” refers to fertility treatments in first, second and third lactation, respectively.
  • the X-axis represents the distance of the chromosome expressed in Morgan according to the positions employed in this analysis.
  • the Y-axis represents the test-statistics of the QTL analysis expressed in the F-value. High
  • F-values are indicative of genes, which affect the investigated fertility traits.
  • FIG. 56-59 Genome scan of BTA20 in relation to fertility. Numbers refer to
  • phe# refers to the following fertility traits: phe4: AISC; phe5: AISH; phe12:ICF; phe13: IFLC; phe14: IFLH; phe15: NRRC; phe16: NRRH; pheSEI O: HSTC; and pheSE1 1 : HSTH, as defined elsewhere herein.
  • the abbreviation "nyafertj4", “nyafertj ⁇ ” and “nyafertj ⁇ ” refers to fertility treatments in first, second and third lactation, respectively.
  • the X-axis represents the distance of the chromosome expressed in Morgan according to the positions employed in this analysis.
  • the Y-axis represents the test-statistics of the QTL analysis expressed in the F-value. High F-values are indicative of genes, which affect the investigated fertility traits.
  • Figures 60-65 Genome scan of BTA22 in relation to fertility. Numbers refer to 'herdbook number' and fertility trait, respectively.
  • the abbreviation phe# refers to the following fertility traits: phe4: AISC; phe5: AISH; phe12:ICF; phe13: IFLC; phe14: IFLH; phe15: NRRC; phe16: NRRH; pheSEI O: HSTC; and pheSE1 1 : HSTH, as defined elsewhere herein.
  • the abbreviation "nyafertj4", “nyafertj ⁇ ” and “nyafertj ⁇ ” refers to fertility treatments in first, second and third lactation, respectively.
  • the X-axis represents the distance of the chromosome expressed in
  • the Y-axis represents the test-statistics of the QTL analysis expressed in the F-value. High F-values are indicative of genes, which affect the investigated fertility traits.
  • Figures 66-71 Genome scan of BTA24 in relation to fertility. Numbers refer to
  • phe# refers to the following fertility traits: phe4: AISC; phe5: AISH; phe12:ICF; phe13: IFLC; phe14: IFLH; phe15: NRRC; phe16: NRRH; pheSEI O: HSTC; and pheSE1 1 : HSTH, as defined elsewhere herein.
  • the abbreviation "nyafertj4", “nyafertj ⁇ ” and “nyafertj6” refers to fertility treatments in first, second and third lactation, respectively.
  • the X-axis represents the distance of the chromosome expressed in Morgan according to the positions employed in this analysis.
  • the Y-axis represents the test-statistics of the QTL analysis expressed in the F-value. High F-values are indicative of genes, which affect the investigated fertility traits.
  • FIG. 12-1 A Genome scan of BTA25 in relation to fertility. Numbers refer to
  • phe# refers to the following fertility traits: phe4: AISC; phe5: AISH; phe12:ICF; phe13: IFLC; phe14: IFLH; phe15: NRRC; phe16: NRRH; pheSEI O: HSTC; and pheSE1 1 : HSTH, as defined elsewhere herein.
  • “nyafertj6” refers to fertility treatments in first, second and third lactation, respectively.
  • the X-axis represents the distance of the chromosome expressed in Morgan according to the positions employed in this analysis.
  • the Y-axis represents the test-statistics of the QTL analysis expressed in the F-value. High F-values are indicative of genes, which affect the investigated fertility traits.
  • phe# refers to the following fertility traits: phe4: AISC; phe5: AISH; phe12:ICF; phe13: IFLC; phe14: IFLH; phe15: NRRC; phe16: NRRH; pheSEI O: HSTC; and pheSE1 1 : HSTH, as defined elsewhere herein.
  • the abbreviation "nyafertj4", “nyafertj ⁇ ” and “nyafertj ⁇ ” refers to fertility treatments in first, second and third lactation, respectively.
  • the X-axis represents the distance of the chromosome expressed in Morgan according to the positions employed in this analysis.
  • the Y-axis represents the test-statistics of the QTL analysis expressed in the F-value. High F-values are indicative of genes, which affect the investigated fertility traits.
  • Figures 90-94 Genome scan of BTA15 in relation to fertility. Numbers refer to
  • phe# refers to the following fertility traits: phe4: AISC; phe5: AISH; phe12:ICF; phe13: IFLC; phe14: IFLH; phe15: NRRC; phe16: NRRH; pheSEI O: HSTC; and pheSE1 1 : HSTH, as defined elsewhere herein.
  • the abbreviation "nyafertj4", “nyafertj ⁇ ” and “nyafertj ⁇ ” refers to fertility treatments in first, second and third lactation, respectively.
  • the X-axis represents the distance of the chromosome expressed in Morgan according to the positions employed in this analysis.
  • the Y-axis represents the test-statistics of the QTL analysis expressed in the F-value. High F-values are indicative of genes, which affect the investigated fertility traits.
  • Figures 96-101 Genome scan of BTA9 in relation to fertility. Numbers refer to
  • phe# refers to the following fertility traits: phe4: AISC; phe5: AISH; phe12:ICF; phe13: IFLC; phe14: IFLH; phe15: NRRC; phe16: NRRH; pheSEI O: HSTC; and pheSE1 1 :
  • HSTH as defined elsewhere herein.
  • the abbreviation "nyafertj4", “nyafertj ⁇ ” and “nyafertj ⁇ ” refers to fertility treatments in first, second and third lactation, respectively.
  • the X-axis represents the distance of the chromosome expressed in Morgan according to the positions employed in this analysis.
  • the Y-axis represents the test-statistics of the QTL analysis expressed in the F-value. High
  • F-values are indicative of genes, which affect the investigated fertility traits.
  • Figure 102 Genome-wide association scan of BTA5 in relation to the trait fertility index characteristic of Danish Holstein cattle.
  • the X-axis represents the SNP number as ordered on BTA5 as employed in this analysis.
  • the Y-axis represents the - Iog1 OP values for each SNPs.
  • Figure 103 Genome-wide association scan of BTA5 in relation to the trait number of insemination per conception in cows characteristic of Danish Holstein cattle. The
  • X-axis represents the SNP number as ordered on BTA5 as employed in this analysis.
  • the Y-axis represents the -logl OP values for each SNPs.
  • Figure 104 Genome-wide association scan of BTA5 in relation to the trait interval from first to last insemination in cows characteristic of Danish Holstein cattle.
  • the X- axis represents the SNP number as ordered on BT A5 as employed in this analysis.
  • the Y-axis represents the -logl OP values for each SNPs.
  • the present invention relates to genetic determinants of fertility in dairy cattle. Fertility is an economically important factor in the dairy industry. Therefore, it is of economic interest to identity those bovine subjects that have a genetic predisposition for specific fertility traits. Furthermore, bovine subjects with genetic predisposition for low fertility are carriers of non-desired traits, which can be passed on to their offspring.
  • bovine subject refers to cattle of any breed and is meant to include both cows and bulls, whether adult or newborn animals. No particular age of the animals are denoted by this term.
  • a bovine subject is a member of the Holstein breed.
  • the bovine subject is a member of the Holstein-Friesian cattle population.
  • the bovine subject is a member of the
  • the bovine subject is a member of the Swedish Holstein cattle population.
  • the bovine subject is a member of the Holstein Swartbont cattle population.
  • the bovine subject is a member of the Deutsche Holstein Schwarzbunt cattle population.
  • the bovine subject is a member of the US Holstein cattle population.
  • the bovine subject is a member of the Red and White Holstein breed.
  • the bovine subject is a member of the Irish Holstein Schwarzbunt cattle population.
  • the bovine subject is a member of any family, which includes members of the Holstein breed.
  • the bovine subject is a member of the Danish Red population.
  • the bovine subject is a member of the Finnish Ayrshire population. In yet another embodiment the bovine subject is a member of the Swedish Red population. In another embodiment, the bovine subject is a member of the Swedish Red and White population. In yet another embodiment, the bovine subject is a member of the Nordic Red population.
  • the bovine subject is selected from the group consisting of Swedish Red and White, Danish Red, Finnish Ayrshire, Holstein- Friesian, Danish Holstein and Nordic Red. In another embodiment of the present invention, the bovine subject is selected from the group consisting of Finnish Ayrshire and Swedish Red cattle. In another embodiment of the present invention, the bovine subject is selected from the group consisting of Finnish Ayrshire and Swedish Red cattle.
  • the bovine subject is a member of the Danish Holstein cattle population. In another preferred embodiment, the bovine subject is a member of the Swedish Holstein cattle population.
  • the bovine subject is selected from the group of breeds shown in table 1 a
  • Table 1 a Breed names and breed codes assigned by ICAR (International Committee for Animal Recording)
  • the bovine subject is a member of a breed selected from the group of breeds shown in table 1 b In one embodiment, the bovine subject is a member of a breed selected from the group of breeds shown in table 1c
  • the term "genetic marker” refers to a variable nucleotide sequence (polymorphism) of the DNA on the bovine chromosome.
  • the variable nucleotide sequence can be identified by methods known to a person skilled in the art, as explained elsewhere herein, for example by using specific oligonucleotides in for example amplification methods and/or hybridization techniques and/or observation of a size difference. However, the variable nucleotide sequence may also be detected by sequencing or for example restriction fragment length polymorphism analysis.
  • the variable nucleotide sequence may be represented by a deletion, an insertion, repeats, and/or a point mutation.
  • a genetic marker comprises a variable number of polymorphic alleles.
  • the at least one genetic marker of the present invention is a quantitative trait locus.
  • Microsatellite markers refer to short sequences repeated after each other. In short sequences are for example one nucleotide, such as two nucleotides, for example three nucleotides, such as four nucleotides, for example five nucleotides, such as six nucleotides, for example seven nucleotides, such as eight nucleotides, for example nine nucleotides, such as ten nucleotides.
  • changes sometimes occur and the number of repeats may increase or decrease.
  • the specific definition and locus of the polymorphic microsatellite markers can be found in the
  • microsatellite locus comprises a variable number of polymorphic alleles.
  • microsatellite marker refers to a specific such allele.
  • the at least one genetic marker of the present invention is detected by identification of a microsatellite marker, which is genetically coupled to said genetic marker.
  • SNP single nucleotide polymorphism
  • An SNP locus comprises at least two alleles, and an SNP locus comprising two, htree, and four alleles are referred to as bi-, tri-, or tetra-allelic polymorphisms, respectively.
  • the bovine genome comprise large amounts of SNPs, and SNP markers are therefore highly suitable for use in selection for desirable phenotypic traits, which are genetically linked to the SNPs.
  • the specific marker alleles are associated with quantitative trait loci affecting fertility, including specific fertility traits as defined herein.
  • the term "associated with” as used herein in regards to the genetic markers and traits for fertility, is meant to comprise both direct and indirect genetic linkages.
  • a genetic marker which is associated with a trait indicative of fertility may be coupled to said trait by direct or indirect genetic linkages.
  • a microsatellite marker allele or an SNP allele which is genetically coupled to a genetic marker associated with at least one trait indicative of fertility according to the present invention, is indicative of said genetic marker, and may consequently be detected in a sample as an alternative of detecting said genetic marker associated with at least one trait indicative of fertility. Therefore, genetic markers, which are genetically coupled with a genetic marker of the present invention, are also within the scope of the present invention, therefore, the present invention claims genetic regions surrounding the genetic markers of the present invention, in order to include such coupled markers in the scope of protection. In general, genetic markers within a genomic distance of 5-10 cM are expected to be genetically coupled, or in linkage disequilibrium. Therefore, the present invention also
  • nucleotide sequences of the genetic markers of the present invention are genetically associated with traits for fertility in a bovine subject. Consequently, it is also understood that a number of genetic markers may be comprised in the nucleotide sequence of the DNA region(s) flanked by and including the genetic markers according to the method of the present invention.
  • Fertility in a bovine subject is affected by a number of traits.
  • fertilizer as used herein relates to the reproductive performance of a bovine subject, i.e. the ability to reproduce.
  • fertility describes the extent to which the bovine is able to produce off-spring, which includes the ability to conceive and calving.
  • Fertility is for example reflected by a number of different traits, which may be used as quantitative measures of fertility.
  • fertility trait refers to any trait, which affect fertility in a bovine subject or its off-spring.
  • fertility of a bovine subject in the context of the present application may be physically manifested by the fertility of its off-spring - both female and male.
  • the fertility of a bull may be measured by a specific fertility trait in its female off-spring and/or the female off-spring of its off-spring.
  • the present invention relates to any trait, which affects fertility and/or is indicative of fertility. Specifically, the present invention relates to traits such as those listed below (see also table 22):
  • AISH Number of inseminations heifers
  • FRT1 Fertility treatment 1 st lactation
  • NRRH Non-return rate heifers
  • FTI Fertility index
  • AIS Number of inseminations
  • Cows(C) and heifers (H) are considered separately as AISC or AISH.
  • Fertility treatments 1 st , 2 nd and 3 rd lactation (FERT1 , FERT2, FERT3) Fertility treatments are divided into three groups. Group 1 represents hormonal reproductive disorders and consists of ovarian cysts treatments. Group 2 represents infective reproductive disorders and consists of recordings of endometritis, metritis and vaginitis treatments. The last group consists of treatments for abortion, uterine prolaps, uterine torsion and other reproductive disorders. A disorder code is 1 if the cow has the corresponding disease or otherwise 0. The three lactations are considered as different traits. The trait may be recalculated into a breeding value for every sire. In Denmark fertility treatments are recorded by veterinarians and Al-technicians. Thus the traits FERT1 , FERT2 and FERT3 describe fertility treatments for first to third lactation, respectively.
  • HST measures the ability to show oestrus. The trait is measured subjectively by the individual farmer on a predefined relative scale from 1 to 5. Cows and heifers are considered separately as HSTC or HSTH. This may be recalculated into a breeding value for every sire.
  • IFL First to last insemination This is measured as the time from first insemination to the last insemination.
  • the recording unit is days.
  • IFL describes pregnancy rate and heat strength defined above.
  • Cows and heifers are considered separately as IFLC or IFLH.
  • NRR is based on whether the cow or heifer had a second insemination within 56 days after the first insemination. All cows and heifers not offered Al within 56 days were considered pregnant. NRR describes the cows' or heifers' ability to become pregnant after insemination, defined as pregnancy rate. The recording unit is days. It is recorded by an artificial insemination technician (Al-technician) or a licensed farmer.
  • Cows and heifers are considered separately as NRRC or NRRH, respectively. This is later recorded in the national recording database and in this case recalculated into a breeding value for every sire.
  • FTI Fertility index
  • This index primarily describes how quickly and easily cows become pregnant. For all breeds the index for female fertility is a joint Nordic index, based on insemination data from Denmark, Sweden and Finland.
  • ICF Interval from calving to first insemination (cows)
  • IFL Interval from first to last insemination (cows and heifers)
  • NRR Non-return rate 56 days (cows and heifers)
  • HST Heat strength (cows and heifers) (data only recorded in Sweden)
  • AIS hereins and cows
  • ICF cows
  • IFL Costs of one more day open (equal to ICF)
  • IFL Costs of a day later calving age
  • HST and NRR are zero. This means that the economic value of HST and NRR are expressed through the other fertility traits.
  • the only economic weight, which HST has in this case, is a value due to less work when detecting heat when HST is stronger. This value is assumed to be zero.
  • Table 1 d Economic values of fertility traits, NAV fertility index (expressed in Danish kroner, DKK). In the table all values for the cow traits AIS, ICF and IFL include first and later parities. Heifer traits are only expressed once.
  • the genetic markers such as SNP markers or combinations thereof according to the present invention are associated with at least one trait indicative of fertility.
  • the trait indicative of fertility is selected from the group consisting of Number of inseminations cows (AISC), Number of inseminations heifers (AISH), Fertility treatment 1 st lactation (FERT1 ), Fertility treatment 2nd lactation (FERT2), Fertility treatments 3rd lactation (FERT3), Heat strength cows (HSTC), Heat strength heifers (HSTH), Calving to first insemination (ICF), First to last insemination cows (IFLC), First to last insemination heifers (IFLH), 56 day Non-return rate cows (NRRC) , 56 day Non-return rate heifers (NRRH), and/or Fertility index (FTI)
  • the trait indicative of fertility is Number of inseminations cows (AISC). In another specific embodiment, the trait indicative of fertility is Number of inseminations heifers (AISH). In yet another specific embodiment, the trait indicative of fertility is Fertility treatment 1 st lactation (FERT1 ). In a further specific embodiment, the trait indicative of fertility is Fertility treatment 2nd lactation (FERT2). In another specific embodiment, the trait indicative of fertility is Fertility treatments 3rd lactation (FERT3). In another specific embodiment, the trait indicative of fertility is Heat strength cows (HSTC). In yet another specific embodiment, the trait indicative of fertility is Heat strength heifers (HSTH).
  • the trait indicative of fertility is Calving to first insemination (ICF).
  • the trait indicative of fertility is First to last insemination cows (IFLC).
  • the trait indicative of fertility is First to last insemination heifers (IFLH).
  • the trait indicative of fertility is 56 day Non-return rate cows (NRRC) and 56 day Non-return rate heifers (NRRH).
  • the trait indicative of fertility is Fertility index (FTI).
  • the fertility of a bovine subject as determined by the presence or absence of a genetic marker or combinations thereof as defined by the present invention is estimated relative to the fertility of a bovine subject, wherein said genetic marker allele is absent from or present in the same locus, respectively.
  • a bovine subject wherein the presence of a genetic marker allele is indicative of a reduced fertility
  • the reduction is estimated relative to a bovine subject, wherein said genetic marker allele is absent from the same genetic locus, i.e. a bovine subject that carries an alternative allele at that genetic marker locus.
