[en] We herein study genetic recombination in three cattle populations from France, New Zealand, and the Netherlands. We identify 2,395,177 crossover (CO) events in 94,516 male gametes, and 579,996 CO events in 25,332 female gametes. The average number of COs was found to be larger in males (23.3) than in females (21.4). The heritability of global recombination rate (GRR) was estimated at 0.13 in males and 0.08 in females, with a genetic correlation of 0.66 indicating that shared variants are influencing GRR in both sexes. A genome-wide association study identified seven quantitative trait loci (QTL) for GRR. Fine-mapping following sequence-based imputation in 14,401 animals pinpointed likely causative coding (5) and noncoding (1) variants in genes known to be involved in meiotic recombination (HFM1, MSH4, RNF212, MLH3, MSH5) for 5/7 QTL, and noncoding variants (3) in RNF212B for 1/7 QTL. This suggests that this RNF212 paralog might also be involved in recombination. Most of the identified mutations had significant effects in both sexes, with three of them each accounting for approximately 10% of the genetic variance in males.
Disciplines :
Genetics & genetic processes
Author, co-author :
Kadri, Naveen Kumar ; Université de Liège > Département des productions animales (DPA) > GIGA-R : Génomique animale
Harland, Chad ; Université de Liège > Département des productions animales (DPA) > GIGA-R : Génomique animale
Faux, Pierre ; Université de Liège > Département des productions animales (DPA) > GIGA-R : Génomique animale
Cambisano, Nadine
Karim, Latifa
Coppieters, Wouter ; Université de Liège > Département des productions animales (DPA) > GIGA-R : Génomique animale
Fritz, Sebastien
Mullaart, Erik
Baurain, Denis ; Université de Liège > Département des sciences de la vie > Phylogénomique des eucaryotes
Boichard, Didier
Spelman, Richard
Charlier, Carole ; Université de Liège > Département des productions animales (DPA) > GIGA-R : Génomique animale
Georges, Michel ; Université de Liège > Département des productions animales (DPA) > GIGA-R : Génomique animale
Druet, Tom ; Université de Liège > Département des productions animales (DPA) > GIGA-R : Génomique animale
Agarwal S, Roeder GS. 2000. Zip3 provides a link between recombination enzymes and synaptonemal complex proteins. Cell 102: 245-255.
Andersson L. 2008. Genome-wide association analysis in domestic animals: a powerful approach for genetic dissection of trait loci. Genetica 136: 341-349.
Battagin M, Gorjanc G, Faux A-M, Johnston SE, Hickey JM. 2016. Effect of manipulating recombination rates on response to selection in livestock breeding programs. Genet Sel Evol 48: 44.
Baudat F, Buard J, Grey C, Fledel-Alon A, Ober C, Przeworski M, Coop G, De Massy B. 2010. PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice. Science 327: 836-840.
Baudat F, Imai Y, de Massy B. 2013. Meiotic recombination in mammals: localization and regulation. Nat Rev Genet 14: 794-806.
Bocker T, Barusevicius A, Snowden T, Rasio D, Guerrette S, Robbins D, Schmidt C, Burczak J, Croce CM, Copeland T. 1999. hMSH5: a human MutS homologue that forms a novel heterodimer with hMSH4 and is expressed during spermatogenesis. Cancer Res 59: 816-822.
Broman KW, Murray JC, Sheffield VC, White RL, Weber JL. 1998. Comprehensive human genetic maps: individual and sex-specific variation in recombination. Am J Hum Genet 63: 861-869.
Brown MS, Lim E, Chen C, Nishant K, Alani E. 2013. Genetic analysis of mlh3 mutations reveals interactions between crossover promoting factors during meiosis in baker's yeast. G3 (Bethesda) 3: 9-22.
Browning SR, Browning BL. 2007. Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering. Am J Hum Genet 81: 1084-1097.
