Meiotic recombination is an essential biological process that generates genetic diversity and ensures proper segregation of chromosomes during meiosis. From a large USDA dairy cattle pedigree with over half a million genotyped animals, we extracted 186,927 three-generation families, identified over 8.5 million maternal and paternal recombination events, and constructed sex-specific recombination maps for 59,309 autosomal SNPs. The recombination map spans for 25.5 Morgans in males and 23.2 Morgans in females, for a total studied region of 2,516 Mb (986 kb/cM in males and 1,085 kb/cM in females). The male map is 10% longer than the female map and the sex difference is most pronounced in the subtelomeric regions. We identified 1,792 male and 1,885 female putative recombination hotspots, with 720 hotspots shared between sexes. These hotspots encompass 3% of the genome but account for 25% of the genome-wide recombination events in both sexes. During the past forty years, males showed a decreasing trend in recombination rate that coincided with the artificial selection for milk production. Sex-specific GWAS analyses identified PRDM9 and CPLX1 to have significant effects on genome-wide recombination rate in both sexes. Two novel loci, NEK9 and REC114, were associated with recombination rate in both sexes, whereas three loci, MSH4, SMC3 and CEP55, affected recombination rate in females only. Among the multiple PRDM9 paralogues on the bovine genome, our GWAS of recombination hotspot usage together with linkage analysis identified the PRDM9 paralogue on chromosome 1 to be associated in the U.S. Holstein data. Given the largest sample size ever reported for such studies, our results reveal new insights into the understanding of cattle and mammalian recombination.
References
[1]
Stumpf MP, McVean GA (2003) Estimating recombination rates from population-genetic data. Nature Reviews Genetics 4: 959–968. pmid:14631356 doi: 10.1038/nrg1227
[2]
Kauppi L, Jeffreys AJ, Keeney S (2004) Where the crossovers are: recombination distributions in mammals. Nature Reviews Genetics 5: 413–424. pmid:15153994 doi: 10.1038/nrg1346
[3]
Coop G, Przeworski M (2006) An evolutionary view of human recombination. Nature Reviews Genetics 8: 23–34. pmid:17146469 doi: 10.1038/nrg1947
[4]
Paigen K, Petkov P (2010) Mammalian recombination hot spots: properties, control and evolution. Nature Reviews Genetics 11: 221–233. doi: 10.1038/nrg2712. pmid:20168297
[5]
Lipkin SM, Moens PB, Wang V, Lenzi M, Shanmugarajah D, et al. (2002) Meiotic arrest and aneuploidy in MLH3-deficient mice. Nature genetics 31: 385–390. pmid:12091911 doi: 10.1038/ng931
[6]
Hassold T, Hunt P (2001) To err (meiotically) is human: the genesis of human aneuploidy. Nature Reviews Genetics 2: 280–291. pmid:11283700 doi: 10.1038/35066065
[7]
Coop G, Myers SR (2007) Live hot, die young: transmission distortion in recombination hotspots. PLoS genetics 3: e35. pmid:17352536 doi: 10.1371/journal.pgen.0030035.eor
[8]
Barton NH, Charlesworth B (1998) Why sex and recombination? Science 281: 1986–1990. pmid:9748151 doi: 10.1126/science.281.5385.1986
[9]
Kong A, Thorleifsson G, Gudbjartsson DF, Masson G, Sigurdsson A, et al. (2010) Fine-scale recombination rate differences between sexes, populations and individuals. Nature 467: 1099–1103. doi: 10.1038/nature09525. pmid:20981099
[10]
Shifman S, Bell JT, Copley RR, Taylor MS, Williams RW, et al. (2006) A high-resolution single nucleotide polymorphism genetic map of the mouse genome. PLoS biology 4: e395. pmid:17105354 doi: 10.1371/journal.pbio.0040395
[11]
Baudat F, Buard J, Grey C, Fledel-Alon A, Ober C, et al. (2010) PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice. Science 327: 836–840. doi: 10.1126/science.1183439. pmid:20044539
[12]
Parvanov ED, Petkov PM, Paigen K (2010) Prdm9 controls activation of mammalian recombination hotspots. Science 327: 835–835. doi: 10.1126/science.1181495. pmid:20044538
[13]
Myers S, Bowden R, Tumian A, Bontrop RE, Freeman C, et al. (2010) Drive against hotspot motifs in primates implicates the PRDM9 gene in meiotic recombination. Science 327: 876–879. doi: 10.1126/science.1182363. pmid:20044541
[14]
