Common and low-frequency variants associated with genome-wide recombination rate

Abstract

Meiotic recombination contributes to genetic diversity by yielding new combinations of alleles. Individuals vary with respect to the genome-wide recombination counts in their gametes. Exploiting data resources in Iceland, we compiled a data set consisting of 35,927 distinct parents and 71,929 parent-offspring pairs. Within this data set, we called over 2.2 million recombination events and imputed variants with sequence-level resolution from 2,261 whole genome-sequenced individuals into the parents to search for variants influencing recombination rate. We identified 13 variants in 8 regions that are associated with genome-wide recombination rate, 8 of which were previously unknown. Three of these variants associate with male recombination rate only, seven variants associate with female recombination rate only and three variants affect both. Two are low-frequency variants with large effects, one of which is estimated to increase the male and female genetic maps by 111 and 416 cM, respectively. This variant, located in an intron, would not be found by exome sequencing.

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

“…We nevertheless observed three variants that appeared to only affect GRR in males, and one only in females. The female-specificity of the MSH4 variant (rs210318688) is in agreement with previous findings in human (Y589C) (Kong et al 2014) and in cattle (Ma et al 2015). It is noteworthy that knocking-out MSH4 in the mouse affects both male and female recombination (Kneitz et al 2000).…”

“…This contradicts reports in humans, where male and female GRR were shown to be genetically uncorrelated (Fledel-Alon et al 2011). This suggests that, contrary to the situation in humans (where most variants were shown to be active in only one sex, or-in the case of RNF212-even have opposite effects in the two sexes [Kong et al 2008[Kong et al , 2014Chowdhury et al 2009;Fledel-Alon et al 2011]), at least some variants (including in RNF212) consistently affect male and female GRR. Indeed, six of the 10 identified variants had a significant and consistent effect in both sexes.…”

“…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

“…R. Soc. B 371: 20160001 surplus COs [147,148]; indeed, the identification of loci affecting variation in CO rates indicates the potential for rapid evolution of CO rates within and between species [149].…”

“…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].…”