Sequence-based association analysis identifies coding and non-coding variants in HFM1, MLH3, MSH4, MSH5, RNF212 and RNF212B with large effects on male and female recombination rate in cattle

We herein study genetic recombination in three dairy cattle populations from France, New-Zealand and the Netherlands. We identify 2,395,177 crossover (CO) events in sperm cells transmitted by 2,940 sires to 94,516 offspring, and 579,996 CO events in oocytes transmitted by 11,461 cows to 25,332 offspring. When measured in identical family structures, the average number of CO in males (23.3) was found to be larger than in females (21.4). The heritability of global recombination rate (GRR) was estimated at 0.13 in males and 0.08 in females. The genetic correlation was equal to 0.66, indicating that shared variants are influencing GRR in both genders. Haplotype-based genome-wide association studies revealed seven genome-wide significant QTL. Variants identified by next-generating sequencing in 5 Mb windows encompassing the QTL peaks were imputed in order to perform a sequence-based association analysis. For four QTLs, we identified missense mutations in genes known to be involved in meiotic recombination among the most significantly associated variants. Most of the identified mutations had significant effects in both genders with three of them accounting each for approximately 10% of the genetic variance in males (the allelic substitution effect being approximately equal to one additional CO per genome). Thus, a large fraction of the genetic variance is associated with missense mutations in genes known to be involved in meiotic recombination. Our results are very different from reports of recombination in other species. For instance, in human, recombination rate is higher in females, distinct variants affect recombination rate in males and females, and the genetic correlation is close to 0, whereas in cattle, we observed a higher recombination rate in males controlled by shared variants effective in both sexes.