Chowdhury R, Bois P, Feingold E, Sherman SL, Cheung VG. 2009. Genetic analysis of variation in human meiotic recombination. PLoS Genet 5: e1000648.
Cingolani P, Platts A, Wang LL, Coon M, Nguyen T, Wang L, Land SJ, Lu X, Ruden DM. 2012. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly 6: 80-92.
Coop G, Przeworski M. 2007. An evolutionary view of human recombination. Nat Rev Genet 8: 23-34.
Crawford A, Dodds K, Ede A, Pierson C, Montgomery G, Garmonsway H, Beattie A, Davies K, Maddox J, Kappes S. 1995. An autosomal genetic linkage map of the sheep genome. Genetics 140: 703-724.
Crismani W, Girard C, Froger N, Pradillo M, Santos JL, Chelysheva L, Copenhaver GP, Horlow C, Mercier R. 2012. FANCM limits meiotic crossovers. Science 336: 1588-1590.
Dehal P, Boore JL. 2005. Two rounds of whole genome duplication in the ancestral vertebrate. PLoS Biol 3: e314.
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.
Druet T, Georges M. 2015. LINKPHASE3: an improved pedigree-based phasing algorithm robust to genotyping and map errors. Bioinformatics 31: 1677-1679.
Druet T, Ahariz N, Cambisano N, Tamma N, Michaux C, Coppieters W, Charlier C, Georges M. 2014. Selection in action: dissecting the molecular underpinnings of the increasing muscle mass of Belgian Blue Cattle. BMC Genomics 15: 796.
Edelmann W, Cohen PE, Kneitz B, Winand N, Lia M, Heyer J, Kolodner R, Pollard JW, Kucherlapati R. 1999. Mammalian MutS homologue 5 is required for chromosome pairing in meiosis. Nat Genet 21: 123-127.
Finucane HK, Bulik-Sullivan B, Gusev A, Trynka G, Reshef Y, Loh P-R, Anttila V, Xu H, Zang C, Farh K. 2015. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat Genet 47: 1228-1235.
Fledel-Alon A, Leffler EM, Guan Y, Stephens M, Coop G, Przeworski M. 2011. Variation in human recombination rates and its genetic determinants. PLoS One 6: e20321.
Flint J, Mackay TF. 2009. Genetic architecture of quantitative traits in mice, flies, and humans. Genome Res 19: 723-733.
The Gene Ontology Consortium. 2015. Gene Ontology Consortium: going forward. Nucleic Acids Res 43: D1049-D1056.
Groenen MA, Wahlberg P, Foglio M, Cheng HH, Megens H-J, Crooijmans RP, Besnier F, Lathrop M, Muir WM, Wong GK-S. 2009. A high-density SNP-based linkage map of the chicken genome reveals sequence features correlated with recombination rate. Genome Res 19: 510-519.
Guiraldelli MF, Eyster C, Wilkerson JL, Dresser ME, Pezza RJ. 2013. Mouse HFM1/Mer3 is required for crossover formation and complete synapsis of homologous chromosomes during meiosis. PLoS Genet 9: e1003383.
Haldane JB. 1922. Sex ratio and unisexual sterility in hybrid animals. J Genet 12: 101-109.
Holland PW, Garcia-Fernandez J, Williams NA, Sidow A. 1994. Gene duplications and the origins of vertebrate development. Development 1994: 125-133.
Hollingsworth NM, Ponte L, Halsey C. 1995. MSH5, a novel MutS homolog, facilitates meiotic reciprocal recombination between homologs in Saccharomyces cerevisiae but not mismatch repair. Genes Dev 9: 1728-1739.
Jantsch V, Pasierbek P, Mueller MM, Schweizer D, Jantsch M, Loidl J. 2004. Targeted gene knockout reveals a role in meiotic recombination for ZHP- 3, a Zip3-related protein in Caenorhabditis elegans. Mol Cell Biol 24: 7998-8006.