  • a bovine subject, wherein the absence of a genetic marker allele is indicative of a reduced fertility the reduction is estimated relative to a bovine subject, wherein said genetic marker allele is present from the same genetic locus.
  • the granddaughter design includes analysing data from DNA-based markers for grandsires that have been used extensively in breeding and for sons of grandsires where the sons have produced offspring.
  • the phenotypic data that are to be used together with the DNA-marker data are derived from the daughters of the sons.
  • Such phenotypic data could be for example milk production features, features relating to calving, fertility, meat quality, or disease.
  • One group of daughters has inherited one allele from their father whereas a second group of daughters has inherited the other allele from their father.
  • DNA markers can be used directly to provide information of the traits passed on from parents to one or more of their offspring when a number of DNA markers on a chromosome have been determined for one or both parents and their offspring.
  • the markers may be used to calculate the genetic history of the chromosome linked to the DNA markers.
  • the frequency of recombination is the likelihood that a recombination event will occur between two genes or two markers.
  • the frequency of recombination may be calculated as the genetic distance between the two genes or the two markers. Genetic distance is measured in units of centiMorgan (cM). One centiMorgan is equal to a 1% chance that a marker at one genetic locus will be separated from a marker at a second locus due to crossing over in a single generation. One centiMorgan is equivalent, on average, to one million base pairs.
  • the frequency of recombination is the likelihood that a recombination event will occur between two genes or two markers.
  • the frequency of recombination may be calculated as the genetic distance between the two genes or the two markers. Genetic distance is measured in units of centiMorgan (cM). One centiMorgan is the length of chromosome wherein there is on average 0.01 cross-over per meiosis. If an uneven number of cross -overs occurs between two genetic markers, then a marker at one genetic locus will be separated from a marker at a second locus due to crossing over in a single generation. One centiMorgan is equivalent, on average, to one million base pairs.
  • the relative position of a genetic marker for example a microsatellite marker, may be designated in Morgan or centiMorgan with reference to its distance from a proximal position in the chromosome located at 0 cM.
  • the specific genetic marker or combination thereof mat be identified according to the present invention, by detecting a genetic marker, such as a microsatellite marker or an SNP marker, which is genetically coupled to said first genetic marker.
  • a genetic marker such as a microsatellite marker or an SNP marker
  • the specific genetic marker, which affects fertility can be defined according to the present invention, by a genetic region flanked by and including specific genetic markers, such as microsatellite markers or SNP markers.
  • fertility is determined by detecting the absence or presence of a genetic marker allele in a sample of any source comprising genetic material.
  • detection of a genetic marker may be performed on samples selected from the group consisting of blood, semen (sperm), urine, liver tissue, muscle, skin, hair, follicles, ear, tail, fat, testicular tissue, lung tissue, saliva, spinal cord biopsy and any other tissue.
  • the sample is selected from the group consisting of blood, urine, skin, hair, ear, tail, liver and muscle. In another preferred embodiment the sample is selected from the group consisting of blood, liver tissue and muscle. In particularly preferred embodiments the sample is blood. In another particularly preferred embodiment the sample is liver tissue. In yet another particularly preferred embodiment the sample is muscle.
  • nucleic acid may be extracted from the samples by a variety of techniques.
  • Genomic DNA may be isolated from the sample by treatment with proteinase K followed by extraction with phenol (see e.g. Sambrook et al. 1989).
  • the sample may also be used directly.
  • the amount of the nucleic acid used for microsatellite or SNP genotyping for detection of a genetic marker according to the method of the present invention is in the range of nanograms to micrograms. It is appreciated by the person skilled in the art that in practical terms no upper limit for the amount of nucleic acid to be analysed exists. The problem that the skilled person encounters is that the amount of sample to be analysed is limited. Therefore, it is beneficial that the method of the present invention can be performed on a small amount of sample and thus a limited amount of nucleic acid in the sample is required.
  • the amount of the nucleic acid to be analysed is thus at least 1 ng, such as at least 10 ng, for example at least 25 ng, such as at least 50 ng, for example at least 75 ng, such as at least 100 ng, for example at least 125 ng, such as at least 150 ng, for example at least 200 ng, such as at least 225 ng, for example at least 250 ng, such as at least 275 ng, for example at least 300 ng, 400 ng, for example at least 500 ng, such as at least 600 ng, for example at least 700 ng, such as at least 800, ng, for example at least 900 ng or such as at least 1000 ng.
  • the amount of nucleic acid as the starting material for the method of the present invention is 20-50 ng. In a specifically preferred embodiment, the starting material for the method of the present invention is at 30-40 ng.
  • One aspect of the present invention relates to a method of determining fertility in a bovine subject, comprising detecting in a sample from said bovine subject the presence or absence of at least one genetic marker that is associated with at least one trait indicative of fertility of said bovine subject and/or off-spring therefrom, wherein said at least one genetic marker is located on the bovine chromosome BTA1 in a region flanked by and including polymorphic microsatellite markers AGLA17 and URB014, and/or BT A2 in the region flanked by and including polymorphic microsatellite markers TGLA44 and IDVGA-2, and/or BT A4 in the region flanked by and including polymorphic microsatellite markers BMS1788 and MGTG4B, and/or BT A7 in the region flanked by and including polymorphic microsatellite markers BM7160 and BL1043, and/or BTA9 in the region flanked by and including polymorphic microsatellite markers BMS2151 and B
  • the at least one genetic marker may be a combination of at least two or more genetic markers such that the accuracy may be increased, such as at least three genetic markers, for example four genetic markers, such as at least five genetic markers, for example six genetic markers, such as at least seven genetic markers, for example eight genetic markers, such as at least nine genetic markers, for example ten genetic markers.
  • the at least one genetic marker may be located on at least one bovine chromosome, such as at least two chromosomes, for example at least three chromosomes, such as at least four chromosomes, for example at least five chromosomes, and/or such as at least six chromosomes, for example at least seven chromosomes, such as at least eight chromosomes, for example at least nine chromosomes, and/or such as at least ten chromosomes.
  • at least one bovine chromosome such as at least two chromosomes, for example at least three chromosomes, such as at least four chromosomes, for example at least five chromosomes, and/or such as at least six chromosomes, for example at least seven chromosomes, such as at least eight chromosomes, for example at least nine chromosomes, and/or such as at least ten chromosomes.
  • the at least one marker is selected from any of the individual markers of the tables shown herein.
  • the at least one genetic marker is located on the bovine chromosome BTA1 . In one specific embodiment of the present invention, the at least one genetic marker is located in the region from about 0 Morgan (M) to about 1.6 M on the bovine chromosome BTA1 . In one embodiment the at least one genetic marker is located on the bovine chromosome BTA1 in the region flanked by and including the microsatellite markers AGLA17 and URB014.
  • the at least one genetic marker is located on the bovine chromosome BTA1 in the region flanked by and including the SNP markers Hapmap38806-BTA-1 10152 and UA-IFASA- 2167, or flanked by and including the SNP markers Hapmap41527-BTA-38460 and Hapmap60827-rs29019866, or flanked by and including the SNP markers BTA-53322- no-rs and ARS-BFGL-NGS-1 10293.
  • the at least one genetic marker is predictive for fertility of a bovine subject. In a particular embodiment the at least one genetic marker is predictive for at least one trait indicative of fertility, as defined elsewhere herein.
  • the at least one genetic marker is predictive for any traits indicative of fertility.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the at least one genetic marker is detected by microsatellite genotyping using at least one oligonucleotide selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 46, as shown in table 20.
  • the at least one genetic marker is located in a region flanked by and including any of the microsatellite markers selected from the group of markers shown in table 2a.
  • the at least one genetic marker is selected from the group of markers shown in Table 2a
  • the at least one genetic marker is located in the region from about 0.75813 M to about 1 .54672 M on the bovine chromosome BTA1. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA1 in the region flanked by and including the markers INRA049 and URB014.
  • the at least one genetic marker is selected from the group of markers shown in Table 2b.
  • the fertility trait affected by said genetic marker is preferably FERT1 and/or ICF. Table 2b
  • the at least one genetic marker is located in the region from about 1 .22094 M to about 1 .54672 M on the bovine chromosome BTA1. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA1 in the region flanked by and including the markers CSSM019 and URB014. The at least one genetic marker is selected from the group of markers shown in Table 2c.
  • the fertility trait affected by said genetic marker is preferably FERT1 and/or ICF.
  • the at least one genetic marker is located in the region from about 1 .22094 M to about 1 .42244 M on the bovine chromosome BTA1. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA1 in the region flanked by and including the markers CSSM019 and BMS4043. The at least one genetic marker is selected from the group of markers shown in Table 2d.
  • the fertility trait affected by said genetic marker is preferably FERT1 and/or ICF.
  • the at least one genetic marker is located at 1.326 Morgan (M) or in the region between microsatellite markers BMS918 and BMS4043 on the bovine chromosome BTA1 .
  • the fertility trait affected by said genetic marker is preferably FERT1
  • the at least one genetic marker is located at the chromosomal position 1 .326 Morgan (M) or in the region between microsatellite markers BMS918 and BMS4043 on the bovine chromosome BTA1.
  • the fertility trait affected by said genetic marker is preferably ICF BTA2
  • the at least one genetic marker is located on the bovine chromosome BT A2. In one specific embodiment of the present invention, the at least one genetic marker is located in the region from about 0.03856 M to about 1 .26352 M on the bovine chromosome BTA2. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA2 in the region flanked by and including the microsatellite markers TGLA44 and IDVGA-2.
  • the at least one genetic marker is predictive for fertility of a bovine subject. In a particular embodiment the at least one genetic marker is predictive for at least one trait indicative of fertility, as defined elsewhere herein. However, in a further embodiment the at least one genetic marker is predictive for any traits indicative of fertility.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the at least one genetic marker is detected by microsatellite genotyping using at least one oligonucleotide selected from the group consisting of SEQ ID NO: 47 to SEQ ID NO: 66, as shown in table 20.
  • the at least one genetic marker is located in a region flanked by and including any of the microsatellite markers selected from the group of markers shown in table 3a.
  • the at least one genetic marker is selected from the group of markers shown in Table 3a Table 3a
  • the at least one genetic marker is located in the region from about 0.03856 M to about 0.61725 M on the bovine chromosome BTA2. In one embodiment the at least one genetic marker is located on the bovine chromosome BT A2 in the region flanked by and including the markers TGLA44 and BMS1 126.
  • the at least one genetic marker is selected from the group of markers shown in Table 3b. The fertility trait affected by said genetic marker is preferably NRRC. Table 3b
  • the at least one genetic marker is located in the region from about 0.03856 M to about 0.10772 M on the bovine chromosome BTA2. In one embodiment the at least one genetic marker is located on the bovine chromosome BT A2 in the region flanked by and including the markers TGLA44 and ILSTS026.
  • the at least one genetic marker is selected from the group of markers shown in Table 3c.
  • the fertility trait affected by said genetic marker is any trait preferably NRRC. Table 3c
  • the at least one genetic marker is located at the chromosomal position 0.039 M or is genetically coupled to the microsatellite marker TGLA44 on the bovine chromosome BT A2.
  • the fertility trait affected by said genetic marker is preferably NRRC.
  • the at least one genetic marker is located on the bovine chromosome BT A3. In one specific embodiment of the present invention, the at least one genetic marker is located in the region from about 0 Morgan (M) to about 1.6 M on the bovine chromosome BT A3. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA3 in the region flanked by and including the SNP markers Hapmap38375-BTA- 108207 and ARS-BFGL-NGS- 106599, or flanked by and including the SNP markers BTB-01933332 and BTB- 00140470, or flanked by and including the SNP markers BTB-01326963 and Hapmap47380-BTA-69661.
  • the at least one genetic marker is predictive for fertility of a bovine subject.
  • the at least one genetic marker is predictive for at least one trait indicative of fertility, as defined elsewhere herein.
  • the at least one genetic marker is predictive for any traits indicative of fertility.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the at least one genetic marker is located on the bovine chromosome BT A4. In one specific embodiment of the present invention, the at least one genetic marker is located in the region from about 0 M to about 1.2 M on the bovine chromosome BT A4. In one embodiment the at least one genetic marker is located on the bovine chromosome BT A4 in the region flanked by and including the microsatellite markers BMS1788 and MGTG4B.
  • the at least one genetic marker is located on the bovine chromosome BT A4 in the region flanked by and including the SNP markers BTB-01308655 and BTB-00186089, or flanked by and including the SNP markers Hapmap27404-BTA- 142249 and Hapmap50451 -BTA- 70851 , or flanked by and including the SNP markers BTB-01565771 and BTB- 00202376.
  • the at least one genetic marker is predictive for fertility of a bovine subject.
  • the at least one genetic marker is predictive for at least one trait indicative of fertility, as defined elsewhere herein.
  • the at least one genetic marker is predictive for any traits indicative of fertility.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the at least one genetic marker is detected by microsatellite genotyping using at least one oligonucleotide selected from the group consisting of SEQ ID NO: 67 to SEQ ID NO: 82, as shown in table 20.
  • the at least one genetic marker is located in a region flanked by and including any of the microsatellite markers selected from the group of markers shown in table 4a.
  • the at least one genetic marker is selected from the group of markers shown in Table 4a. Table 4a
  • the at least one genetic marker is located in the region from about 0.12544 M to about 0.62953 M on the bovine chromosome BTA4. In one embodiment the at least one genetic marker is located on the bovine chromosome BT A4 in the region flanked by and including the markers BMS1788 and INRA072.
  • the at least one genetic marker is selected from the group of markers shown in Table 4b.
  • the fertility trait affected by said genetic marker is preferably IFLC Table 4b
  • the at least one genetic marker is located in the region from about 0.12544 M to about 0.5249 M on the bovine chromosome BTA4. In one embodiment the at least one genetic marker is located on the bovine chromosome BT A4 in the region flanked by and including the markers BMS1788 and TGLA1 16.
  • the at least one genetic marker is selected from the group of markers shown in Table 4c.
  • the fertility trait affected by said genetic marker is preferably IFLC Table 4c
  • the at least one genetic marker is located in the region from about 0.73447 M to about 1 .12755 M on the bovine chromosome BTA4. In one embodiment the at least one genetic marker is located on the bovine chromosome BT A4 in the region flanked by and including the markers BM8233 and MGTG4B .
  • the at least one genetic marker is selected from the group of markers shown in Table 4d.
  • the fertility trait affected by said genetic marker is preferably IFLC Table 4d
  • the at least one genetic marker is located in the region from about 0.91 196 M to about 1 .12755 M on the bovine chromosome BT A4. In one embodiment the at least one genetic marker is located on the bovine chromosome BT A4 in the region flanked by and including the markers BMS648 and MGTG4B.
  • the at least one genetic marker is selected from the group of markers shown in Table 4e.
  • the fertility trait affected by said genetic marker is preferably IFLC Table 4e
  • the at least one genetic marker is located at the chromosomal position 0.432 M or is genetically coupled to the microsatellite marker BMS2646 on the bovine chromosome BT A4.
  • the fertility trait affected by said genetic marker is preferably IFLC
  • the at least one genetic marker is located on the bovine chromosome BT A5. In one specific embodiment of the present invention, the at least one genetic marker is located in the region from about 0 Morgan (M) to about 1.6 M on the bovine chromosome BT A5. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA5 in the region flanked by and including the SNP markers Hapmap55237-rs29010308 and ARS-BFGL-NGS- 44991 , or flanked by and including the SNP markers ARS-BFGL-NGS-40451 and ARS- BFGL-NGS-61091 . The at least one genetic marker is predictive for fertility of a bovine subject.
  • the at least one genetic marker is predictive for at least one trait indicative of fertility, as defined elsewhere herein.
  • the at least one genetic marker is predictive for any traits indicative of fertility.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the at least one genetic marker is located on the bovine chromosome BT A6. In one specific embodiment of the present invention, the at least one genetic marker is located in the region from about O Morgan (M) to about 1.6 M on the bovine chromosome BT A6. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA6 in the region flanked by and including the SNP markers Hapmap23860-BTC-065677 and ARS-BFGL-NGS- 1 12982, or flanked by and including the SNP markers ARS-BFGL-NGS-86825 and ARS-BFGL-NGS-17376. The at least one genetic marker is predictive for fertility of a bovine subject.
  • the at least one genetic marker is predictive for at least one trait indicative of fertility, as defined elsewhere herein.
  • the at least one genetic marker is predictive for any traits indicative of fertility.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the at least one genetic marker is located on the bovine chromosome BT A7. In one specific embodiment of the present invention, the at least one genetic marker is located in the region from about 0 M to about 1.35564 M on the bovine chromosome BTA7. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA7 in the region flanked by and including the microsatellite markers BM7160 and BL1043.
  • the at least one genetic marker is located on the bovine chromosome BT A7 in the region flanked by and including the SNP markers ARS-BFGL-NGS-3967 and BTB-00313229, or flanked by and including the SNP markers Hapmap27428-BTA-151920 and ARS- BFGL-NGS-5139.
  • the at least one genetic marker is predictive for fertility of a bovine subject.
  • the at least one genetic marker is predictive for at least one trait indicative of fertility, as defined elsewhere herein.
  • the at least one genetic marker is predictive for any traits indicative of fertility.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the at least one genetic marker is detected by microsatellite genotyping using at least one oligonucleotide selected from the group consisting of SEQ ID NO: 83 to SEQ ID NO: 124, as shown in table 20.
  • the at least one genetic marker is located in a region flanked by and including any of the microsatellite markers selected from the group of markers shown in table 5a.
