Transmission Distortion Affecting Human Noncrossover but Not Crossover Recombination: A Hidden Source of Meiotic Drive

Meiosis is a potentially important source of germline mutations, as sites of meiotic recombination experience recurrent double-strand breaks (DSBs). However, evidence for a local mutagenic effect of recombination from population sequence data has been equivocal, likely because mutation is only one of several forces shaping sequence variation. By sequencing large numbers of single crossover molecules obtained from human sperm for two recombination hotspots, we find direct evidence that recombination is mutagenic: Crossovers carry more de novo mutations than nonrecombinant DNA molecules analyzed for the same donors and hotspots. The observed mutations were primarily CG to TA transitions, with a higher frequency of transitions at CpG than non-CpGs sites. This enrichment of mutations at CpG sites at hotspots could predominate in methylated regions involving frequent single-stranded DNA processing as part of DSB repair. In addition, our data set provides evidence that GC alleles are preferentially transmitted during crossing over, opposing mutation, and shows that GC-biased gene conversion (gBGC) predominates over mutation in the sequence evolution of hotspots. These findings are consistent with the idea that gBGC could be an adaptation to counteract the mutational load of recombination. meiotic recombination | crossover | sequence evolution | biased gene conversion | mutation M eiotic recombination, localized in recombination hotspots, not only increases genetic diversity via the formation of new haplotypes but is also an important driver of sequence evolution. The binding sites used by the human recombination machinery involving PRDM9 (PR domain containing 9) are more eroded in humans than the same sequences in chimps, given that PRDM9 in chimps uses different binding sites (1). Moreover, regions in close vicinity to these PRDM9 binding sites also showed a significant enrichment of polymorphisms in humans (2). In addition, within-and between-species sequence diversity positively correlates with regions of high recombination activity in humans (3-7) and other eukaryotes (reviewed in refs. 8-10).One process recognized as a major evolutionary force reshaping the genomic nucleotide landscape at recombination hotspots, as shown in humans (6), chimpanzees (6, 11), mice (12), yeast (13), and metazoans (14), is GC-biased gene conversion (gBGC). In gBGC, the repair of heteroduplex tracts formed during meiotic recombination leads to the nonMendelian segregation of alleles favoring GC over AT variants. The precise molecular mechanisms leading to gBGC have yet to be unraveled, but experimental evidence has shown that in crossovers (COs) of fission yeast, GC alleles can be overtransmitted within ∼1-2 kb in length of the double-strand break (DSB) region (13), implicating mismatch repair (15).However, it is also plausible that the higher sequence variation observed at recombination hotspots is a result of a mutagenic effect of recombination: meiotic recombination is initiated by DSBs, which are associated with an increased mutati...

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“…35 and 36 and references in ref. 37), or gene conversion favoring GC-alleles, leading to gBGC (15). Patterns seen in our data ( Fig.…”

Section: Significancesupporting

confidence: 71%

Crossovers are associated with mutation and biased gene conversion at recombination hotspots

Arbeithuber

Betancourt²,

Ebner

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

225

218

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“…Comparable estimates have been obtained based on sperm genotyping 6,7 (not genomewide) and coalescent inferences 14,15,25 . Our genomewide estimate of G is 9.5/Mb/generation in the chip dataset (unadjusted for SNP ascertainment) and 5.9/Mb/generation in the sequencing dataset (cf.…”

Section: Resultsmentioning

confidence: 99%

“…Crossover events, which arise through the resolution of the double Holliday junction (dHj) 4 , are also frequently accompanied by gene conversions, hereafter referred to as CO gene conversions. NCO gene conversions most commonly arise via the synthesis-dependent strand annealing (SDSA) pathway 5 , generating short regions of unidirectional homologous exchange 6,7 , but the resolution of the dHj can also lead to NCO gene conversions 8,9 . A schematic overview of these DSB repair mechanisms is given in Supplementary Figure 1.…”

Section: Introductionmentioning

confidence: 99%

The rate of meiotic gene conversion varies by sex and age

et al. 2016

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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 Mb 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 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 conversions in oocytes.

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“…Gene conversion is biased in favor of transmission of GC alleles in many eukaryotes (Duret and Galtier 2009). Such a bias has been observed directly in noncrossover (Odenthal-Hesse et al 2014) and crossover (Arbeithuber et al 2015) recombination products in human sperm and can explain patterns of GC content enrichment at mouse hot spots (Clement and Arndt 2013). Accordingly, we found that, in males, noncrossovers frequently showed significant bias, resulting in more conversion to GC than to AT (Supplemental Table S2).…”

Section: Biased Gene Conversion In Noncrossoversmentioning

confidence: 53%

Local and sex-specific biases in crossover vs. noncrossover outcomes at meiotic recombination hot spots in mice

2015

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Meiotic recombination initiated by programmed double-strand breaks (DSBs) yields two types of interhomolog recombination products, crossovers and noncrossovers, but what determines whether a DSB will yield a crossover or noncrossover is not understood. In this study, we analyzed the influence of sex and chromosomal location on mammalian recombination outcomes by constructing fine-scale recombination maps in both males and females at two mouse hot spots located in different regions of the same chromosome. These include the most comprehensive maps of recombination hot spots in oocytes to date. One hot spot, located centrally on chromosome 1, behaved similarly in male and female meiosis: Crossovers and noncrossovers formed at comparable levels and ratios in both sexes. In contrast, at a distal hot spot, crossovers were recovered only in males even though noncrossovers were obtained at similar frequencies in both sexes. These findings reveal an example of extreme sex-specific bias in recombination outcome. We further found that estimates of relative DSB levels are surprisingly poor predictors of relative crossover frequencies between hot spots in males. Our results demonstrate that the outcome of mammalian meiotic recombination can be biased, that this bias can vary depending on location and cellular context, and that DSB frequency is not the only determinant of crossover frequency.

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Transmission Distortion Affecting Human Noncrossover but Not Crossover Recombination: A Hidden Source of Meiotic Drive

Cited by 62 publications

References 52 publications

Crossovers are associated with mutation and biased gene conversion at recombination hotspots

Crossovers are associated with mutation and biased gene conversion at recombination hotspots

The rate of meiotic gene conversion varies by sex and age

Local and sex-specific biases in crossover vs. noncrossover outcomes at meiotic recombination hot spots in mice

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