Johnston SE, Berenos C, Slate J, Pemberton JM. 2016. Conserved genetic architecture underlying individual recombination rate variation in a wild population of Soay sheep (Ovis aries). Genetics 203: 583-598.
Kemper KE, Goddard ME. 2012. Understanding and predicting complex traits: knowledge from cattle. Hum Mol Genet 21: R45-R51.
Kneitz B, Cohen PE, Avdievich E, Zhu L, Kane MF, Hou H, Kolodner RD, Kucherlapati R, Pollard JW, EdelmannW. 2000. MutS homolog 4 localization to meiotic chromosomes is required for chromosome pairing during meiosis in male and female mice. Genes Dev 14: 1085-1097.
Kohl KP, Sekelsky J. 2013. Meiotic and mitotic recombination in meiosis. Genetics 194: 327-334.
Kong A, Barnard J, Gudbjartsson DF, Thorleifsson G, Jonsdottir G, Sigurdardottir S, Richardsson B, Jonsdottir J, Thorgeirsson T, Frigge ML. 2004. Recombination rate and reproductive success in humans. Nat Genet 36: 1203-1206.
Kong A, Thorleifsson G, Stefansson H, Masson G, Helgason A, Gudbjartsson DF, Jonsdottir GM, Gudjonsson SA, Sverrisson S, Thorlacius T. 2008. Sequence variants in the RNF212 gene associate with genome-wide recombination rate. Science 319: 1398-1401.
Kong A, Thorleifsson G, Frigge ML, Masson G, Gubjartsson DF, Villemoes R, Magnusdottir E, Olafsdottir SB, Thorsteinsdottir U, Stefansson K. 2014. Common and low-frequency variants associated with genome-wide recombination rate. Nat Genet 46: 11-16.
Lenormand T, Dutheil J. 2005. Recombination difference between sexes: a role for haploid selection. PLoS Biol 3: e63.
Lipkin SM, Moens PB, Wang V, Lenzi M, Shanmugarajah D, Gilgeous A, Thomas J, Cheng J, Touchman JW, Green ED. 2002. Meiotic arrest and aneuploidy in MLH3-deficient mice. Nat Genet 31: 385-390.
Liu EY, Morgan AP, Chesler EJ, Wang W, Churchill GA, de Villena FP-M. 2014. High-resolution sex-specific linkage maps of the mouse reveal polarized distribution of crossovers in male germline. Genetics 197: 91-106.
Lynn A, Koehler KE, Judis L, Chan ER, Cherry JP, Schwartz S, Seftel A, Hunt PA, Hassold TJ. 2002. Covariation of synaptonemal complex length and mammalian meiotic exchange rates. Science 296: 2222-2225.
Ma L, O'Connell JR, VanRaden PM, Shen B, Padhi A, Sun C, Bickhart DM, Cole JB, Null DJ, Liu GE. 2015. Cattle sex-specific recombination and genetic control from a large pedigree analysis. PLoS Genet 11: e1005387.
Mercier R, Jolivet S, Vezon D, Huppe E, Chelysheva L, Giovanni M, Nogue F, Doutriaux M-P, Horlow C, Grelon M. 2005. Two meiotic crossover classes cohabit in Arabidopsis: One is dependent on MER3, whereas the other one is not. Curr Biol 15: 692-701.
Misztal I, Tsuruta S, Strabel T, Auvray B, Druet T, Lee D. 2002. BLUPF90 and related programs (BGF90). In Proceedings of the 7th world congress on genetics applied to livestock production, Vol. 28, pp. 21-22, Montpellier, France.
Moen T, Hoyheim B, Munck H, Gomez-Raya L. 2004. A linkage map of Atlantic salmon (Salmo salar) reveals an uncommonly large difference in recombination rate between the sexes. Anim Genet 35: 81-92.
Morgan TH. 1912. Complete linkage in the second chromosome of the male of Drosophila. Science 36: 719-720.
Morgan T. 1914. No crossing over in the male of Drosophila of genes in the second and third pairs of chromosomes. Biol Bull 26: 195-204.