  • the at least one genetic marker is selected from the group of markers shown in Table 5a
  • the at least one genetic marker is located in the region from about 0.39337 M to about 1 .35564 M on the bovine chromosome BTA7. In one embodiment the at least one genetic marker is located on the bovine chromosome BT A7 in the region flanked by and including the markers TGLA303 and BL1043 The at least one genetic marker is selected from the group of markers shown in Table 5b.
  • the fertility trait affected by said genetic marker is preferably AISH and/or HST. Table 5b
  • the at least one genetic marker is located in the region from about 0.57263 M to about 1 .35564 M on the bovine chromosome BTA7. In one embodiment the at least one genetic marker is located on the bovine chromosome BT A7 in the region flanked by and including the markers BM7247 and BL1043.
  • the at least one genetic marker is selected from the group of markers shown in Table 5c.
  • the fertility trait affected by said genetic marker is preferably AISH and/or HST.
  • the at least one genetic marker is located in the region from about 0.58552 M to about 1 .16629 M on the bovine chromosome BTA7. In one embodiment the at least one genetic marker is located on the bovine chromosome BT A7 in the region flanked by and including the markers UWCA20 and MB057.
  • the at least one genetic marker is selected from the group of markers shown in Table 5d.
  • the fertility trait affected by said genetic marker is preferably AISH and/or HST. Table 5d
  • the at least one genetic marker is located at the chromosomal position 1.1 16 M or in the region between microsatellite markers DIK2895 and MB057 on the bovine chromosome BT A7.
  • the fertility trait affected by said genetic marker is preferably AISH.
  • the at least one genetic marker is located at the chromosomal position 0.957 M or in the region between microsatellite markers BMS2258 and AE129 on the bovine chromosome BT A7.
  • the fertility trait affected by said genetic marker is preferably HSTH
  • the at least one genetic marker is located on the bovine chromosome BT A9. In one specific embodiment of the present invention, the at least one genetic marker is located in the region from about O M to about 1.09287 M on the bovine chromosome BTA9. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA9 in the region flanked by and including the microsatellite markers BMS2151 and BMS1967.
  • the at least one genetic marker is predictive for fertility of a bovine subject. In a particular embodiment the at least one genetic marker is predictive for at least one trait indicative of fertility, as defined elsewhere herein. However, in a further embodiment the at least one genetic marker is predictive for any traits indicative of fertility.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the at least one genetic marker is detected by microsatellite genotyping using at least one oligonucleotide selected from the group consisting of SEQ ID NO: 125 to SEQ ID NO: 176, as shown in table 20.
  • the at least one genetic marker is located in a region flanked by and including any of the microsatellite markers selected from the group of markers shown in table 2a.
  • the at least one genetic marker is selected from the group of markers shown in Table 6a
  • the at least one genetic marker is located in the region from about 0.04892 M to about 0.30921 M on the bovine chromosome BTA9. In one embodiment the at least one genetic marker is located on the bovine chromosome BT A9 in the region flanked by and including the markers BMS2151 and DIK2892.
  • the at least one genetic marker is selected from the group of markers shown in Table 6b.
  • the fertility trait affected by said genetic marker is preferably IFLH and/or IFLC. Table 6b
  • the at least one genetic marker is located in the region from about 0.45739 M to about 0.52352 M on the bovine chromosome BTA9. In one embodiment the at least one genetic marker is located on the bovine chromosome BT A9 in the region flanked by and including the markers DIK5364 and DIK2303. The at least one genetic marker is selected from the group of markers shown in Table 6c.
  • the fertility trait affected by said genetic marker is preferably IFLH and/or
  • the at least one genetic marker is located in the region from about 0.57088 M to about 0.68072 M on the bovine chromosome BTA9. In one embodiment the at least one genetic marker is located on the bovine chromosome BT A9 in the region flanked by and including the markers DIK4926 and DIK2816.
  • the at least one genetic marker is selected from the group of markers shown in Table 6d.
  • the fertility trait affected by said genetic marker is preferably IFLH and/or IFLC. Table 6d
  • the at least one genetic marker is located in the region from about 0.49996 M to about 0.909801 M on the bovine chromosome BT A9. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA9 in the region flanked by and including the markers UWCA9 and INRA084. The at least one genetic marker is selected from the group of markers shown in Table 6e. The fertility trait affected by said genetic marker is preferably IFLH and/or IFLC. Table 6e
  • the at least one genetic marker is located at the chromosomal position 0.50 M or in the region between microsatellite markers UWCA9 and DIK4912 on the bovine chromosome BT A9.
  • the fertility trait affected by said genetic marker is preferably IFLC
  • the at least one genetic marker is located at the chromosomal position 0.049 M or is genetically coupled to the microsatellite marker BMS2151 on the bovine chromosome BT A9.
  • the fertility trait affected by said genetic marker is preferably IFLH
  • the at least one genetic marker is located on the bovine chromosome BTA10. In one specific embodiment of the present invention, the at least one genetic marker is located in the region from about 0.08991 M to about 1.09393 M on the bovine chromosome BTA10. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA10 in the region flanked by and including the microsatellite markers DIK2503 and BMS2614.
  • the at least one genetic marker is located on the bovine chromosome BTA10 in the region flanked by and including the SNP markers Hapmap60219- rs29009655 and BTB-01400807, or flanked by and including the SNP markers ARS- BFGL-NGS-1 17446 and BTB-00424298, or flanked by and including the SNP markers ARS-BFGL-NGS-54030 and ARS-BFGL-NGS-84473, or flanked by and including the SNP markers ARS-BFGL-BAC-14182 and ARS-BFGL-NGS-1 17202, or flanked by and including the SNP markers BTA-106513-no-rs and BTB-01970848.
  • the at least one genetic marker is predictive for fertility of a bovine subject.
  • the at least one genetic marker is predictive for at least one trait indicative of fertility, as defined elsewhere herein.
  • the at least one genetic marker is predictive for any traits indicative of fertility.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the at least one genetic marker is detected by microsatellite genotyping using at least one oligonucleotide selected from the group consisting of SEQ ID NO: 177 to SEQ ID NO: 212, as shown in table 20.
  • the at least one genetic marker is located in a region flanked by and including any of the microsatellite markers selected from the group of markers shown in table 7a.
  • the at least one genetic marker is selected from the group of markers shown in Table 7a
  • the at least one genetic marker is located in the region from about 0.08991 M to about 0.247 M on the bovine chromosome BTA10. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA10 in the region flanked by and including the markers DIK2503 and BM1237.
  • the at least one genetic marker is selected from the group of markers shown in Table 7b.
  • the fertility trait affected by said genetic marker is preferably FERT3 and/or IFLC. Table 7b
  • the at least one genetic marker is located in the region from about 0.08991 M to about 0.24014 M on the bovine chromosome BTA10. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA10 in the region flanked by and including the markers DIK2503 and BMS528.
  • the at least one genetic marker is selected from the group of markers shown in Table 7c.
  • the fertility trait affected by said genetic marker is preferably FERT3 and/or IFLC. Table 7c
  • the at least one genetic marker is located in the region from about 0.80435 M to about 1 .09393 M on the bovine chromosome BTA10. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA10 in the region flanked by and including the markers BMS1620 and BMS2614. The at least one genetic marker is selected from the group of markers shown in Table 7d.
  • the fertility trait affected by said genetic marker is preferably FERT3 and/or IFLC.
  • the at least one genetic marker is located in the region from about 0.8746 M to about 1.00013 M on the bovine chromosome BTA10. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA10 in the region flanked by and including the markers BMS2641 and BMS614. The at least one genetic marker is selected from the group of markers shown in Table 7e.
  • the fertility trait affected by said genetic marker is preferably FERT3 and/or IFLC.
  • the at least one genetic marker is located in the region from about 0.44254 M to about 0.8746 M on the bovine chromosome BTA10. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA10 in the region flanked by and including the markers BMS2742 and BMS2641.
  • the at least one genetic marker is selected from the group of markers shown in Table 7f.
  • the fertility trait affected by said genetic marker is preferably FERT3 and/or IFLC.
  • the at least one genetic marker is located in the region from about 0. 24014 M to about 0. 59988 M on the bovine chromosome BTA10. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA10 in the region flanked by and including the markers BMS528 and BM888.
  • the at least one genetic marker is selected from the group of markers shown in Table 7g.
  • the fertility trait affected by said genetic marker is preferably FERT3 and/or IFLC. Table 7g
  • the at least one genetic marker is located at the chromosomal position 0.1 1 1 M or in the region between microsatellite markers CSSM38 and BMS528 on the bovine chromosome BTA10.
  • the fertility trait affected by said genetic marker is preferably FERT3.
  • the at least one genetic marker is located at the chromosomal position 0.908 M or in the region between microsatellite markers BMS2641 and BMS614 on the bovine chromosome BTA10.
  • the fertility trait affected by said genetic marker is preferably IFLC
  • the at least one genetic marker is located on the bovine chromosome BTA1 1. In one specific embodiment of the present invention, the at least one genetic marker is located in the region from about 0.1944 M to about 1.2237 M on the bovine chromosome BTA1 1. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA1 1 in the region flanked by and including the microsatellite markers BM716 and HEL13.
  • the at least one genetic marker is predictive for fertility of a bovine subject. In a particular embodiment the at least one genetic marker is predictive for at least one trait indicative of fertility, as defined elsewhere herein. However, in a further embodiment the at least one genetic marker is predictive for any traits indicative of fertility.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the at least one genetic marker is detected by microsatellite genotyping using at least one oligonucleotide selected from the group consisting of SEQ ID NO: 213 to SEQ ID NO: 240, as shown in table 20.
  • the at least one genetic marker is located in a region flanked by and including any of the microsatellite markers selected from the group of markers shown in table 8a.
  • the at least one genetic marker is selected from the group of markers shown in Table 8a
  • the at least one genetic marker is located in the region from about 0.40481 M to about 1 .2237 M on the bovine chromosome BTA1 1 . In one embodiment the at least one genetic marker is located on the bovine chromosome BTA1 1 in the region flanked by and including the markers RM096 and HEL13.
  • the at least one genetic marker is selected from the group of markers shown in Table 8b. The fertility trait affected by said genetic marker is preferably ICF. Table 8b
  • the at least one genetic marker is located in the region from about 0.50312 M to about 1 .2237 M on the bovine chromosome BTA1 1 . In one embodiment the at least one genetic marker is located on the bovine chromosome BTA1 1 in the region flanked by and including the markers BM7169 and HEL13.
  • the at least one genetic marker is selected from the group of markers shown in Table 8c. The fertility trait affected by said genetic marker is preferably ICF. Table 8c
  • the at least one genetic marker is located in the region from about 0.73136 M to about 1 .2237 M on the bovine chromosome BTA1 1 . In one embodiment the at least one genetic marker is located on the bovine chromosome BTA1 1 in the region flanked by and including the markers TGLA58 and HEL13.
  • the at least one genetic marker is selected from the group of markers shown in Table 8d. The fertility trait affected by said genetic marker is preferably ICF. Table 8d
  • the at least one genetic marker is located in the region from about 0.65879 M to about 0.92179 M on the bovine chromosome BTA1 1 . In one embodiment the at least one genetic marker is located on the bovine chromosome BTA1 1 in the region flanked by and including the markers BMS1822 and HUJV174.
  • the at least one genetic marker is selected from the group of markers shown in Table 8e. The fertility trait affected by said genetic marker is preferably ICF Table 8e
  • the at least one genetic marker is located at the chromosomal position 0.925 M or in the region between microsatellite markers HUJV174 and TGLA436 on the bovine chromosome BTA1 1.
  • the fertility trait affected by said genetic marker is preferably ICF
  • the at least one genetic marker is located on the bovine chromosome BTA12. In one specific embodiment of the present invention, the at least one genetic marker is located in the region from about 0 M to about 1.08978 M on the bovine chromosome BTA12. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA12 in the region flanked by and including the microsatellite markers BMS410 and BMS2724.
  • the at least one genetic marker is predictive for fertility of a bovine subject. In a particular embodiment the at least one genetic marker is predictive for at least one trait indicative of fertility, as defined elsewhere herein. However, in a further embodiment the at least one genetic marker is predictive for any traits indicative of fertility.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the at least one genetic marker is detected by microsatellite genotyping using at least one oligonucleotide selected from the group consisting of SEQ ID NO: 241 to SEQ ID NO: 252, as shown in table 20.
  • the at least one genetic marker is located in a region flanked by and including any of the microsatellite markers selected from the group of markers shown in table 9a.
  • the at least one genetic marker is selected from the group of markers shown in Table 9a
  • the at least one genetic marker is located in the region from about 0.151 19 M to about 1 .01972 M on the bovine chromosome BTA12. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA12 in the region flanked by and including the markers BM6108 and BMS1316.
  • the at least one genetic marker is selected from the group of markers shown in Table 9b.
  • the fertility trait affected by said genetic marker is preferably NRRC
  • the at least one genetic marker is located in the region from about 0.151 19 M to about 0.6384 M on the bovine chromosome BTA12. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA12 in the region flanked by and including the markers BM6108 and BMS975. The at least one genetic marker is selected from the group of markers shown in Table 9c.
  • the fertility trait affected by said genetic marker is preferably NRRC
  • the at least one genetic marker is located in the region from about 0.151 19 M to about 0.50376 M on the bovine chromosome BTA12. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA12 in the region flanked by and including the markers BM6108 and BM860.
  • the at least one genetic marker is selected from the group of markers shown in Table 9d.
  • the fertility trait affected by said genetic marker is preferably NRRC
  • the at least one genetic marker is located at the chromosomal position 0.406 M or in the region between microsatellite markers BM6108 and BM860 on the bovine chromosome BTA12.
  • the fertility trait affected by said genetic marker is preferably NRRC
  • the at least one genetic marker is located on the bovine chromosome BTA13. In one specific embodiment of the present invention, the at least one genetic marker is located in the region from about 0.22997 M to about 1 M on the bovine chromosome BTA13. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA13 in the region flanked by and including the microsatellite markers BMS1742 and AGLA232.
  • the at least one genetic marker is located on the bovine chromosome BTA13 in the region flanked by and including the SNP markers BTA-33924-no-rs and BTA-33932- no-rs, or flanked by and including the SNP markers ARS-BFGL-NGS-1 10285 and ARS-BFGL-NGS-18039, or flanked by and including the SNP markers Hapmap58773- rs29015694 and ARS-BFGL-NGS-4795, or flanked by and including the SNP markers ARS-BFGL-NGS-109563and ARS-BFGL-NGS-1 14957.
  • the at least one genetic marker is predictive for fertility of a bovine subject.
  • the at least one genetic marker is predictive for at least one trait indicative of fertility, as defined elsewhere herein.
  • the at least one genetic marker is predictive for any traits indicative of fertility.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the at least one genetic marker is detected by microsatellite genotyping using at least one oligonucleotide selected from the group consisting of SEQ ID NO: 253 to SEQ ID NO: 264, as shown in table 20.
  • the at least one genetic marker is located in a region flanked by and including any of the microsatellite markers selected from the group of markers shown in table 10a.
  • the at least one genetic marker is selected from the group of markers shown in Table 10a
  • the at least one genetic marker is located in the region from about 0.4663 M to about 0.91379 M on the bovine chromosome BTA13. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA13 in the region flanked by and including the markers BM720 and AGLA232.
  • the at least one genetic marker is selected from the group of markers shown in Table 10b. The fertility trait affected by said genetic marker is preferably ICF. Table 10b
  • the at least one genetic marker is located in the region from about 0.62807 M to about 0.91379 M on the bovine chromosome BTA13. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA13 in the region flanked by and including the markers BM9248 and AGLA232. The at least one genetic marker is selected from the group of markers shown in Table 10c. The fertility trait affected by said genetic marker is preferably ICF.
  • the at least one genetic marker is located in the region from about 0.62807 M to about 0.80983 M on the bovine chromosome BTA13. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA13 in the region flanked by and including the markers BM9248 and BL1071 .
  • the at least one genetic marker is selected from the group of markers shown in Table 1 Od.
  • the fertility trait affected by said genetic marker is preferably ICF.
  • the at least one genetic marker is located in the region from about 0.80983 M to about 0.91379 M on the bovine chromosome BTA13. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA13 in the region flanked by and including the markers BL1071 and AGLA232. The at least one genetic marker is selected from the group of markers shown in Table 1 Oe. The fertility trait affected by said genetic marker is preferably ICF.
  • the at least one genetic marker is located at the chromosomal position 0.897 M or in the region between microsatellite markers BL1071 and AGLA232 on the bovine chromosome BTA13.
  • the fertility trait affected by said genetic marker is preferably ICF.
  • the at least one genetic marker is located on the bovine chromosome BTA14. In one specific embodiment of the present invention, the at least one genetic marker is located in the region from about 0.25 M to about 1.00016 M on the bovine chromosome BTA14. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA14 in the region flanked by and including the microsatellite markers RM180 and BL1036.
  • the at least one genetic marker is predictive for fertility of a bovine subject. In a particular embodiment the at least one genetic marker is predictive for at least one trait indicative of fertility, as defined elsewhere herein. However, in a further embodiment the at least one genetic marker is predictive for any traits indicative of fertility.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the at least one genetic marker is detected by microsatellite genotyping using at least one oligonucleotide selected from the group consisting of SEQ ID NO: 265 to SEQ ID NO: 284, as shown in table 20.
  • the at least one genetic marker is located in a region flanked by and including any of the microsatellite markers selected from the group of markers shown in table 1 1 a.
  • the at least one genetic marker is selected from the group of markers shown in Table 1 1 a
  • the at least one genetic marker is located in the region from about 0.3331 1 M to about 0.67671 M on the bovine chromosome BTA14. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA143 in the region flanked by and including the markers RM180 and BMS108. The at least one genetic marker is selected from the group of markers shown in Table 1 1 b. The fertility trait affected by said genetic marker is preferably FERT3.