Jeffreys AJ, Murray J, Neumann R (1998) High-resolution mapping of crossovers in human sperm defines a minisatellite-associated recombination hotspot. Molecular cell 2: 267–273. pmid:9734365 doi: 10.1016/s1097-2765(00)80138-0
[15]
Myers S, Bottolo L, Freeman C, McVean G, Donnelly P (2005) A fine-scale map of recombination rates and hotspots across the human genome. Science 310: 321–324. pmid:16224025 doi: 10.1126/science.1117196
[16]
McVean GA, Myers SR, Hunt S, Deloukas P, Bentley DR, et al. (2004) The fine-scale structure of recombination rate variation in the human genome. Science 304: 581–584. pmid:15105499 doi: 10.1126/science.1092500
[17]
Pratto F, Brick K, Khil P, Smagulova F, Petukhova GV, et al. (2014) Recombination initiation maps of individual human genomes. Science 346: 1256442. doi: 10.1126/science.1256442. pmid:25395542
[18]
Otto SP, Lenormand T (2002) Resolving the paradox of sex and recombination. Nature Reviews Genetics 3: 252–261. pmid:11967550 doi: 10.1038/nrg761
[19]
Lynn A, Schrump S, Cherry J, Hassold T, Hunt P (2005) Sex, not genotype, determines recombination levels in mice. The American Journal of Human Genetics 77: 670–675. pmid:16175513 doi: 10.1086/491718
[20]
Kong A, Gudbjartsson DF, Sainz J, Jonsdottir GM, Gudjonsson SA, et al. (2002) A high-resolution recombination map of the human genome. Nature genetics 31: 241–247. pmid:12053178 doi: 10.1038/ng917
[21]
Zenger KR, McKenzie LM, Cooper DW (2002) The first comprehensive genetic linkage map of a marsupial: the tammar wallaby (Macropus eugenii). Genetics 162: 321–330. pmid:12242243
[22]
Marklund L, Moller MJ, Juneja R, Mariani P, Ellegren H, et al. (1996) A comprehensive linkage map of the pig based on a wild pig‐Large White intercross. Animal genetics 27: 255–269. pmid:8856923 doi: 10.1111/j.1365-2052.1996.tb00487.x
[23]
Maddox JF, Davies KP, Crawford AM, Hulme DJ, Vaiman D, et al. (2001) An enhanced linkage map of the sheep genome comprising more than 1000 loci. Genome research 11: 1275–1289. pmid:11435411 doi: 10.1101/gr.gr-1350r
[24]
Bishop MD, Kappes SM, Keele JW, Stone RT, Sunden S, et al. (1994) A genetic linkage map for cattle. Genetics 136: 619–639. pmid:7908653
[25]
Barendse W, Armitage S, Kossarek L, Shalom A, Kirkpatrick B, et al. (1994) A genetic linkage map of the bovine genome. Nature genetics 6: 227–235. pmid:8012383 doi: 10.1038/ng0394-227
[26]
Barendse W, Vaiman D, Kemp S, Sugimoto Y, Armitage S, et al. (1997) A medium-density genetic linkage map of the bovine genome. Mammalian Genome 8: 21–28. pmid:9021143 doi: 10.1007/s003359900340
[27]
Kappes S, Keele JW, Stone RT, McGraw RA, Sonstegard TS, et al. (1997) A second-generation linkage map of the bovine genome. Genome Research 7: 235–249. pmid:9074927 doi: 10.1101/gr.7.3.235
[28]
Ihara N, Takasuga A, Mizoshita K, Takeda H, Sugimoto M, et al. (2004) A comprehensive genetic map of the cattle genome based on 3802 microsatellites. Genome Research 14: 1987–1998. pmid:15466297 doi: 10.1101/gr.2741704
[29]
Sandor C, Li W, Coppieters W, Druet T, Charlier C, et al. (2012) Genetic variants in REC8, RNF212, and PRDM9 influence male recombination in cattle. PLoS genetics 8: e1002854. doi: 10.1371/journal.pgen.1002854. pmid:22844258
[30]
Weng Z-Q, Saatchi M, Schnabel RD, Taylor JF, Garrick DJ (2014) Recombination locations and rates in beef cattle assessed from parent-offspring pairs. Genetics Selection Evolution 46: 34. doi: 10.1186/1297-9686-46-34
[31]
Oliver PL, Goodstadt L, Bayes JJ, Birtle Z, Roach KC, et al. (2009) Accelerated evolution of the Prdm9 speciation gene across diverse metazoan taxa. PLoS genetics 5: e1000753. doi: 10.1371/journal.pgen.1000753. pmid:19997497
[32]
Zimin AV, Delcher AL, Florea L, Kelley DR, Schatz MC, et al. (2009) A whole-genome assembly of the domestic cow, Bos taurus. Genome Biol 10: R42. doi: 10.1186/gb-2009-10-4-r42. pmid:19393038
[33]
VanRaden P, Null D, Sargolzaei M, Wiggans G, Tooker M, et al. (2013) Genomic imputation and evaluation using high-density Holstein genotypes. Journal of dairy science 96: 668–678. doi: 10.3168/jds.2012-5702. pmid:23063157
[34]
Druet T, Georges M. Pedigree-based haplotype reconstruction, identification of cross-overs and detection of map and genotyping errors using PHASEBOOK; 2014.