Munoz M, Alves E, Ramayo-Caldas Y, Casellas J, Rodriguez C, Folch J, Silio L, Fernandez A. 2012. Recombination rates across porcine autosomes inferred from high-density linkage maps. Anim Genet 43: 620-623.
Nakagawa T, Kolodner RD. 2002. Saccharomyces cerevisiae Mer3 is a DNA helicase involved in meiotic crossing over. Mol Cell Biol 22: 3281-3291.
Neff MW, Broman KW, Mellersh CS, Ray K, Acland GM, Aguirre GD, Ziegle JS, Ostrander EA, Rine J. 1999. A second-generation genetic linkage map of the domestic dog, Canis familiaris. Genetics 151: 803-820.
Nishant K, Chen C, Shinohara M, Shinohara A, Alani E. 2010. Genetic analysis of baker's yeast Msh4-Msh5 reveals a threshold crossover level for meiotic viability. PLoS Genet 6: e1001083.
Ohno S. 1970. Evolution by gene duplication. Springer, New York.
Paldi A, Gyapay G, Jami J. 1995. Imprinted chromosomal regions of the human genome display sex-specific meiotic recombination frequencies. Curr Biol 5: 1030-1035.
Petkov PM, Broman KW, Szatkiewicz JP, Paigen K. 2007. Crossover interference underlies sex differences in recombination rates. Trends Genet 23: 539-542.
Petryszak R, Burdett T, Fiorelli B, Fonseca NA, Gonzalez-Porta M, Hastings E, HuberW, Jupp S, Keays M, Kryvych N. 2014. Expression Atlas update-a database of gene and transcript expression from microarray- and sequencing- based functional genomics experiments. Nucleic Acids Res 42: D926-D932.
Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D. 2006. Principal components analysis corrects for stratification in genome- wide association studies. Nat Genet 38: 904-909.
Reynolds A, Qiao H, Yang Y, Chen JK, Jackson N, Biswas K, Holloway JK, Baudat F, de Massy B, Wang J. 2013. RNF212 is a dosage-sensitive regulator of crossing-over during mammalian meiosis. Nat Genet 45: 269-278.
Ross-Macdonald P, Roeder GS. 1994. Mutation of a meiosis-specific MutS homolog decreases crossing over but not mismatch correction. Cell 79: 1069-1080.
Sandor C, Li W, Coppieters W, Druet T, Charlier C, Georges M. 2012. Genetic variants in REC8, RNF212, and PRDM9 influence male recombination in cattle. PLoS Genet 8: e1002854.
Santucci-Darmanin S, Neyton S, Lespinasse F, Saunieres A, Gaudray P, Paquis-Flucklinger V. 2002. The DNA mismatch-repair MLH3 protein interacts with MSH4 in meiotic cells, supporting a role for this MutL homolog in mammalian meiotic recombination. Hum Mol Genet 11: 1697-1706.
Scheet P, Stephens M. 2006. A fast and flexible statistical model for largescale population genotype data: applications to inferring missing genotypes and haplotypic phase. Am J Hum Genet 78: 629-644.
Singer A, Perlman H, Yan Y, Walker C, Corley-Smith G, Brandhorst B, Postlethwait J. 2002. Sex-specific recombination rates in zebrafish (Danio rerio). Genetics 160: 649-657.
Venn O, Turner I, Mathieson I, de Groot N, Bontrop R, McVean G. 2014. Strong male bias drives germline mutation in chimpanzees. Science 344: 1272-1275.
Yang J, Benyamin B, McEvoy BP, Gordon S, Henders AK, Nyholt DR, Madden PA, Heath AC, Martin NG, Montgomery GW. 2010. Common SNPs explain a large proportion of the heritability for human height. Nat Genet 42: 565-569.
Yang J, Lee SH, Goddard ME, Visscher PM. 2011. GCTA: a tool for genomewide complex trait analysis. Am J Hum Genet 88: 76-82.
