HIGHER MALE THAN FEMALE RECOMBINATION RATE LARGELY CONTROLLED BY MISSENSE VARIANTS IN RNF212, MLH3, HFM1, MSH5 AND MSH4 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. The P259S variant identified in RNF212 had already been reported,
whereas missense mutations in MLH3 (N408S), HFM1 (S1189L), MSH5
(R631Q), MSH4 (C342Y) and a second in RNF212 (A77T) are new.
Surprisingly, variants previously identified in REC8 were not associated with a
QTL detected on BTA10 whereas variants in RNF212B, a paralog of RNF212,
showed much stronger association with the phenotype in this region. This
suggests that RNF212B might be involved in the recombination process. 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.