Cattle Sex-Specific Recombination and Genetic Control from a Large Pedigree Analysis

Abstract

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.

Coding and noncoding variants in HFM1, MLH3, MSH4, MSH5, RNF212, and RNF212B affect recombination rate in cattle

“…The frequency distributions of the number of COs in sperm and oocytes in the different populations are presented in Supplemental Note S1. Consistently with recent findings in cattle (Ma et al 2015) and sheep , the GRR was found to be higher in males (23.3 Morgans [M]) than in females (21.4 M). This was consistent across populations (ratio of male to female GRR ranging from 1.06 to 1.10, corresponding to genetic maps being from +120 to +220 centimorgans [cM] larger in males) and chromosomes.…”

“…The longer male than female map in cattle is primarily due to the higher frequency of terminal COs (particularly on the distal end) in males than in females. Increased recombination rates near telomeres have also been observed in human (Broman et al 1998), mouse (Liu et al 2014), chimpanzee (Venn et al 2014), and cattle (Ma et al 2015). In species other than cattle, the higher density of COs in subterminal regions in males (vs. females) is only relative to the corresponding chromosome average, while in cattle it is also higher in absolute terms.…”

“…These can be used to map quantitative trait loci (QTL) affecting individual variation in genome-wide or global recombination rate (GRR). Such GWAS have been conducted in humans (Kong et al 2008(Kong et al , 2014Chowdhury et al 2009;Fledel-Alon et al 2011), cattle (Sandor et al 2012;Ma et al 2015), and sheep , revealing the role of genes such as RNF212 in the three species. In humans, most identified variants were found to have sexspecific effects (Chowdhury et al 2009;Fledel-Alon et al 2011;Kong et al 2014).…”

Evolutionary mysteries in meiosis

“…Within species, the correlation between genetic map length (in cM, with 50 cM being equivalent to 1 CO per bivalent) and physical length (in megabases, Mb) per chromosome is very strong (R 2 . 0.95) [126][127][128][129][130][131], and often has an intercept of approximately 50 cM, consistent with occurrence of one obligate CO per bivalent. There is direct evidence indicating that bivalents lacking a CO have an increased probability of non-disjunction, resulting in unviable or unfit aneuploid offspring [132,133].…”

“…A number of explanations have been proposed, relating to mechanistic factors such as differences in chromatin structure [167][168][169], sexual dimorphism in the action of loci associated with CO rate (e.g. RNF212, [127,128,148]), and evolutionarily widespread processes such as sperm competition, sexual dimorphism and dispersal [162,170,171]. Some models point to a role of sex differences in selection during the haploid phase [172].…”