The rate of meiotic gene conversion varies by sex and age

Abstract

Meiotic recombination involves a combination of gene conversion and crossover events that, along with mutations, produce germline genetic diversity. Here we report the discovery of 3,176 SNP and 61 indel gene conversions. Our estimate of the non-crossover (NCO) gene conversion rate (G) is 7.0 for SNPs and 5.8 for indels per megabase per generation, and the GC bias is 67.6%. For indels, we demonstrate a 65.6% preference for the shorter allele. NCO gene conversions from mothers are longer than those from fathers, and G is 2.17 times greater in mothers. Notably, G increases with the age of mothers, but not the age of fathers. A disproportionate number of NCO gene conversions in older mothers occur outside double-strand break (DSB) regions and in regions with relatively low GC content. This points to age-related changes in the mechanisms of meiotic gene conversion in oocytes.

Figure 1

The study design and method used for detecting gene conversions. Including a) the family structure and b) the two sources of genotypes. c) The genotypes of the siblings are necessary to verify the haplotypes of both parents. We require at least one child of the proband to verify the gene conversion. The method is shown for NCO gene conversion.

Figure 2

NCO gene conversion rate, G. As a function of a) age of parent, b) distance from telomere, c) age of mother stratified by presence in DSB region and d) age of mother stratified by presence in crossover recombination hotspots. e) percent GC content of neighboring 100 bases for gene converted markers outside of double strand break regions as a functionof age of mother. Blue represents paternal and red maternal transmission. Error bars represent 95% confidence intervals. a) Number of parents in each age bin are presented in top of figure. a,c,d,e) Individuals are grouped into 2 year age bins with all individuals younger than 20 grouped together and all individuals 40 years or older grouped together. b) mpps are grouped into 5Mb bins. Crossover recombination rate is computed as the average over all marker proband pairs in a bin of average crossover recombination rate in +/– 5kb interval around a marker. cM = centiMorgan, Mb = 1 million base pairs.

Figure 3

NCO gene conversion rate G, as a function of GC content of neighboring 100bp. a) G outside of male DSB regions. b) G inside of male DSB regions. Error bars represent 95% confidence intervals. The dotted line represents a linear model. NCO = non-crossover, DSB = double strand break

Figure 4

Complex crossovers (CCO) and maternal age. a) Complex crossover (CCO) gene conversion rate by maternal age in the chip dataset. b) Fraction of maternally transmitted crossovers in the chip dataset that are complex, as a function of mother's age. Error bars represent 95% confidence intervals. The dotted line represents a linear model.