  • the at least one genetic marker is located in the region from about 0.3331 1 M to about 0.45799 M on the bovine chromosome BTA14. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA14 in the region flanked by and including the markers RM180 and BM4630. The at least one genetic marker is selected from the group of markers shown in Table 1 1c. The fertility trait affected by said genetic marker is preferably FERT3.
  • the at least one genetic marker is located in the region from about 0.3331 1 M to about 0.43633 M on the bovine chromosome BTA14. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA14 in the region flanked by and including the markers RM180 and RM01 1 . The at least one genetic marker is selected from the group of markers shown in Table 1 1 d. The fertility trait affected by said genetic marker is preferably FERT3.
  • the at least one genetic marker is located at the chromosomal position 0.333 M or is genetically coupled to the microsatellite marker RM180 on the bovine chromosome BTA14.
  • the fertility trait affected by said genetic marker is preferably FERT3.
  • the at least one genetic marker is located on the bovine chromosome BTA15. In one specific embodiment of the present invention, the at least one genetic marker is located in the region from about 0.09415 M to about 1.2 M on the bovine chromosome BTA15. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA15 in the region flanked by and including the microsatellite markers BR3510 and BMS429.
  • the at least one genetic marker is predictive for fertility of a bovine subject. In a particular embodiment the at least one genetic marker is predictive for at least one trait indicative of fertility, as defined elsewhere herein. However, in a further embodiment the at least one genetic marker is predictive for any traits indicative of fertility.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the at least one genetic marker is detected by microsatellite genotyping using at least one oligonucleotide selected from the group consisting of SEQ ID NO: 285 to SEQ ID NO: 318, as shown in table 20.
  • the at least one genetic marker is located in a region flanked by and including any of the microsatellite markers selected from the group of markers shown in table 12a.
  • the at least one genetic marker is selected from the group of markers shown in Table 12a
  • the at least one genetic marker is located in the region from about 0.51918 M to about 1 .09753 M on the bovine chromosome BTA15. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA15 in the region flanked by and including the markers DIK1 106 and BMS429. The at least one genetic marker is selected from the group of markers shown in Table 12b. The fertility trait affected by said genetic marker is preferably FERT3. Table 12b
  • the at least one genetic marker is located in the region from about 0.74083 M to about 1 .09753 M on the bovine chromosome BTA15. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA15 in the region flanked by and including the markers DIK4850 and BMS429. The at least one genetic marker is selected from the group of markers shown in Table 12c. The fertility trait affected by said genetic marker is preferably FERT3. Table 12c
  • the at least one genetic marker is located in the region from about 0.77947 M to about 1 .04998 M on the bovine chromosome BTA15. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA15 in the region flanked by and including the markers DIK2768 and BMS927. The at least one genetic marker is selected from the group of markers shown in Table 12d. The fertility trait affected by said genetic marker is preferably FERT3.
  • the at least one genetic marker is located in the region from about 0.77947 M to about 1 .04998 M on the bovine chromosome BTA15. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA15 in the region flanked by and including the markers DIK2768 and BMS927. The at least one genetic marker is selected from the group of markers shown in Table 12e. The fertility trait affected by said genetic marker is preferably FERT3.
  • the at least one genetic marker is located at the chromosomal position 0.983 M or in the region between microsatellite markers BMS820 and BMS927 on the bovine chromosome BTA15.
  • the fertility trait affected by said genetic marker is preferably FERT3.
  • the at least one genetic marker is located on the bovine chromosome BTA17. In one specific embodiment of the present invention, the at least one genetic marker is located in the region from about 0.0241 1 M to about 1 M on the bovine chromosome BTA17. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA17 in the region flanked by and including the microsatellite markers RM156 and BM1233.
  • the at least one genetic marker is located on the bovine chromosome BTA17 in the region flanked by and including the SNP markers ARS-BFGL-NGS-40557 and Hapmap56175- rs29013219, or flanked by and including the SNP markers Hapmap48324-BTA-41405 and UA-IFASA-5513.
  • the at least one genetic marker is predictive for fertility of a bovine subject.
  • the at least one genetic marker is predictive for at least one trait indicative of fertility, as defined elsewhere herein.
  • the at least one genetic marker is predictive for any traits indicative of fertility.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the at least one genetic marker is detected by microsatellite genotyping using at least one oligonucleotide selected from the group consisting of SEQ ID NO: 319 to SEQ ID NO: 340, as shown in table 20.
  • the at least one genetic marker is located in a region flanked by and including any of the microsatellite markers selected from the group of markers shown in table 13a.
  • the at least one genetic marker is selected from the group of markers shown in Table 13a
  • the at least one genetic marker is located in the region from about 0.38273 M to about 0.92066 M on the bovine chromosome BTA17. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA17 in the region flanked by and including the markers CSSM9 and BM1233. The at least one genetic marker is selected from the group of markers shown in Table 13b. The fertility trait affected by said genetic marker is preferably FERT2. Table 13b
  • the at least one genetic marker is located in the region from about 0.92066 M to about 0.4679 M on the bovine chromosome BTA17. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA17 in the region flanked by and including the markers ILSTS023 and BM1233. The at least one genetic marker is selected from the group of markers shown in Table 13c. The fertility trait affected by said genetic marker is preferably FERT2. Table 13c
  • the at least one genetic marker is located in the region from about 0.59594 M to about 0.92066 M on the bovine chromosome BTA17. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA17 in the region flanked by and including the markers IDVGA-40 and BM1233. The at least one genetic marker is selected from the group of markers shown in Table 13d. The fertility trait affected by said genetic marker is preferably FERT2. Table 13d
  • the at least one genetic marker is located at the chromosomal position 0.863 M or in the region between microsatellite markers BM1862 and BM1233 on the bovine chromosome BTA17.
  • the fertility trait affected by said genetic marker is preferably FERT2.
  • the at least one genetic marker is located on the bovine chromosome BTA20. In one specific embodiment of the present invention, the at least one genetic marker is located in the region from about 0 M to about 0.77091 M on the bovine chromosome BTA20. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA20 in the region flanked by and including the microsatellite markers BM3517 and UWCA26.
  • the at least one genetic marker is located on the bovine chromosome BTA20 in the region flanked by and including the SNP markers BTA-1 15956-no-rs and Hapmap41280-BTA-50090, or flanked by and including the SNP markers Hapmap39724-BTA-122305 and Hapmap52690-ss46526609, or flanked by and including the SNP markers BTB-01263022 and BTB-00788976, or flanked by and including the SNP markers Hapmap51375-BTA-105537 and ARS-BFGL-NGS-38032.
  • the at least one genetic marker is predictive for fertility of a bovine subject.
  • the at least one genetic marker is predictive for at least one trait indicative of fertility, as defined elsewhere herein.
  • the at least one genetic marker is predictive for any traits indicative of fertility.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the at least one genetic marker is detected by microsatellite genotyping using at least one oligonucleotide selected from the group consisting of SEQ ID NO: 341 to SEQ ID NO: 360, as shown in table 20.
  • the at least one genetic marker is located in a region flanked by and including any of the microsatellite markers selected from the group of markers shown in table 14a.
  • the at least one genetic marker is selected from the group of markers shown in Table 14a
  • the at least one genetic marker is located in the region from about 0.19144 M to about 0.77091 M on the bovine chromosome BTA20. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA20 in the region flanked by and including the markers BMS1282 and UWCA26. The at least one genetic marker is selected from the group of markers shown in Table 14b. The fertility trait affected by said genetic marker is preferably FERT2 and/or HST.
  • the at least one genetic marker is located in the region from about 0.19144 M to about 0.71809 M on the bovine chromosome BTA20. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA20 in the region flanked by and including the markers BMS1282 and BM5004. The at least one genetic marker is selected from the group of markers shown in Table 14c. The fertility trait affected by said genetic marker is preferably FERT2 and/or HST. Table 14c
  • the at least one genetic marker is located in the region from about 0.31866 M to about 0.71809 M on the bovine chromosome BTA20. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA20 in the region flanked by and including the markers TGLA126 and BM5004. The at least one genetic marker is selected from the group of markers shown in Table 14d. The fertility trait affected by said genetic marker is preferably FERT2 and/or HST. Table 14d
  • the at least one genetic marker is located in the region from about 0.49727 M to about 0.60079 M on the bovine chromosome BTA20. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA20 in the region flanked by and including the markers BMS2361 and BMS703.
  • the at least one genetic marker is selected from the group of markers shown in Table 14e.
  • the fertility trait affected by said genetic marker is preferably FERT2 and/or HST. Table 14e
  • the at least one genetic marker is located at the chromosomal position 0.643 M or in the region between microsatellite markers BMS703 and BM5004 on the bovine chromosome BTA20.
  • the fertility trait affected by said genetic marker is preferably FERT2.
  • the at least one genetic marker is located at the chromosomal position 0.431 M or in the region between microsatellite markers TGLA126 and BMS2361 on the bovine chromosome BTA20.
  • the fertility trait affected by said genetic marker is preferably HST.
  • the at least one genetic marker is located on the bovine chromosome BTA1 . In one specific embodiment of the present invention, the at least one genetic marker is located in the region from about 0 M to about 0.9 M on the bovine chromosome BTA1 . In one embodiment the at least one genetic marker is located on the bovine chromosome BTA1 in the region flanked by and including the microsatellite markers CSSM26 and BM4102.
  • the at least one genetic marker is predictive for fertility of a bovine subject. In a particular embodiment the at least one genetic marker is predictive for at least one trait indicative of fertility, as defined elsewhere herein. However, in a further embodiment the at least one genetic marker is predictive for any traits indicative of fertility.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the at least one genetic marker is detected by microsatellite genotyping using at least one oligonucleotide selected from the group consisting of SEQ ID NO: 361 to SEQ ID NO: 372, as shown in table 20.
  • the at least one genetic marker is located in a region flanked by and including any of the microsatellite markers selected from the group of markers shown in table 15a.
  • the at least one genetic marker is selected from the group of markers shown in Table 15a Table 15a
  • the at least one genetic marker is located in the region from about 0 M to about 0.47066 M on the bovine chromosome BTA22. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA22 in the region flanked by and including the markers CSSM26 and BM3628.
  • the at least one genetic marker is selected from the group of markers shown in Table 15b.
  • the fertility trait affected by said genetic marker is preferably FERT2 and/or NRRH. Table 15b
  • the at least one genetic marker is located in the region from about 0 M to about 0.8293 M on the bovine chromosome BTA22. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA22 in the region flanked by and including the markers CSSM26 and BM4102.
  • the at least one genetic marker is selected from the group of markers shown in Table 15c.
  • the fertility trait affected by said genetic marker is preferably FERT2 and/or NRRH. Table 15c
  • the at least one genetic marker is located in the region from about 0.02864 M to about 0.47066 M on the bovine chromosome BTA22. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA22 in the region flanked by and including the markers INRA026 and BM3628.
  • the at least one genetic marker is selected from the group of markers shown in Table 15d.
  • the fertility trait affected by said genetic marker is preferably FERT2 and/or NRRH. Table 15d
  • the at least one genetic marker is located in the region from about 0.47066 M to about 0.8293 M on the bovine chromosome BTA22. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA22 in the region flanked by and including the markers BM3628 and BM4102.
  • the at least one genetic marker is selected from the group of markers shown in Table 15e.
  • the fertility trait affected by said genetic marker is preferably FERT2 and/or NRRH. Table 15e
  • the at least one genetic marker is located at the chromosomal position 0.83 M or is genetically coupled to the microsatellite marker BM4102 on the bovine chromosome BTA22.
  • the fertility trait affected by said genetic marker is preferably FERT2
  • the at least one genetic marker is located at the chromosomal position 0.431 M or in the region between microsatellite markers BM1558 and BM3628 on the bovine chromosome BTA22.
  • the fertility trait affected by said genetic marker is preferably NRRH.
  • the at least one genetic marker is located on the bovine chromosome BTA24. In one specific embodiment of the present invention, the at least one genetic marker is located in the region from about O M to about 0.65928 M on the bovine chromosome BTA24. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA24 in the region flanked by and including the microsatellite markers BMS917 and BMS3024.
  • the at least one genetic marker is located on the bovine chromosome BTA24 in the region flanked by and including the SNP markers BTB-01485274 and BTB-00884791 , or flanked by and including the SNP markers BTB-00886719 and ARS-BFGL-NGS-1 1 1285, or flanked by and including the SNP markers Hapmap56316-rs29025240 and ARS-BFGL-NGS-18151.
  • the at least one genetic marker is predictive for fertility of a bovine subject.
  • the at least one genetic marker is predictive for at least one trait indicative of fertility, as defined elsewhere herein.
  • the at least one genetic marker is predictive for any traits indicative of fertility.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the at least one genetic marker is detected by microsatellite genotyping using at least one oligonucleotide selected from the group consisting of SEQ ID NO: 373 to SEQ ID NO: 400, as shown in table 20.
  • the at least one genetic marker is located in a region flanked by and including any of the microsatellite markers selected from the group of markers shown in table 16a.
  • the at least one genetic marker is selected from the group of markers shown in Table 16a
  • the at least one genetic marker is located in the region from about 0.06249 M to about 0.19285 M on the bovine chromosome BTA24. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA24 in the region flanked by and including the markers BMS917 and BM7228.
  • the at least one genetic marker is selected from the group of markers shown in Table 16b.
  • the fertility trait affected by said genetic marker is preferably AISC and/or ICF. Table 16b
  • the at least one genetic marker is located in the region from about 0.06249 M to about 0.1 1 1 1 M on the bovine chromosome BTA24. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA24 in the region flanked by and including the markers BMS917 and TGLA351 .
  • the at least one genetic marker is selected from the group of markers shown in Table 16c.
  • the fertility trait affected by said genetic marker is preferably AISC and/or ICF. Table 16c
  • the at least one genetic marker is located in the region from about 0.1 1 1 1 M to about 0.23688 M on the bovine chromosome BTA24. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA24 in the region flanked by and including the markers TGLA351 and BMS2270.
  • the at least one genetic marker is selected from the group of markers shown in Table 16d.
  • the fertility trait affected by said genetic marker is preferably AISC and/or ICF. Table 16d
  • the at least one genetic marker is located in the region from about 0.20562 M to about 0.23688 M on the bovine chromosome BTA24. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA24 in the region flanked by and including the markers CSSM23 and BMS2270. The at least one genetic marker is selected from the group of markers shown in Table 16e.
  • the fertility trait affected by said genetic marker is preferably AISC and/or ICF.
  • the at least one genetic marker is located at the chromosomal position 0.062 M or is genetically coupled to the microsatellite marker BMS917 on the bovine chromosome BTA24.
  • the fertility trait affected by said genetic marker is preferably AISC
  • the at least one genetic marker is located at the chromosomal position 0.304 M or in the region between microsatellite markers ILSTS065 and BMS1862 on the bovine chromosome BTA24.
  • the fertility trait affected by said genetic marker is preferably ICF
  • the at least one genetic marker is located on the bovine chromosome BTA25. In one specific embodiment of the present invention, the at least one genetic marker is located in the region from about 0 M to about 0.61669 M on the bovine chromosome BTA25. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA25 in the region flanked by and including the microsatellite markers ILSTS102 and AF5.
  • the at least one genetic marker is predictive for fertility of a bovine subject. In a particular embodiment the at least one genetic marker is predictive for at least one trait indicative of fertility, as defined elsewhere herein. However, in a further embodiment the at least one genetic marker is predictive for any traits indicative of fertility.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the at least one genetic marker is detected by microsatellite genotyping using at least one oligonucleotide selected from the group consisting of SEQ ID NO: 401 to SEQ ID NO: 412, as shown in table 20.
  • the at least one genetic marker is located in a region flanked by and including any of the microsatellite markers selected from the group of markers shown in table 17a.
  • the at least one genetic marker is selected from the group of markers shown in Table 17a
  • the at least one genetic marker is located in the region from about 0.07199 M to about 0.46438 M on the bovine chromosome BTA25. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA25 in the region flanked by and including the markers ILSTS102 and BMS1353.
  • the at least one genetic marker is selected from the group of markers shown in Table 17b. The fertility trait affected by said genetic marker is preferably NRRH. Table 17b
  • the at least one genetic marker is located in the region from about 0.07199 M to about 0.3332 M on the bovine chromosome BTA25. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA25 in the region flanked by and including the markers ILSTS102 and ILSTS046.
  • the at least one genetic marker is selected from the group of markers shown in Table 17c. The fertility trait affected by said genetic marker is preferably NRRH. Table 17c
  • the at least one genetic marker is located in the region from about 0.07199 M to about 0.22636 M on the bovine chromosome BTA25. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA25 in the region flanked by and including the markers ILSTS102 and BMS2843.
  • the at least one genetic marker is selected from the group of markers shown in Table 17d. The fertility trait affected by said genetic marker is preferably NRRH. Table 17d
  • the at least one genetic marker is located at the chromosomal position 0.173 M or in the region between microsatellite markers ILSTS102 and BMS2843 on the bovine chromosome BTA25.
  • the fertility trait affected by said genetic marker is preferably NRRH.
  • the at least one genetic marker is located on the bovine chromosome BTA26. In one specific embodiment of the present invention, the at least one genetic marker is located in the region from about 0.02839 M to about 0.66763 M on the bovine chromosome BTA26. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA26 in the region flanked by and including the microsatellite markers BMS651 and BM7237.