[35]
Garbe J, Da Y (2003) Locusmap user manual Version 1.1. Department of Animal Science, University of Minnesota, St Paul.
[36]
Band MR, Larson JH, Rebeiz M, Green CA, Heyen DW, et al. (2000) An ordered comparative map of the cattle and human genomes. Genome research 10: 1359–1368. pmid:10984454 doi: 10.1101/gr.145900
[37]
Broman KW, Murray JC, Sheffield VC, White RL, Weber JL (1998) Comprehensive human genetic maps: individual and sex-specific variation in recombination. The American Journal of Human Genetics 63: 861–869. pmid:9718341 doi: 10.1086/302011
[38]
Liu EY, Morgan AP, Chesler EJ, Wang W, Churchill GA, et al. (2014) High-resolution sex-specific linkage maps of the mouse reveal polarized distribution of crossovers in male germline. Genetics 197: 91–106. doi: 10.1534/genetics.114.161653. pmid:24578350
[39]
Kong A, Thorleifsson G, Frigge ML, Masson G, Gudbjartsson DF, et al. (2014) Common and low-frequency variants associated with genome-wide recombination rate. Nature genetics 46: 11–16. doi: 10.1038/ng.2833. pmid:24270358
[40]
Yang S-W, Gao C, Chen L, Song Y-L, Zhu J-L, et al. (2012) Nek9 regulates spindle organization and cell cycle progression during mouse oocyte meiosis and its location in early embryo mitosis. Cell Cycle 11: 4366–4377. doi: 10.4161/cc.22690. pmid:23159858
[41]
Santucci-Darmanin S, Walpita D, Lespinasse F, Desnuelle C, Ashley T, et al. (2000) MSH4 acts in conjunction with MLH1 during mammalian meiosis. The FASEB Journal 14: 1539–1547. pmid:10928988 doi: 10.1096/fj.14.11.1539
[42]
Ross-Macdonald P, Roeder GS (1994) Mutation of a meiosis-specific MutS homolog decreases crossing over but not mismatch correction. Cell 79: 1069–1080. pmid:8001134 doi: 10.1016/0092-8674(94)90037-x
[43]
Eijpe M, Heyting C, Gross B, Jessberger R (2000) Association of mammalian SMC1 and SMC3 proteins with meiotic chromosomes and synaptonemal complexes. Journal of Cell Science 113: 673–682. pmid:10652260
[44]
Ma L, Han S, Yang J, Da Y (2010) Multi-locus test conditional on confirmed effects leads to increased power in genome-wide association studies. PloS one 5: e15006. doi: 10.1371/journal.pone.0015006. pmid:21103364
[45]
Liu Y, Qin X, Song X-ZH, Jiang H, Shen Y, et al. (2009) Bos taurus genome assembly. BMC genomics 10: 180. doi: 10.1186/1471-2164-10-180. pmid:19393050
[46]
Mu？oz-Fuentes V, Marcet-Ortega M, Alkorta-Aranburu G, Forsberg CL, Morrell JM, et al. (2015) Strong artificial selection in domestic mammals did not result in an increased recombination rate. Molecular biology and evolution 32: 510–523. doi: 10.1093/molbev/msu322. pmid:25414125
[47]
Hayes B, Bowman P, Chamberlain A, Goddard M (2009) Invited review: Genomic selection in dairy cattle: Progress and challenges. Journal of dairy science 92: 433–443. doi: 10.3168/jds.2008-1646. pmid:19164653
[48]
VanRaden P, Van Tassell C, Wiggans G, Sonstegard T, Schnabel R, et al. (2009) Invited Review: Reliability of genomic predictions for North American Holstein bulls. Journal of Dairy Science 92: 16–24. doi: 10.3168/jds.2008-1514. pmid:19109259
[49]
Sodeland M, Kent M, Hayes BJ, Grove H, Lien S (2011) Recent and historical recombination in the admixed Norwegian Red cattle breed. BMC genomics 12: 33. doi: 10.1186/1471-2164-12-33. pmid:21232164
[50]
Pál C, Papp B, Hurst LD (2001) Does the recombination rate affect the efficiency of purifying selection? The yeast genome provides a partial answer. Molecular biology and evolution 18: 2323–2326. pmid:11719582 doi: 10.1093/oxfordjournals.molbev.a003779
[51]