  • the at least one genetic marker is predictive for fertility of a bovine subject. In a particular embodiment the at least one genetic marker is predictive for at least one trait indicative of fertility, as defined elsewhere herein. However, in a further embodiment the at least one genetic marker is predictive for any traits indicative of fertility.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • the at least one genetic marker is detected by microsatellite genotyping using at least one oligonucleotide selected from the group consisting of SEQ ID NO: 413 to SEQ ID NO: 432, as shown in table 20.
  • the at least one genetic marker is located in a region flanked by and including any of the microsatellite markers selected from the group of markers shown in table 18a.
  • the at least one genetic marker is selected from the group of markers shown in Table 18a Table 18a
  • the at least one genetic marker is located in the region from about 0.02839 M to about 0.53094 M on the bovine chromosome BTA26. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA26 in the region flanked by and including the markers BMS651 and IDVGA-59.
  • the at least one genetic marker is selected from the group of markers shown in Table 18b.
  • the fertility trait affected by said genetic marker is preferably FERT1 and/or NRRH and/or IFLC. Table 18b
  • the at least one genetic marker is located in the region from about 0.22862 M to about 0.53477 M on the bovine chromosome BTA26. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA26 in the region flanked by and including the markers HEL1 1 and BMS882.
  • the at least one genetic marker is selected from the group of markers shown in Table 18c.
  • the fertility trait affected by said genetic marker is preferably FERT1 and/or NRRH and/or IFLC.
  • the at least one genetic marker is located in the region from about 0.37635 M to about 0.60476 M on the bovine chromosome BTA26. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA26 in the region flanked by and including the markers RM026 and BM804. The at least one genetic marker is selected from the group of markers shown in Table 18d.
  • the fertility trait affected by said genetic marker is preferably FERT1 and/or NRRH and/or IFLC.
  • the at least one genetic marker is located in the region from about 0.4322 M to about 0.66763 M on the bovine chromosome BTA26. In one embodiment the at least one genetic marker is located on the bovine chromosome BTA26 in the region flanked by and including the markers RME40 and BM7237.
  • the at least one genetic marker is selected from the group of markers shown in Table 18e.
  • the fertility trait affected by said genetic marker is preferably FERT1 and/or NRRH and/or IFLC. Table 18e
  • the at least one genetic marker is located at the chromosomal position 0.317 M or in the region between microsatellite markers BMS332 and RM026 on the bovine chromosome BTA26.
  • the fertility trait affected by said genetic marker is preferably FERT1.
  • the at least one genetic marker is located at the chromosomal position 0.537 M or in the region between microsatellite markers BMS882 and BM804 on the bovine chromosome BTA26.
  • the fertility trait affected by said genetic marker is preferably IFLC.
  • the at least one genetic marker is located at the chromosomal position 0.457 M or in the region between microsatellite markers RME40 and IDVGA-59 on the bovine chromosome BTA26.
  • the fertility trait affected by said genetic marker is preferably NRRH.
  • BTA29 In one embodiment of the present invention, the at least one genetic marker is located on the bovine chromosome BTA29. In one specific embodiment of the present invention, the at least one genetic marker is located in the region from about 0 Morgan (M) to about 1.6 M on the bovine chromosome BTA29.
  • the at least one genetic marker is located on the bovine chromosome BTA29 in the region flanked by and including the SNP markers ARS-BFGL-NGS-1 17865 and BTA-66429-no-rs, or flanked by and including the SNP markers ARS-BFGL-NGS-1 12101 and ARS-BFGL- NGS-1 12101 , or flanked by and including the SNP markers ARS-BFGL-NGS-24769 and ARS-BFGL-NGS-90760.
  • the at least one genetic marker is predictive for fertility of a bovine subject.
  • the at least one genetic marker is predictive for at least one trait indicative of fertility, as defined elsewhere herein.
  • the at least one genetic marker is predictive for any traits indicative of fertility.
  • the genetic marker may be identified in a bovine subject by microsatellite or SNP genotyping.
  • a number of SNP marker alleles and/or combinations thereof are predictive of fertility in a bovine subject according to the present invention.
  • the at least one genetic marker such as two or more genetic marker alleles, associated with at least one trait indicative of fertility in a bovine subject is selected from the group of SNPs set out in table 26, and/or tables 27a-k and/or tables 18a-m.
  • a specific combination of genetic marker alleles such as a specific combination of said SNP alleles, are associated with at least one trait indicative of fertility of a bovine subject and/or off-spring therefrom.
  • One aspect of the present invention relates to a method of determining fertility in a bovine subject, comprising detecting in a sample from said bovine subject the presence or absence of at least one, such as two or more genetic marker alleles that are associated with at least one trait indicative of fertility of said bovine subject and/or offspring therefrom.
  • the two or more genetic marker alleles are single nucleotide polymorphisms selected from the group consisting of
  • BFGL-BAC-32896 ARS-BFGL-BAC-32896, ARS-BFGL-BAC-32896, ARS-BFGL-NGS-1 14712, BTA-1 10335- no-rs, Hapmap48975-BTA-99363, Hapmap48975-BTA-99363, ARS-BFGL-NGS- 94761 , ARS-BFGL-NGS-18743, Hapmap47174-BTA-1 10289, BTB-01914655, BTB- 01914655, ARS-BFGL-NGS-63947, ARS-BFGL-NGS-63947, Hapmap36459- SCAFFOLD9563_462, Hapmap36459-SCAFFOLD9563_462, ARS-BFGL-NGS-
  • Hapmap58408-rs29020693 ARS-BFGL-NGS-26218, ARS-BFGL-NGS-26218, ARS- BFGL-NGS-26218, ARS-BFGL-NGS-26218, BTB-00202348, BTB- 00202376Hapmap55237-rs29010308, BTA-72966-no-rs, Hapmap53250-rs29027200, ARS-BFGL-NGS-4312, ARS-BFGL-NGS-100971 , ARS-BFGL-NGS-90297, ARS- BFGL-NGS-1 12542, ARS-BFGL-NGS-1 12542, UA-IFASA-5621 , BTA-73413-no-rs, Hapmap43550-BTA-28784, Hapmap38042-BTA-73420, Hapmap52717-rs29026394, ARS-BFGL-NGS-98210, BTA-983
  • ARS-BFGL-NGS-1 10387 ARS-BFGL-NGS-1 10387, ARS-BFGL-NGS-1 10387, ARS-BFGL-NGS-1 10387, ARS-BFGL-NGS-1 10387, ARS-BFGL-NGS-39007, ARS-BFGL- NGS-39007, ARS-BFGL-NGS-106716, Hapmap29808-BTA-128693, ARS-BFGL-NGS- 1 14957ARS-BFGL-NGS-40557, Hapmap54444-rs29026028, Hapmap56175- rs29013219, Hapmap48324-BTA-41405, ARS-BFGL-NGS-23944, ARS-BFGL-NGS- 102559, BTA-41935-no-rs, UA-IFASA-5513BTA-1 15956-no-rs, BTA-1 15956-no-rs, BTA-986
  • ARS-BFGL-NGS-18151 ARS-BFGL-NGS-1 17865, BTA-66429-no-rs, ARS-BFGL-NGS- 1 12101 , ARS-BFGL-NGS-1 12101 , ARS-BFGL-NGS-1 12101 ARS-BFGL-NGS-24769, ARS-BFGL-NGS-56408, ARS-BFGL-NGS-33015, and/or ARS-BFGL-NGS-90760, and/or a genetic marker allele, which is genetically coupled to any of said single nucleotide polymorphisms.
  • the SNP markers are selected from the group consisting of Hapmap60827-rs29019866, ARS-BFGL-NGS-40979, Hapmap47854-BTA-1 19090, ARS-BFGL-NGS-1 14679, Hapmap43841 -BTA-34601 , Hapmap43407-BTA-93630, Hapmap43407-BTA-93630, BTB-01536946, ARS-BFGL-NGS-31952, Hapmap44123- BTA-70017, Hapmap50451 -BTA-70851 , Hapmap58408-rs29020693, ARS-BFGL- NGS-106105, ARS-BFGL-NGS-1461 , ARS-BFGL-NGS-106105, ARS-BFGL-NGS- 1461 , ARS-BFGL-NGS-106105, ARS-BFGL-NGS-1461 , ARS-BFGL-NGS-1 18182, Ha
  • any genetic marker which is genetically coupled to a genetic marker of the present invention, is within the scope of the present invention.
  • genetic markers which are located within a distance of 5 to 10 cM is expected to be genetically coupled in bovidae.
  • a which is located within 10 cM, such as 9, 8, 7, 6, 5, 4, 3, 2, or 1 cM upstream or downstream of any genetic marker mentioned herein, including any SNP marker mentioned herein is within the scope of the present invention. Therefore, the method of determining fertility according to the present invention also comprise detecting any other genetic marker allele, which is genetically coupled to any of said single nucleotide polymorphisms, as described above.
  • genetic markers which are genetically coupled to an SNP marker of the methods and kits of the present invention are in one embodiment located within 10 cM, such as within 9, such as within 8, such as within 7, such as within 6, such as within 5 cM, such as within 4, such as within 3, for example within 2, such as within 1 cM upstream or downstream of said SNP.
  • the present invention comprises a method of determining fertility, wherein a specific combination of genetic marker alleles, e.g. a specific combination of SNPs is detected in a sample from a bovine subject.
  • the specific combination comprises two or more genetic markers, such as two or more SNPs, such as at least 3, 4, 5, 6, 7, 8, 9, such as at least 10, such as at least 15, such as at least 20, such as at least 25, such as at least 30, such as at least 35, such as at least 40, such as at least 45, such as at least 50, such as at least 55, such as at least 60, such as at least 65, such as at least 70, such as at least 75, such as at least 80, such as at least 85, such as at least 90, such as at least 95, such as at least 100 SNPs, such as at least 200, such as at least 300, such as at least 400, such as at least 500, such as at least 600, such as at least 700 SNPs, such as at least 800, such as at least 900, such as at least 1000,
  • the SNP markers of the present invention are in one embodiment selected from the group consisting of Hapmap60827-rs29019866, ARS-BFGL-NGS-40979, Hapmap47854-BTA-1 19090, ARS-BFGL-NGS-1 14679, Hapmap43841 -BTA-34601 , Hapmap43407-BTA-93630, Hapmap43407-BTA-93630, BTB-01536946, ARS-BFGL- NGS-31952, Hapmap44123-BTA-70017, Hapmap50451 -BTA-70851 , Hapmap58408- rs29020693, ARS-BFGL-NGS-106105, ARS-BFGL-NGS-1461 , ARS-BFGL-NGS- 106105, ARS-BFGL-NGS-1461 , ARS-BFGL-NGS-106105, ARS-BFGL-NGS-1461 , ARS-BFGL-NGS-106
  • SNP markers mentioned above is indicative of increased or reduced fertility.
  • the effect of multiple SNP markers may be combined to increase the precision of predicting fertility according to the present invention.
  • the effect of specific SNP marker alleles in respect of different fertility traits are disclosed in table 26.
  • the Hapmap47854-BTA-1 19090 SNP allele carrying a G at position 148765346 is associated with decreased fertility according to the present invention.
  • the Hapmap47854-BTA-1 19090 SNP allele carrying an A at position 148765346 is associated with increased fertility according to the present invention.
  • the SNP markers mentioned herein are predictive of fertility in a bovine subject or offspring therefrom.
  • the SNP markers are associated with a number of fertility traits, as mentioned herein below.
  • the at least one genetic marker such as a combination of two or more genetic markers indicative of fertility in a bovine subject according to the present invention is associated with Number of inseminations/ conception (cow), wherein said genetic marker is an SNP selected from the group consisting of ARS-BFGL-NGS- 106105, Hapmap50451 -BTA-70851 , Hapmap58408-rs29020693, ARS-BFGL-NGS- 21335, Hapmap52259-rs29019756, BTB-01347067, ARS-BFGL-NGS-82228,
  • Hapmap46988-BTA-34591 Hapmap51375-BTA-105537, Hapmap27428-BTA-151920, ARS-BFGL-NGS-1 19491 , ARS-BFGL-NGS-38032, BTA-62184-no-rs, Hapmap42034- BTA-100462, ARS-BFGL-NGS-10941 , BTB-01984646, ARS-BFGL-NGS-1 13339, BTB- 01066167, Hapmap43361 -BTA-80384, Hapmap47854-BTA-1 19090, Hapmap53206- rs29014774, ARS-BFGL-NGS-1 16953, ARS-BFGL-NGS-80736, ARS-BFGL-NGS- 18246, and/or ARS-BFGL-NGS-84473.
  • the genetic marker is an SNP selected from the group consisting of ARS-BFGL-NGS-106105, Hapmap50451 -BTA-70851 , Hapmap58408- rs29020693, ARS-BFGL-NGS-21335, and/or Hapmap52259-rs29019756, such as ARS-BFGL-NGS-106105, and/or Hapmap50451 -BTA-70851.
  • the genetic marker is an SNP selected from the group consisting of Hapmap36459-SCAFFOLD9563_462, Hapmap60827-rs29019866, Hapmap47854-BTA-1 19090, ARS-BFGL-NGS-40979, BTB-00614426, Hapmap50451 - BTA-70851 , Hapmap58408-rs29020693, ARS-BFGL-NGS-1 12542, ARS-BFGL-NGS- 106105, Hapmap27428-BTA-151920, BTA-122483-no-rs, BTB-01984646, ARS-BFGL- NGS-84473, ARS-BFGL-BAC-14182, Hapmap43361 -BTA-80384, BTB-00525367, Hapmap41280-BTA-50090, ARS-BFGL-NGS-18037, Hapmap51375-BTA-105537, ARS-BFGL-
  • the at least one genetic marker such as a combination of two or more genetic markers indicative of fertility in a bovine subject according to the present invention is associated with Number of inseminations/ conception(heifer), wherein said genetic marker is an SNP selected from the group consisting of ARS-BFGL-NGS- 10234, ARS-BFGL-NGS-23616, ARS-BFGL-NGS-99096, ARS-BFGL-BAC-20862, ARS-BFGL-NGS-67978, ARS-BFGL-NGS-105944, ARS-BFGL-NGS-102802, ARS- BFGL-NGS-1 18366, and/or Hapmap60827-rs29019866.
  • SNP SNP selected from the group consisting of ARS-BFGL-NGS- 10234, ARS-BFGL-NGS-23616, ARS-BFGL-NGS-99096, ARS-BFGL-BAC-20862, ARS-BFGL-NGS-67978, ARS-BF
  • the genetic marker is an SNP selected from the group consisting of ARS-BFGL-NGS-10234, ARS-BFGL-NGS-23616, ARS-BFGL-NGS- 99096, ARS-BFGL-BAC-20862, and/or ARS-BFGL-NGS-67978, such as ARS-BFGL- NGS-10234, and/or ARS-BFGL-NGS-23616.
  • the at least one genetic marker such as a combination of two or more genetic markers indicative of fertility in a bovine subject according to the present invention is associated with Fertility treatment (1 st lactation), wherein said genetic marker is an SNP selected from the group consisting of ARS-BFGL-NGS-5478, ARS- BFGL-NGS-5139, ARS-BFGL-NGS-103549, ARS-BFGL-NGS-91501 , and/or BTA- 105966-no-rs
  • the genetic marker is an SNP selected from the group consisting of ARS-BFGL-NGS-5478, ARS-BFGL-NGS-5139, and/or ARS-BFGL-NGS- 103549, such as ARS-BFGL-NGS-5478, and/or ARS-BFGL-NGS-5139.
  • the genetic marker is an SNP selected from the group consisting of BTB-01839901 , BTB-00139072, Hapmap52717-rs29026394, ARS-BFGL- NGS-14492, ARS-BFGL-NGS-5139, ARS-BFGL-NGS-101923, Hapmap54444- rs29026028, Hapmap52690-ss46526609, BTB-00788976, and/or BTB-00887328.
  • the at least one genetic marker such as a combination of two or more genetic markers indicative of fertility in a bovine subject according to the present invention is associated with Fertility treatment (2nd lactation), wherein said genetic marker is an SNP selected from the group consisting of Hapmap51453-BTA-45251 , and/or BTA-58720-no-rs.
  • the genetic marker is an SNP selected from the group consisting of BTB-01933332, ARS-BFGL-NGS-40451 , ARS-BFGL-NGS-1 15388, Hapmap45550-BTA-32092, ARS-BFGL-NGS-4795, Hapmap48297-BTA-33286, and/or BTB-01263022.
  • the at least one genetic marker such as a combination of two or more genetic markers indicative of fertility in a bovine subject according to the present invention is associated with Fertility treatment (3rd lactation), wherein said genetic marker is an SNP selected from the group consisting of ARS-BFGL-NGS-152, BTB- 01592826, BTB-01565771 , BTA-98399-no-rs, Hapmap60219-rs29009655, ARS-BFGL- NGS-1 17446, BTB-01970848, BTA-33924-no-rs, ARS-BFGL-NGS-1 1 1603, Hapmap41280-BTA-50090, ARS-BFGL-NGS-1 1 1285, and/or ARS-BFGL-NGS-33015.
  • the genetic marker is the SNP Hapmap51453-BTA-45251. Examples of specific alleles and their effects on fertility are provided in the table below. Table 18g
  • the at least one genetic marker such as a combination of two or more genetic markers indicative of fertility in a bovine subject according to the present invention is associated with Fertility index, wherein said genetic marker is an SNP selected from the group consisting of ARS-BFGL-NGS-106105, ARS-BFGL-BAC- 13827, ARS-BFGL-BAC-15431 , Hapmap31855-BTA-17995, ARS-BFGL-NGS-3967, Hapmap60827-rs29019866, Hapmap58408-rs29020693, ARS-BFGL-NGS-79186, ARS-BFGL-NGS-2697, BTB-00092589, ARS-BFGL-NGS-3965, Hapmap48975-BTA- 99363, BTA-90428-no-rs, H apmap44444- BTA- 1 15434, Hapmap38032-BTA-37826, ARS-BFGL-NGS-1 1818
  • the genetic marker is an SNP selected from the group consisting of ARS-BFGL-NGS-106105, ARS-BFGL-BAC-13827, ARS-BFGL-BAC- 15431 , Hapmap31855-BTA-17995, and/or ARS-BFGL-NGS-3967, such as ARS-BFGL- NGS-106105, or ARS-BFGL-BAC-13827.
  • the genetic marker is an SNP selected from the group consisting of BTA-1 14651 -no-rs, Hapmap60827-rs29019866, Hapmap47854-BTA- 1 19090, ARS-BFGL-NGS-40979, BTB-00181232, Hapmap58408-rs29020693, ARS- BFGL-NGS-100971 , ARS-BFGL-NGS-106105, ARS-BFGL-NGS-2697, BTA-10392-no- rs, ARS-BFGL-NGS-3967, Hapmap27428-BTA-151920, Hapmap34648- BES8_Contig530_743, BTB-01984646, ARS-BFGL-NGS-84473, ARS-BFGL-BAC- 15431 , Hapmap43361 -BTA-80384, ARS-BFGL-NGS-55024, ARS-BFGL-NGS-104930
  • the at least one genetic marker such as a combination of two or more genetic markers indicative of fertility in a bovine subject according to the present invention is associated with Heat strength (heifer), wherein said genetic marker is an
  • SNP selected from the group consisting of ARS-BFGL-NGS-17085, Hapmap58028-
  • the genetic marker is the SNP ARS-BFGL-NGS-17085, and/or Hapmap58028-ss46526484,
  • the at least one genetic marker such as a combination of two or more genetic markers indicative of fertility in a bovine subject according to the present invention is associated with Interval between calving to 1 st insemination, wherein said genetic marker is an SNP selected from the group consisting of ARS-BFGL-NGS- 60179, ARS-BFGL-NGS-100433, BTA-41935-no-rs, ARS-BFGL-NGS-57955, BTA- 68535-no-rs, Hapmap54222-rs29017183, Hapmap48462-BTA-77136, ARS-BFGL- NGS-62628, ARS-BFGL-NGS-95516, ARS-BFGL-NGS-98210, BTA-84106-no-rs, Hapmap41756-BTA-1 15061 , BTB-01395754, ARS-BFGL-NGS-7020, Hapmap50462- BTA-76734, BTA-55154-
  • SNP
  • the genetic marker is an SNP selected from the group consisting of ARS-BFGL-NGS-60179, ARS-BFGL-NGS-100433, BTA-41935-no-rs, ARS-BFGL-NGS-57955, and/or BTA-68535-no-rs, such as ARS-BFGL-NGS-60179, and/or ARS-BFGL-NGS-100433.
  • the genetic marker is an SNP selected from the group consisting of ARS-BFGL-NGS-1 14679, ARS-BFGL-NGS-100433, ARS-BFGL- NGS-31952, ARS-BFGL-NGS-29544, BTA-73413-no-rs, ARS-BFGL-NGS-1 12982, ARS-BFGL-NGS-1 18182, ARS-BFGL-NGS-60179, ARS-BFGL-NGS-57955, BTA- 1 19014-no-rs, ARS-BFGL-NGS-35771 , BTA-41935-no-rs, BTB-01263022, and/or BTB- 01485274
  • the at least one genetic marker such as a combination of two or more genetic markers indicative of fertility in a bovine subject according to the present invention is associated with Interval between 1 st and last insemination (cow), wherein said genetic marker is an SNP selected from the group consisting of ARS-BFGL-NGS- 106105, ARS-BFGL-NGS-1 12101 , Hapmap47854-BTA-1 19090, Hapmap41280-BTA- 50090, ARS-BFGL-NGS-1 19491 , ARS-BFGL-NGS-10254, ARS-BFGL-NGS-23521 , BTA-66912-no-rs, Hapmap51710-BTA-27877, ARS-BFGL-NGS-40979, Hapmap42099-BTA-120289, ARS-BFGL-NGS-1 10387, Hapmap27428-BTA-151920, Hapmap53206-rs29014774, ARS-BFGL-NG
  • the genetic marker is an SNP selected from the group consisting of ARS-BFGL-NGS-106105, ARS-BFGL-NGS-1 12101 , Hapmap47854-BTA- 1 19090, Hapmap41280-BTA-50090, and/or ARS-BFGL-NGS-1 19491 , such as ARS- BFGL-NGS-106105, and/or ARS-BFGL-NGS-1 12101.
  • the genetic marker is an SNP selected from the group consisting of ARS-BFGL-NGS-1 12553, Hapmap60827-rs29019866, Hapmap47854-BTA-1 19090, ARS-BFGL-NGS-40979, BTB-00181232, Hapmap58408- rs29020693, ARS-BFGL-NGS-1 12542, ARS-BFGL-NGS-106105, ARS-BFGL-NGS- 2697, Hapmap32578-BTA-144239, BTB-00313229, Hapmap27428-BTA-151920, BTA- 122483-no-rs, BTB-01984646, ARS-BFGL-NGS-84473, ARS-BFGL-NGS-32233, Hapmap43361 -BTA-80384, ARS-BFGL-BAC-13827, UA-IFASA-4272, ARS-BFGL- NGS-1 10387, Ha
  • the at least one genetic marker such as a combination of two or more genetic markers indicative of fertility in a bovine subject according to the present invention is associated with Interval between 1 st and last insemination (heifer), wherein said genetic marker is an SNP selected from the group consisting of ARS-BFGL-NGS- 8751 1 , ARS-BFGL-NGS-104297, ARS-BFGL-NGS-82538, ARS-BFGL-NGS-99096, Hapmap52246-rs29010319, ARS-BFGL-BAC-36399, ARS-BFGL-NGS-1 17973, and/or ARS-BFGL-NGS-23616.
  • SNP SNP selected from the group consisting of ARS-BFGL-NGS- 8751 1 , ARS-BFGL-NGS-104297, ARS-BFGL-NGS-82538, ARS-BFGL-NGS-99096, Hapmap52246-rs29010319, ARS-BFGL-
  • the genetic marker is an SNP selected from the group consisting of ARS-BFGL-NGS-8751 1 , ARS-BFGL-NGS-104297, ARS-BFGL-NGS- 82538, ARS-BFGL-NGS-99096, and/or Hapmap52246-rs29010319, such as ARS- BFGL-NGS-8751 1 , and/or ARS-BFGL-NGS-104297.
  • the genetic marker is BTA-40495-no-rs.
  • the at least one genetic marker such as a combination of two or more genetic markers indicative of fertility in a bovine subject according to the present invention is associated with 56-day non-return (cow), wherein said genetic marker is an SNP selected from the group consisting of BTA-19381 -no-rs, ARS-BFGL-NGS-1 15717, ARS-BFGL-NGS-1 18588, and/or Hapmap27139-BTA-102152.
  • the genetic marker is the SNP 19381 -no-rs, or ARS-BFGL- NGS-1 15717.
  • the at least one genetic marker such as a combination of two or more genetic markers indicative of fertility in a bovine subject according to the present invention is associated with 56-day non-return (heifer), wherein said genetic marker is an SNP selected from the group consisting of BTB-01431374, ARS-BFGL-NGS- 1 10622, BTB-01541976, BTB-01794263, BTA-87492-no-rs, ARS-BFGL-NGS-36906, Hapmap591 17-rs29018906, Hapmap41812-BTA-27269, and/or ARS-BFGL-NGS- 35587.
  • SNP selected from the group consisting of BTB-01431374, ARS-BFGL-NGS- 1 10622, BTB-01541976, BTB-01794263, BTA-87492-no-rs, ARS-BFGL-NGS-36906, Hapmap591 17-rs29018906, Hapmap41812-BTA-27269
  • the genetic marker is an SNP selected from the group consisting of BTB-01431374, ARS-BFGL-NGS-1 10622, BTB-01541976, BTB- 01794263, BTA-87492-no-rs, and/or ARS-BFGL-NGS-36906, such as BTB-01431374 or ARS-BFGL-NGS-1 10622.
  • the genetic marker is ARS-BFGL-NGS-24769
  • Table 18k displays a list of specific SNP alleles and corresponding effects on fertility traits (regression coefficient). All SNP markers listed in table 18k may be detected according to the present invention. Thus, the at least one, such as two or more genetic markers are in one embodiment selected from the group of SNP alleles set out in table 18k.
  • a regression coefficient reflects that when bases are ordered alphabetically (A; C; G; T), the changes in breeding value of the trait for replacing the first allele with the second allele.
  • a negative regression coefficient reflects that when bases are ordered alphabetically (A; C; G; T), the alphabetically first base in the polymorphic position is indicative of a higher breeding value for the respective fertility traits and is therefore, the desirable one.
  • the at least one genetic marker is a combination of markers, as indicated in tables 19a to 19r. It is understood that the term BTA1 , BTA2. BT A4, BT A7, BT A9, BTA10, BTA1 1 , BTA12, BTA13, BTA14, BTA15, BTA17, BTA20, BTA22, BTA24, BTA25, and BTA26, respectively, in tables 19a to 19r is meant to comprise any regions and genetic markers located on those bovine chromosomes, respectively, as described elsewhere herein.
  • the present invention relates to a method of determining fertility in a bovine subject, comprising detecting in a sample from said bovine subject the presence or absence of at least one genetic marker that is associated withat least one trait indicative of fertility of said bovine subject and/or off-spring therefrom, wherein the at least one genetic marker is a combination of markers located on the bovine chromosome BTA1 in a region flanked by and including polymorphic microsatellite markers AGLA17 and URB014, and/or BT A2 in the region flanked by and including polymorphic microsatellite markers TGLA44 and IDVGA-2, and/or BT A4 in the region flanked by and including polymorphic microsatellite markers BMS1788 and MGTG4B, and/or BTA7 in the region flanked by and including polymorphic microsatellite markers BM7160 and BL1043, and/or BTA9 in the region flanked by and including polymorphic microsatellite markers B
  • ILSTS102 and AF5, and/or BTA26 in the region flanked by and including polymorphic microsatellite markers BMS651 and BM7237.
  • the tables 19a to 19r show different embodiments, wherein a combined number of markers are located on multiple bovine chromosomes, and the specific bovine chromosome in each embodiment is indicated with X.
  • the method according to the present invention for determining the fertility of a bovine subject comprises detecting in a sample from said bovine subject the presence or absence of at least one genetic marker that is associated with at least one trait indicative of fertility of said bovine subject and/or off-spring therefrom, wherein said at least one genetic marker is located on the bovine chromosome BTA1 in a region flanked by and including polymorphic microsatellite markers AGLA17 and URB014, and/or BT A2 in the region flanked by and including polymorphic microsatellite markers TGLA44 and IDVGA-2, and/or BT A4 in the region flanked by and including polymorphic microsatellite markers BMS1788 and MGTG4B, and/or BTA7 in the region flanked by and including polymorphic microsatellite markers BM7160 and BL1043, and/or BTA9 in the region flanked by and including polymorphic microsatellite markers BMS2151 and BMS1967, and/or
  • the genetic markers including microsatellite markers, or a complementary sequence as well as transciptional (mRNA) and translational products (polypeptides, proteins) therefrom may be identified by any method known to those of skill within the art.
  • PCR polymerase chain reaction
  • the method according to the present invention includes a step for amplification of the nucleotide sequence of interest in the presence of primers based on the nucleotide sequence of the variable nucleotide sequence.
  • the methods may be used in combination with a number of signal generation systems, a selection of which is listed further below.
  • the detection of genetic markers can according to one embodiment of the present invention be achieved by a number of techniques known to the skilled person, including typing of microsatellites or short tandem repeats (STR), restriction fragment length polymorphisms (RFLP), detection of deletions or insertions, random amplified polymorphic DNA (RAPIDs) or the typing of single nucleotide polymorphisms by methods such as restriction fragment length polymerase chain reaction, allele-specific oligomer hybridisation, oligomer-specific ligation assays, hybridisation with PNA or locked nucleic acids (LNA) probes.
  • STR microsatellites or short tandem repeats
  • RFLP restriction fragment length polymorphisms
  • RAPIDs random amplified polymorphic DNA
  • LNA locked nucleic acids
  • a primer of the present invention is a nucleic acid molecule sufficiently complementary to the sequence on which it is based and of sufficiently length to selectively hybridise to the corresponding region of a nucleic acid molecule intended to be amplified.
  • the primer is able to prime the synthesis of the corresponding region of the intended nucleic acid molecule in the methods described above.
  • a probe of the present invention is a molecule for example a nucleic acid molecule of sufficient length and sufficiently complementary to the nucleic acid sequence of interest which selectively binds to the nucleic acid sequence of interest under high or low stringency conditions.
  • the genetic marker associated with fertility according to the present invention can be detected by a number of methods known to those of skill within the art.
  • the genetic marker may be identified by genotyping using a method selected from the group consisting of single nucleotide polymorphisms (SNPs), microsatellite markers, restriction fragment length polymorphisms (RFLPs), DNA chips, amplified fragment length polymorphisms (AFLPs), randomly amplified polymorphic sequences (RAPDs), sequence characterised amplified regions (SCARs), cleaved amplified polymorphic sequences (CAPSs), nucleic acid sequencing, and microsatellite genotyping.
  • SNPs single nucleotide polymorphisms
  • RFLPs restriction fragment length polymorphisms
  • DNA chips amplified fragment length polymorphisms
  • AFLPs amplified fragment length polymorphisms
  • RAPDs randomly amplified polymorphic sequences
  • SCARs sequence characterised amplified regions
  • CASs cleaved amplified polymorphic sequences
  • the genetic markers associated with fertility traits as disclosed in the present invention is detected by microsatellite genotyping.
  • Microsatellite genotyping may be performed by amplification of the microsatellite marker by sequence specific oligonucleotide primers, and subsequent analysis of the amplification product, in terms of for example length, quantity and/or sequence of the amplification product.
  • the at least one genetic marker according to the present invention may be detected by use of at least one oligonucleotide selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 432, as disclosed in table 20
  • the present invention relates to a diagnostic kit for detecting the presence or absence in a bovine subject of at least one genetic marker as described herein. In one embodiment, the present invention relates to a diagnostic kit for detecting the presence or absence in a bovine subject of two or more genetic marker alleles as described elsewhere herein, said kit comprising at least one detection member.
  • the diagnostic kit is suitable for detection of the presence or absence of at least one genetic marker, such as two or more genetic markers, which are associated with at least one trait indicative of fertility of said bovine subject and/or off-spring therefrom. Examples of specific traits which are indicative of fertility are disclosed elsewhere herein.
  • Detection members of the present invention include any entity, which is suitable for detecting a genetic marker on the genomic (including epigenomic), transcriptional or translational level. Detection members comprise oligonucleotide primers and/or probes, antibodies, aptamers, chemical substances etc.
  • the diagnostic kit comprises at least one oligonucleotide for detecting said genetic marker allele in said bovine subject.
  • the genetic markers to be detected by the detection members of the present invention are disclosed elsewhere herein.
  • the genetic markers, such as two or more genetic marker alleles are single nucleotide polymorphisms selected from the group consisting of Hapmap60827-rs29019866, ARS-BFGL-NGS-40979, Hapmap47854-BTA-1 19090, ARS-BFGL-NGS-1 14679, Hapmap43841 -BTA-34601 , Hapmap43407-BTA-93630, Hapmap43407-BTA-93630, BTB-01536946, ARS-BFGL- NGS-31952, Hapmap44123-BTA-70017, Hapmap50451 -BTA-70851 , Hapmap58408- rs29020693, ARS-BFGL-NGS-106105,
  • Genotyping of a bovine subject in order to establish the genetic determinants of traits for fertility for that subject according to the present invention can be based on the analysis of genomic DNA which can be provided using standard DNA extraction methods as described herein.
  • the genomic DNA may be isolated and amplified using standard techniques such as the polymerase chain reaction using oligonucleotide primers corresponding (complementary) to the polymorphic marker regions. Additional steps of purifying the DNA prior to amplification reaction may be included.
  • a diagnostic kit for determining fertility comprises, in a separate packing, at least one oligonucleotide sequence selected from the group of SEQ ID NO.: 1 -432 and/or any combinations thereof.
  • the kit of the present invention comprises at least one oligonucleotide selected from the group consisting of SEQ ID NO.: 433 to SEQ ID NO.: 740 and/or any combination thereof.
  • the kit comprises components for genotyping a bovine subject. Methods for genotyping are disclosed elsewhere herein.
  • genotyping is microsatellite genotyping.
  • the kit may comprise various components for performing microsatellite genotyping.
  • the kit may comprise at least one oligonucleotide for genotyping of a bovine subject.
  • the kit comprises at least one oligonucleotide selected from the group consisting of SEQ ID NO.: 1 to SEQ ID NO.: 46 and/or any combination thereof.
  • the kit comprises at least one oligonucleotide is selected from the group consisting of SEQ ID NO.: 47 to SEQ ID NO.: 66 and/or any combination thereof. In another specific embodiment, the kit comprises at least one oligonucleotide is selected from the group consisting of SEQ ID NO.: 67 to SEQ ID NO.: 82 and/or any combination thereof. In another specific embodiment, the kit comprises at least one oligonucleotide is selected from the group consisting of SEQ ID NO.: 83 to SEQ ID NO.: 124 and/or any combination thereof.