Lenormand T, Dutheil J (2005) Recombination difference between sexes: a role for haploid selection. PLoS biology 3: e63. pmid:15736976 doi: 10.1371/journal.pbio.0030063
[52]
Dumont BL, Payseur BA (2011) Genetic analysis of genome-scale recombination rate evolution in house mice. PLoS genetics 7: e1002116. doi: 10.1371/journal.pgen.1002116. pmid:21695226
[53]
Murdoch B, Owen N, Shirley S, Crumb S, Broman KW, et al. (2010) Multiple loci contribute to genome-wide recombination levels in male mice. Mammalian Genome 21: 550–555. doi: 10.1007/s00335-010-9303-5. pmid:21113599
[54]
Decker JE, McKay SD, Rolf MM, Kim J, Alcalá AM, et al. (2014) Worldwide patterns of ancestry, divergence, and admixture in domesticated cattle. PLoS genetics 10: e1004254. doi: 10.1371/journal.pgen.1004254. pmid:24675901
Ross‐Ibarra J (2004) The evolution of recombination under domestication: a test of two hypotheses. The American Naturalist 163: 105–112. pmid:14767840 doi: 10.1086/380606
[57]
Burt A, Bell G (1987) Mammalian chiasma frequencies as a test of two theories of recombination. Nature 326: 803–805. pmid:3574451 doi: 10.1038/326803a0
[58]
Maddox JF, Cockett NE (2007) An update on sheep and goat linkage maps and other genomic resources. Small ruminant research 70: 4–20. doi: 10.1016/j.smallrumres.2007.01.008
[59]
Chessa B, Pereira F, Arnaud F, Amorim A, Goyache F, et al. (2009) Revealing the history of sheep domestication using retrovirus integrations. Science 324: 532–536. doi: 10.1126/science.1170587. pmid:19390051
[60]
Poissant J, Hogg JT, Davis CS, Miller JM, Maddox JF, et al. (2010) Genetic linkage map of a wild genome: genomic structure, recombination and sexual dimorphism in bighorn sheep. BMC genomics 11: 524. doi: 10.1186/1471-2164-11-524. pmid:20920197
[61]
Arias JA, Keehan M, Fisher P, Coppieters W, Spelman R (2009) A high density linkage map of the bovine genome. BMC genetics 10: 18. doi: 10.1186/1471-2156-10-18. pmid:19393043
[62]
Groenen MA, Wahlberg P, Foglio M, Cheng HH, Megens H-J, et al. (2009) A high-density SNP-based linkage map of the chicken genome reveals sequence features correlated with recombination rate. Genome Research 19: 510–519. doi: 10.1101/gr.086538.108. pmid:19088305
[63]
Lucy M (2001) Reproductive loss in high-producing dairy cattle: where will it end? Journal of dairy science 84: 1277–1293. pmid:11417685 doi: 10.3168/jds.s0022-0302(01)70158-0
[64]
Pryce J, Royal M, Garnsworthy P, Mao IL (2004) Fertility in the high-producing dairy cow. Livestock Production Science 86: 125–135. doi: 10.1016/s0301-6226(03)00145-3
[65]
Wiggans G, Cooper T, Null D, VanRaden P Increasing the Number of Single Nucleotide Polymorphisms Used in Genomic Evaluations of Dairy Cattle.
[66]
Druet T, Georges M (2010) A hidden Markov model combining linkage and linkage disequilibrium information for haplotype reconstruction and quantitative trait locus fine mapping. Genetics 184: 789–798. doi: 10.1534/genetics.109.108431. pmid:20008575
Haldane J (1919) The combination of linkage values and the calculation of distances between the loci of linked factors. Journal of Genetics 8: 299–939.
[69]
R Core Team R (2014) R: A language and environment for statistical computing.
[70]
VanRaden PM, O’Connell JR, Wiggans GR, Weigel KA (2011) Genomic evaluations with many more genotypes. Genet Sel Evol 43. doi: 10.1186/1297-9686-43-10
[71]
O’Connell JR (2014) MMAP User Guide (2014). .
[72]
O'Connell J (2013) MMAP: a comprehensive mixed model program for analysis of pedigree and population data. 63th Annual Meeting of The American Society of Human Genetics, Oct 22–262013, Boston, USA.