  • the kit comprises at least one oligonucleotide is selected from the group consisting of SEQ ID NO.: 125 to SEQ ID NO.: 176 and/or any combination thereof. In another specific embodiment, the kit comprises at least one oligonucleotide is selected from the group consisting of SEQ ID NO.: 177 to SEQ ID NO.: 212 and/or any combination thereof. In another specific embodiment, the kit comprises at least one oligonucleotide is selected from the group consisting of SEQ ID NO.: 213 to SEQ ID NO.: 240 and/or any combination thereof.
  • the kit comprises at least one oligonucleotide is selected from the group consisting of SEQ ID NO.: 241 to SEQ ID NO.: 252 and/or any combination thereof. In another specific embodiment, the kit comprises at least one oligonucleotide is selected from the group consisting of SEQ ID NO.: 253 to SEQ ID NO.: 264 and/or any combination thereof. In another specific embodiment, the kit comprises at least one oligonucleotide is selected from the group consisting of SEQ ID NO.: 265 to SEQ ID NO.: 284 and/or any combination thereof.
  • the kit comprises at least one oligonucleotide is selected from the group consisting of SEQ ID NO.: 285 to SEQ ID NO.: 318 and/or any combination thereof. In another specific embodiment, the kit comprises at least one oligonucleotide is selected from the group consisting of SEQ ID NO.: 319 to SEQ ID NO.: 340 and/or any combination thereof. In another specific embodiment, the kit comprises at least one oligonucleotide is selected from the group consisting of SEQ ID NO.: 341 to SEQ ID NO.: 360 and/or any combination thereof.
  • the kit comprises at least one oligonucleotide is selected from the group consisting of SEQ ID NO.: 361 to SEQ ID NO.: 372 and/or any combination thereof. In another specific embodiment, the kit comprises at least one oligonucleotide is selected from the group consisting of SEQ ID NO.: 373 to SEQ ID NO.: 400 and/or any combination thereof. In another specific embodiment, the kit comprises at least one oligonucleotide is selected from the group consisting of SEQ ID NO.: 401 to SEQ ID NO.: 412 and/or any combination thereof. In another specific embodiment, the kit comprises at least one oligonucleotide is selected from the group consisting of SEQ ID NO.: 413 to SEQ ID NO.: 432 and/or any combination thereof.
  • the kit according to the present invention may comprise reagents and buffers required for genotyping.
  • the exact composition of buffers and reagents depend on the method used for genotyping.
  • the kit comprises buffers required for amplification of DNA.
  • the kit comprises components for purification of DNA.
  • the diagnostic kit according to the present invention may further comprise at least one reference sample.
  • the reference sample serves to verify that the genetic marker is correctly detected in the sample.
  • the reference sample may either be a negative control, which does not comprise genetic material comprising a genetic marker according to the present invention, or the reference sample may be a positive control, which comprises genetic material comprising a genetic marker according to the present invention.
  • the reference sample thus serves to verify that the kit is used correctly.
  • the reference sample comprises an oligonucleotide sequence of a microsatellite marker associated with at least one trait indicative of fertility, as defined elsewhere herein.
  • the reference sample comprises a microsatellite marker oligonucleotide sequence indicative of reduced fertility, as defined elsewhere herein. In another specific embodiment, the reference sample comprises a microsatellite marker oligonucleotide sequence indicative of increased fertility, as defined elsewhere herein.
  • the kit according to the present invention may be provided with instructions for the performance of the detection method of the kit, and for the interpretation of the results.
  • a method of determining fertility in a bovine subject comprising detecting in a sample from said bovine subject the presence or absence of at least one genetic marker that is associated with at least one trait indicative of fertility of said bovine subject and/or off-spring therefrom, wherein said at least one genetic marker is located on the bovine chromosome BTA1 in a region flanked by and including polymorphic microsatellite markers AGLA17 and URB014, and/or
  • BT A2 in the region flanked by and including polymorphic microsatellite markers TGLA44 and IDVGA-2, and/or
  • BT A4 in the region flanked by and including polymorphic microsatellite markers BMS1788 and MGTG4B, and/or BT A7 in the region flanked by and including polymorphic microsatellite markers BM7160 and BL1043, and/or
  • BTA9 in the region flanked by and including polymorphic microsatellite markers BMS2151 and BMS1967, and/or
  • BTA10 in the region flanked by and including polymorphic microsatellite markers DIK2503 and BMS2614, and/or
  • BTA1 1 in the region flanked by and including polymorphic microsatellite markers BM716 and HEL13, and/or
  • BTA12 in the region flanked by and including polymorphic microsatellite markers BMS410 and BMS2724, and/or BTA13 in the region flanked by and including polymorphic microsatellite markers BMS1742 and AGLA232, and/or
  • BTA14 in the region flanked by and including polymorphic microsatellite markers RM180 and BL1036, and/or
  • BTA15 in the region flanked by and including polymorphic microsatellite markers BR3510 and BMS429, and/or BTA17 in the region flanked by and including polymorphic microsatellite markers RM156 and BM1233, and/or
  • BTA20 in the region flanked by and including polymorphic microsatellite markers BM3517 and UWCA26, and/or BTA22 in the region flanked by and including polymorphic microsatellite markers CSSM26 and BM4102, and/or
  • BTA24 in the region flanked by and including polymorphic microsatellite markers BMS917 and BMS3024, and/or
  • BTA25 in the region flanked by and including polymorphic microsatellite markers ILSTS102 and AF5, and/or
  • BTA26 in the region flanked by and including polymorphic microsatellite markers BMS651 and BM7237.
  • sample is selected from the group consisting of blood, semen (sperm), urine, liver tissue, muscle, skin, hair, follicles, ear, tail, fat, testicular tissue, lung tissue, saliva, spinal cord biopsy, and any other tissue. 4. The method according to any of the preceding items, wherein said sample is blood, muscle tissue or liver tissue.
  • said at least one trait indicative of fertility is selected from the group consisting of Number of inseminations cows (AISC), Number of inseminations heifers (AISH), Fertility treatment 1 st lactation (FERT1 ), Fertility treatment 2nd lactation (FERT2), Fertility treatments 3rd lactation (FERT3), Heat strength cows (HSTC), Heat strength heifers (HSTH), Calving to first insemination (ICF), First to last insemination cows (IFLC), First to last insemination heifers (IFLH), 56 day Non-return rate cows (NRRC) and 56 day Non- return rate heifers (NRRH).
  • the at least one genetic marker is located in the region from about 0 to 1 .6 M, or between genetic markers AGLA17 and URB014 of the bovine chromosome BTA1 .
  • the at least one genetic marker is located in the region from about 0.03856 to 1.26352 M, or between genetic markers TGLA44 and IDVGA-2 of the bovine chromosome BT A2.
  • the at least one genetic marker is located in the region from about 0 to 1 .2 M, or between genetic markers BMS1788 and MGTG4B of the bovine chromosome BTA4. 12. The method according to any of the preceding items, wherein the at least one genetic marker is located in the region from about 0 to 1 .35564 M, or between genetic markers BM7160 and BL1043 of the bovine chromosome BTA7.
  • the at least one genetic marker is located in the region from about 0 to 1 .09287 M, or between genetic markers BMS2151 and BMS1967 of the bovine chromosome BT A9.
  • the at least one genetic marker is located in the region from about 0.08991 to 1.09393 M, or between genetic markers DIK2503 and BMS2614 of the bovine chromosome BTA10.
  • the at least one genetic marker is located in the region from about 0.1944 to 1.2237 M, or between genetic markers BM716 and HEL13 of the bovine chromosome BTA1 1 .
  • the at least one genetic marker is located in the region from about 0 to 1 .08978 M, or between genetic markers BMS410 and BMS2724 of the bovine chromosome BTA12. 17. The method according to any of the preceding items, wherein the at least one genetic marker is located in the region from about 0.22997 to 1 M, or between genetic markers BMS1742 and AGLA232 of the bovine chromosome BTA13.
  • the at least one genetic marker is located in the region from about 0.25 to 1.00016 M, or between genetic markers RM180 and BL1036 of the bovine chromosome BTA14.
  • the at least one genetic marker is located in the region from about 0.09415 to 1.2 M, or between genetic markers BR3510 and BMS429 of the bovine chromosome BTA15.
  • the at least one genetic marker is located in the region from about 0.0241 1 to 1 M, or between genetic markers RM156 and BM1233 of the bovine chromosome BTA17.
  • the at least one genetic marker is located in the region from about 0 to 0.9 M, or between genetic markers CSSM26 and BM4102 of the bovine chromosome BTA22.
  • the at least one genetic marker is located in the region from about 0 to 0.65928 M, or between genetic markers BMS917 and BMS3024 of the bovine chromosome BTA24.
  • the at least one genetic marker is located in the region from about 0 to 0.61669 M, or between genetic markers I LSTS 102 and AF5 of the bovine chromosome BTA25.
  • the at least one genetic marker is located in the region from about 0.02839 to 0.66763 M, or between genetic markers BMS651 and BM7237 of the bovine chromosome BTA26.
  • the at least one genetic marker is located at 1.326 Morgan (M) or in the region between microsatellite markers BMS918 and BMS4043 on the bovine chromosome BTA1.
  • the at least one genetic marker is located at the chromosomal position 0.039 M or is genetically coupled to with the microsatellite marker TGLA44 on the bovine chromosome BT A2.
  • the at least one genetic marker is located at the chromosomal position 0.432 M or is genetically coupled to the microsatellite marker BMS2646 on the bovine chromosome BTA4.
  • the at least one genetic marker is located at the chromosomal position 1.1 16 M or in the region between microsatellite markers DIK2895 and MB057 on the bovine chromosome BTA7.
  • the at least one genetic marker is located at the chromosomal position 0.957 M or in the region between microsatellite markers BMS2258 and AE129 on the bovine chromosome BTA7.
  • the at least one genetic marker is located at the chromosomal position 0.50 M or in the region between microsatellite markers UWCA9 and DIK4912 on the bovine chromosome BTA9.
  • the at least one genetic marker is located at the chromosomal position 0.049 M or is genetically coupled to the microsatellite marker BMS2151 on the bovine chromosome BTA9.
  • the at least one genetic marker is located at the chromosomal position 0.1 1 1 M or in the region between microsatellite markers CSSM38 and BMS528 on the bovine chromosome BTA10.
  • the at least one genetic marker is located at the chromosomal position 0.908 M or in the region between microsatellite markers BMS2641 and BMS614 on the bovine chromosome BTA10.
  • 36 The method according to any of the preceding items, wherein the at least one genetic marker is located at the chromosomal position 0.925 M or in the region between microsatellite markers HUJV174 and TGLA436 on the bovine chromosome BTA1 1 .
  • the at least one genetic marker is located at the chromosomal position 0.406 M or in the region between microsatellite markers BM6108 and BM860 on the bovine chromosome BTA12.
  • the at least one genetic marker is located at the chromosomal position 0.897 M or in the region between microsatellite markers BL1071 and AGLA232 on the bovine chromosome BTA13.
  • the at least one genetic marker is located at the chromosomal position 0.333 M or is genetically coupled to the microsatellite marker RM180 on the bovine chromosome BTA14.
  • the at least one genetic marker is located at the chromosomal position 0.983 M or in the region between microsatellite markers BMS820 and BMS927 on the bovine chromosome BTA15. 41.
  • the at least one genetic marker is located at the chromosomal position 0.863 M or in the region between microsatellite markers BM1862 and BM1233 on the bovine chromosome BTA17.
  • the at least one genetic marker is located at the chromosomal position 0.643 M or in the region between microsatellite markers BMS703 and BM5004 on the bovine chromosome BTA20.
  • the at least one genetic marker is located at the chromosomal position 0.431 M or in the region between microsatellite markers TGLA126 and BMS2361 on the bovine chromosome BTA20.
  • the at least one genetic marker is located at the chromosomal position 0.83 M or is genetically coupled to the microsatellite marker BM4102 on the bovine chromosome BTA22.
  • the at least one genetic marker is located at the chromosomal position 0.431 M or in the region between microsatellite markers BM1558 and BM3628 on the bovine chromosome BTA22.
  • the at least one genetic marker is located at the chromosomal position 0.062 M or is genetically coupled to the microsatellite marker BMS917 on the bovine chromosome BTA24.
  • the at least one genetic marker is located at the chromosomal position 0.304 M or in the region between microsatellite markers ILSTS065 and BMS1862 on the bovine chromosome BTA24.
  • the at least one genetic marker is located at the chromosomal position 0.173 M or in the region between microsatellite markers ILSTS102 and BMS2843 on the bovine chromosome BTA25.
  • the at least one genetic marker is located at the chromosomal position 0.317 M or in the region between microsatellite markers BMS332 and RM026 on the bovine chromosome BTA26. 50.
  • the at least one genetic marker is located at the chromosomal position 0.537 M or in the region between microsatellite markers BMS882 and BM804 on the bovine chromosome BTA26.
  • the at least one genetic marker is located at the chromosomal position 0.457 M or in the region between microsatellite markers RME40 and IDVGA-59 on the bovine chromosome BTA26.
  • the at least one genetic marker is a combination of genetic markers.
  • 53 The method according to item 52, wherein the at least one genetic marker is a combination of at least two genetic markers.
  • the at least one genetic marker is a combination of markers located on the bovine chromosome BTA1 in a region flanked by and including polymorphic microsatellite markers AGLA17 and URB014, and/or BTA2 in the region flanked by and including polymorphic microsatellite markers TGLA44 and IDVGA-2, and/or BTA4 in the region flanked by and including polymorphic microsatellite markers BMS1788 and MGTG4B, and/or BTA7 in the region flanked by and including polymorphic microsatellite markers BM7160 and BL1043, and/or BTA9 in the region flanked by and including polymorphic microsatellite markers BMS2151 and BMS1967, and/or BTA10 in the region flanked by and including polymorphic microsatellite markers DIK2503 and BMS2614, and/or BTA1 1 in the region flanked by and including polymorphic
  • the at least one genetic marker is detected by microsatellite genotyping using at least one oligonucleotide selected from the group consisting of SEQ ID NO: 47 to SEQ ID NO: 66.
  • the at least one genetic marker is detected by microsatellite genotyping using at least one oligonucleotide selected from the group consisting of SEQ ID NO: 67 to SEQ ID NO: 82.
  • the at least one genetic marker is detected by microsatellite genotyping using at least one oligonucleotide selected from the group consisting of SEQ ID NO: 319 to SEQ ID NO: 340.
  • the at least one genetic marker is detected by microsatellite genotyping using at least one oligonucleotide selected from the group consisting of SEQ ID NO: 341 to SEQ ID NO: 360.
  • a method for selecting bovine subjects for breeding purposes comprising detecting in a sample from said bovine subject the presence or absence of at least one genetic marker as defined in any of the preceding items, wherein said at least one genetic marker is associated with at least one trait indicative of fertility of said bovine subject and/or off-spring therefrom.
  • the diagnostic kit according to any of items 76 and 77, comprising at least one oligonucleotide for genotyping said bovine subject.
  • kit according to any of items 76 and 79, further comprising reagents and buffers required for genotyping.
  • genotyping is microsatellite genotyping.
  • diagnostic kit according to any of items 76 to 81 further comprising at least one reference sample.
  • the diagnostic kit according to item 82 wherein said reference sample comprises an oligonucleotide sequence of a microsatellite marker associated with at least one trait indicative of fertility.
  • said kit according to any of items 76 to 83 further comprising instructions for the performance of the detection method of the kit, and for the interpretation of the results.
  • NAV database By using the NAV database, it is possible to use twelve traits to identify QTL; number of inseminations for cows and heifers, fertility treatments for first to third lactation, heat strength for cows and heifers, calving to first insemination for cows, the time in days between first and last insemination for cows and heifers and 56-day non return rate for cows and heifers.
  • the large number of traits and the combined data over two countries allows the detection of useful QTL for female fertility in dairy cattle. To this end, a genome scan was performed on the combined dataset.
  • a granddaughter design was used to locate quantitative trait loci for fertility traits in Danish and Swedish Holstein cattle. Up to thirty-six Holstein grandsires with over 2,000 sons were genotyped for 416 microsatellite markers distributed over the 29 autosomes. Single trait breeding values were used to evaluate 12 fertility traits in an across family analysis using a multi-marker regression analysis. Significance thresholds were calculated using permutation tests. The traits analysed were: number of inseminations for cows and heifers, fertility treatments in first to third lactation, heat strength for cows and heifers, interval from calving to first insemination for cows, time from first to last insemination for cows and heifers and 56-day non return rate for cows and heifers.
  • the total length of the bovine genome is 3,179 cM.
  • the genome was screened using 416 microsatellite markers with an average marker spacing of 7.64 cM. All 29 autosomes were typed for an average of 14 markers. Markers and their positions were taken from the USDA Cattle Genome Mapping Project
  • Marker genotypes were determined by PCR analysis. PCR reactions were analyzed on an automated sequence analyzer (ABI 3730 DNA Analyzer, Applied Biosystems) and the alleles were assigned with the GeneMapper software, version 3.7.
  • STBV Phenotypic Data Single trait breeding values (STBV) for the sires were calculated with best linear unbiased prediction (BLUP) sire model procedures. STBV were adjusted for systematic environmental effects influencing these traits (Nordic cattle genetic evaluation http://www.nordicebv.info/forside.htm).
  • STBV were calculated for 12 fertility traits. Cow and heifer performances were treated as separate traits for number of inseminations (AISC and AISH), 56-day non return rate (NRRC and NRRH), first to last insemination (IFLC and IFLH) and heat strength (HSTC and HSTH). Calving to first insemination (ICF) is only defined for cows. Fertility treatments (FERT1 , FERT2 and FERT3) were recorded for first, second and third lactation and were treated as separate traits. AIS and NRR describes the cows' or heifers' ability to become pregnant after insemination, defined as pregnancy rate. AIS also reflects heat strength.
  • NRR rate is based on whether the cow or heifer had a second insemination within 56 days after the first insemination. All cows and heifers not offered Al within 56 days were considered pregnant.
  • IFL describes pregnancy rate and heat strength.
  • HST measures the ability to show oestrus, the trait is measured subjectively by the individual farmer on a predefined scale from 1 to 5. HST is only measured in Sweden.
  • ICF describes heat strength and reflects the ability to return to cycling after calving (Nordic Cattle Genetic Evaluation http://www.nordicebv.info/forside.htm) (Ancker et al., 2006)
  • Fertility treatments are divided into three groups.
  • Group 1 represents hormonal reproductive disorders and consists of ovarian cysts treatments.
  • Group 2 represents infective reproductive disorders and consists of recordings of endometritis, metritis and vaginitis treatments.
  • the last group consists of treatments for abortion, uterine prolaps, uterine torsion and other reproductive disorders (Nordic cattle genetic evaluation http://www.nordicebv.info/forside.htm)
  • the traits were analyzed with the linear regression mapping procedure adapted from (Haley and Knott, 1992). Each trait and chromosome was analyzed separately and tested for the presence of a single QTL affecting one single trait in the following steps for both the across and within family analysis:
  • the linkage phases of the markers in the grandsires were determined based on the marker types of the sons.
  • Marker allele frequencies were estimated using an expectation-maximization algorithm (Dempster et al., 1977). Segregation probabilities for each position were calculated using all markers on the chromosome simultaneously, together with allele frequencies where segregation was ambiguous. Phenotypes were then regressed onto the segregation probabilities.
  • the following regression model was applied in analyses both across and within families.
  • Y 11 is the single trait estimated breeding value of son / of grandsire / ' ;
  • ⁇ is the overall mean of grandsire / ' ;
  • (p> is the regression coefficient within grandsire i at position p;
  • X, j (p) is the probability that QTL allele 1 being transmitted from grandsire i given all the informative markers of son y;
  • e,j p> is the residual effect given QTL position p.
  • the test probability was determined by using a permutation test with 1 ,000 permutations (Churchill and Doerge, 1994). A QTL was considered significant if the test probability was below a 5% chromosome-wise threshold.
  • NRRC For NRRC, a QTL was detected in the across family analysis on BT A2 and BTA12. For heifers (NRRH) a QTL was detected in the across family analysis on BTA22, BTA25 and BTA26.
  • BTA26 is an interesting chromosome for fertility traits because significant QTL were found for the traits; time from first to last insemination for cows and 56-day non return rate for heifers.
  • the QTL for time from first to last insemination for cows and 56-day non return rate for heifers were not in the same marker bracket but the peaks were only 10 cM apart. Both these traits measures pregnancy rate. It could therefore be the same QTL segregating for these fertility traits.
  • BTA26 is therefore an interesting chromosome to study further.
  • time from first to last insemination for cows which reflects pregnancy rate and heat strength.
  • Five out of a total of seven sires were significant for both traits.
  • the QTL position for these traits was estimated within 20 cM. Therefore it will be important to study this QTL further to refine its position to find out whether it is the same QTL segregating for both traits. For the corresponding trait in heifers no significant results were found.
  • Fertility treatment is a trait that is a combination of a number of sub traits. However, a few of the treatments dominate among the recorded data (Nordic cattle genetic evaluation http://www.nordicebv.info/forside.htm). Treatments for uterine infection of different severity were the most frequent treatment. It therefore seems likely that the result represent a QTL for uterine infection as all other treatments except for abortions occurred at very low frequencies. It will therefore be important to investigate which disease is the underlying cause of this QTL. Holmberg and Andersson-Eklund (2006) and Schulman et al. (2007) have analysed fertility treatments for the Swedish red breed and the Finnish Ayrshire breed respectively. Direct comparisons with the results found in this study are difficult because the diagnoses recorded differ between Denmark, Sweden and Finland.
  • cows and heifers were analysed separately. Cows and heifers were considered as two different traits. In our study no convincing evidence was found for overlapping QTL between cow and heifer traits.
  • One example is the QTL on BTA9 for time from first to last insemination for cows and time from first to last insemination for heifers. These QTL were found on different locations on the chromosome, indicating that these probably are two different QTL. This is consistent with other QTL studies where traits are separated into cow and heifer traits (Holmberg and Andersson-Eklund, 2006).
  • cow and heifer fertility traits have been studied by Kuhn et al. (2006). They found a genetic correlation between cow and heifer conception rate of 0.39 mainly in American Holsteins along with 15 other breeds. Oltenacu et al. (1991 ) reported a genetic correlation between heifer and cow first-service conception rate of 0.59 for Swedish red and white.
  • Chromosomes BTA1 , BT A3, BT A5, BT A7, BT A8 - BTA1 1 , BTA15, BTA16, BTA18, BTA21 , BTA23, BTA26 - BTA29 were typed for all 34 families. Chromosomes BTA2, BTA4, BT A6, BTA14, BTA19, BTA20, BTA22, BTA24, and BTA25 were typed for 19 families and BTA17 was typed for 20 families.
  • Fertility treatments include hormonal reproductive disorders, ovarian cysts treatments, infective reproductive disorders (including endometritis, metritis and vaginitis treatments), treatments for abortion, uterine prolapse, uterine torsion and other reproductive disorders.
  • the unit of measurement was treated or not treated (0 or 1 ) for any of the mentioned diseases.
  • Single trait breeding value (STBV) for fertility treatments was predicted separately for 1 st, 2nd and 3rd lactation using total number of individual records within lactation.
  • FRTA is also a binary trait: if a cow has no uterine infection and no antibiotics placed in the placenta the trait value for FRTA is 0.
  • FRTA FRTA FRTA FRTA FRTA ; 2 genetic components of abortion were studied: 1 ) the direct abortion (DA) effect. This is the effect of a sire's genes acting through the genotype of the foetus. It is measured as the abortion rate among pregnancies sired by this sire; 2) the maternal abortion (MA) effect. This represents the effect of a sire's genes acting through the genotype of pregnant cows. It is measured by the abortion rate among heifers with pregnancies sired by the sire in question.
  • Daughter group averages were calculated from Danish Holstein Friesian population. These daughter group averages were based on the abortion frequencies defined as number of abortions divided by the sum of the numbers of calves born and abortions. The daughter group averages were calculated using calving data for the years from January 1991 to December 2005.
  • Retained placenta was measured as a binary trait with a value 0 or 1 .
  • STBV for these traits were predicted using a single trait repeatability linear sire model including year-month, herd-year, calving-age, lactation, cow (permanent environment), sire, breed-proportion and heterozygosity, based on the data pooled over the first three lactations using the DMU package (Madsen and Jensen, 2007).
  • Production traits Production traits in the analysis were milk yield, protein yield, fat yield, fat percentage and protein percentage.
  • the total length of the bovine genome is 3,179 cM.
  • the genome was screened using 416 microsatellite markers with an average marker spacing of 7.64 cM. All 29 autosomes were typed for an average of 14 markers.
  • the markers and sire families used per chromosome are described in Example 1.
  • GDQTL4 follows the following procedure: The linkage phases of the markers in the grandsires were determined based on the marker types of the sons. The QTL analysis was performed according to the regression model as described in
  • Test for whole genome QTL detection Two types of tests were conducted. First, a joint test was done. An F-statistic was calculated for each combination of trait and chromosome but across those grandsire families where both marker genotypes and STBV were available. Second, within-family tests were done: An F-statistic was calculated for each of the combinations of grandsire family, chromosome and trait, where both marker genotypes and STBV were available. The significance threshold was determined for each test individually by performing a permutation test with 1 ,000 permutations. A QTL was considered significant if it exceeded the 5% chromosome wise threshold in the permutation distribution. For each QTL significant in the joint test, the number of grandsire families individually significant at a 5% level for a QTL on the same chromosome was counted.
  • Test for specific area QTL detection The same type of tests were performed as for the whole genome scan, but the significance threshold was determined for each test individually by performing a permutation test with 1 ,000 permutations based on a smaller interval.
  • the frequency of uterine infection is in the range of 3 to 4% of all calvings.
  • the frequency of 'antibiotics placed in the placenta' is around 0.2%, and the frequency of RP is around 6%.
  • the genome was scanned for the traits FRTA and RP (Table 24). This scan revealed a QTL on BTA1 for FRTA at 53.2 cM. Within a region of 22 cM, QTL were detected on BT A6 for RP (1 16.2 cM), and FRTA (1 19.0 cM). On BTA10 a QTL was detected for RP located at 100.1 cM. On BTA18 a QTL for RP was detected at 83.3 cM.
  • BTA22 On BTA22 a QTL was detected for FRTA and RP at 83.3 cM. Only the QTL for the fertility sub-traits on BTA 22 coincided with the QTL for FRT1. The positions found on BTA1 , BT A6, BTA10 and BTA18 did not coincide with the QTL detected for fertility treatments in Example 1.
  • the QTL regions for fertility traits were further scanned for fat yield, fat percentage, protein yield, protein percentage and milk yield (Table 25). This scan revealed two significant regions for fat yield on BTA1 and BTA26. Three significant regions for fat percentage were detected, one region on BTA26 and two regions on BTA24. Two significant regions for protein yield were detected, one on BTA24 and one on BTA26. Two significant regions for protein percentage were detected, one on BT A9 and one on BTA10. A scan of the fertility QTL regions for milk yield revealed one region on BTA26.
  • RP can be a pre-stage of other uterine disorder as RP can lead to uterine disturbances. RP is not used in the fertility treatments in the Danish breeding value estimation, but it can be considered as part of the uterine disorders.
  • QTL for the trait RP showed up on four different chromosomes. On BTA10 the location of the RP QTL is only 10 cM apart from IFLC. This is interesting as the interval from first to last insemination is extended when problems arise after calving due to RP.
  • BTA22 RP is associated with the same marker (BM4102) as FRT1 even though RP is not a sub-trait of FRT. Uterine infection related traits are part of FRT.
  • BTA26 On BTA26 three regions harbouring QTL for IFLC, NRRH, and FRT1 were selected based on the results of Example 1. Scanning these regions for milk production traits independently revealed QTL for fat yield, fat percentage, protein percentage and milk yield in all three regions. The overlapping regions of the fertility traits are within a 25 cM interval on BTA26. In another study based on the same animal material it was shown that BTA26 also harboured a QTL for clinical mastitis in the same region (Lund et al. 2008). This makes that region BTA26 (between RME40-IDVGA-59) of particular interest for selection of genetic markers according to the present invention. BTA20
  • the traits were NRRC (BT A2, BTA12), NRRH (BT A22, BTA25), IFLC (BT A4), IFLH (BTA9) AISH (BT A7), ICFC (BTA1 1 , BTA13), RP/FRTA (BTA6), FRT1/RP (BT A22), and FRT1 (BTA1 ).
  • the QTL in these regions specifically influence fertility without influencing milk production traits in the Danish Holstein population.
  • results from this example provide information that allows a partial separation of milk production and fertility traits.
  • Example 1 The results of the fertility traits were taken from Example 1. 2 The F-statistic, the P-value in brackets and the number of sires segregating for the production trait QTL
  • association mapping was carried out for 13 fertility traits in Danish Holstein cattle using single nucleotide polymorphisms (SNPs) markers. The objective was to identify SNPs associated with these fertility traits.
  • SNPs single nucleotide polymorphisms
  • the bovinesnp ⁇ O beadchip (http://www.illumina.com) was used for genotyping.
  • the bovinesnp ⁇ O beadchip features more than 54000 probes that target SNPs.
  • genotyping quality scores and fixing minor allele frequency to 0.05 36387 SNPs genotype were left in 29 autosomes.
  • the number of SNPs included for analysis varied from 2320 on chromosome 1 to 675 on chromosome 28. A total of 2531 Danish Holstein bulls were genotyped.
  • association mapping was carried out using a mixed model approach (Yu et al. 2006), where polygenic background effect was fitted as random and the SNP under testing was fitted as fixed effect.
  • y X ⁇ + Sa + Zu + e , where y is a vector of phenotypic observation; ⁇ is a vector of fixed effects other than the SNP under testing; ⁇ is a vector of SNP effects, u is a vector of polygenic background effects, e is a vector of residual effects; and X, S and Z are incidence matrices relating to ⁇ , ⁇ and u, respectively.
  • the analysis was carried out using DMU software package (Madsen et al. 2006). The significance of association was tested at chromosome-wide significant level of 0.05 after Bonferroni correction for multiple testing.
  • Table 26 presents the SNPs those showed significant association with fertility traits.
  • the positions are mentioned in base-pair unit within a chromosome where the SNP is located.
  • the regression coefficients were estimated considering 0, 1 or 2 copy of G or C allele was present in an individual.
  • SNPs A number of specific SNPs was genotyped. For information of the SNPs see for example http://www.illumina.com. A number of the SNP are disclosed in SEQ ID NO:
  • the terms fit any number of QTL (or direct marker) effects, where ⁇ k is a vector with the effects of QTL alleles (direct allele effects), with ⁇ k ⁇ N(O, 1 ) and ⁇ k is a scaling factor modeling the variance explained by that marker.
  • the scaling factors were conditionally estimated as simple Normally distributed regressions, and can be interpreted as a standard deviation. Zu fits polygenic background effects with u ⁇ N (0, A ⁇ 2 u ) with A the numerator relationship matrix between individuals derived from pedigree records, and e are errors with e ⁇ N (0, ⁇ 2 e /w, ), where w, was the weight (reliability of the breeding value).
  • the multi-QTL model requires moderation or shrinkage of the effects of brackets or alleles, otherwise inferences will not be sharp.
  • priors were assigned to the scaling factors using a two-mixture Truncated normal distribution where, the first distribution was the 'null' distribution and modeled the QTLs/markers with no effect. The second distribution modeled the QTLs/markers having an effect.
  • the model estimated a "mixture indicator" which for each marker indicated whether it was estimated to belong to the first ('null') distribution or the second (with an effect) distribution.
  • the first distribution is indicated by 0 and the second one with 1 , so that, after averaging in the MCMC, a value between 0-1 is obtained which can be interpreted as the probability for each marker to have a large effect i.e. the probability to belong to the second distribution(George and McCullogh, 1993).
  • the (averaged) mixture indicator estimates a posterior probability for that marker or QTL position to come from the second mixture distribution - which is interpreted as the probability for presence of an associated marker or QTL.
  • a cut-off of P 1 can be used to indicate the probability that marker is 'in the model than out of the model'.
  • FDR false discovery rate
  • the false discovery rate (FDR) was introduced by Benjamini and Hochberg (1995), and controls the expected proportion of incorrectly rejected null hypothesis. This is suggested in literature, and the probability is also suggested to indicate the false discovery rate (FDR). is the probability of erring when selecting a marker with posterior probability as true.
  • FDR false discovery rate
  • the "group FDR" extends to ⁇ (1 - )/m where the sum is over the m markers selected. The total amount of falsely declared markers )/m) in the selected group of size m.
  • the prior probability for marker was fixed to 1 % ( ⁇ i parameter in the iBay mixture prior 0.01 ), a posterior probability of 0.029 is enough for a 3-fold odds change ("substantial"), 0.092 is enough for a 10-fold odds change (“strong”), and with posterior probability above 0.50 the evidence is "decisive" (100-fold odds change). This shows that, with small prior probability, relatively modest posterior probabilities around 0.10 can be important. Multi-point version of the PPOR by checking if neighbouring markers was pooled and give PPOR values for a region where more than one marker showed effect.
  • Fertility index BTB-01301015 1 148,4 o, 108 11, 96 o, 68 o, 22

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Abstract

L'invention concerne la fertilité bovine. Cette invention concerne, plus particulièrement, des marqueurs génétiques destinés à déterminer la fertilité d'un bovin ainsi que de sa descendance, et un nécessaire de diagnostic destiné à détecter les marqueurs génétiques associés à la fertilité bovine. Ces procédés consistent à détecter une combinaison spécifique de deux ou plusieurs marqueurs génétiques indicateurs de fertilité dans un échantillon biologique d'un bovin. L'invention concerne enfin un certain nombre de polymorphismes d'un nucléotide simple et de marqueurs microsatellites, en corrélation avec la fertilité bovine.
PCT/DK2009/050040 2008-02-08 2009-02-06 Marqueurs génétiques de fertilité Ceased WO2009097862A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DKPA200800180 2008-02-08
DKPA200800180 2008-02-08

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WO2010020252A1 (fr) * 2008-08-19 2010-02-25 Viking Genetics Fmba Procédés de détermination d'une valeur génétique sur la base d'une pluralité de marqueurs génétiques
CN102676514A (zh) * 2012-05-30 2012-09-19 中国农业大学 与中国荷斯坦奶牛产奶性状相关的snp标记及其应用

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WO2007112490A1 (fr) * 2006-03-30 2007-10-11 Innovative Dairy Products Pty Ltd As Trustee For The Participants Of The Cooperative Research Centre For Innovative Dairy Products Blocs chromosomiques en tant que marqueurs de caractères

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WO2007112490A1 (fr) * 2006-03-30 2007-10-11 Innovative Dairy Products Pty Ltd As Trustee For The Participants Of The Cooperative Research Centre For Innovative Dairy Products Blocs chromosomiques en tant que marqueurs de caractères

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010020252A1 (fr) * 2008-08-19 2010-02-25 Viking Genetics Fmba Procédés de détermination d'une valeur génétique sur la base d'une pluralité de marqueurs génétiques
CN102676514A (zh) * 2012-05-30 2012-09-19 中国农业大学 与中国荷斯坦奶牛产奶性状相关的snp标记及其应用

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