Non-crossover gene conversions show strong GC bias and unexpected clustering in humans

Abstract

Although the past decade has seen tremendous progress in our understanding of fine-scale recombination, little is known about non-crossover (NCO) gene conversion. We report the first genome-wide study of NCO events in humans. Using SNP array data from 98 meioses, we identified 103 sites affected by NCO, of which 50/52 were confirmed in sequence data. Overlap with double strand break (DSB) hotspots indicates that most of the events are likely of meiotic origin. We estimate that a site is involved in a NCO at a rate of 5.9 × 10−6/bp/generation, consistent with sperm-typing studies, and infer that tract lengths span at least an order of magnitude. Observed NCO events show strong allelic bias at heterozygous AT/GC SNPs, with 68% (58–78%) transmitting GC alleles (p = 5 × 10−4). Strikingly, in 4 of 15 regions with resequencing data, multiple disjoint NCO tracts cluster in close proximity (∼20–30 kb), a phenomenon not previously seen in mammals.DOI: http://dx.doi.org/10.7554/eLife.04637.001

Quantification of GC-biased gene conversion in the human genome

“…5). This result corroborates a recent study of NCO recombination events in human pedigrees, which revealed the same segregation bias in favor of GC-allele at CpG and non-CpG sites (Williams et al 2015). These observations provide insights about the molecular mechanisms causing gBGC in humans.…”

“…Recently, Williams and colleagues published a large-scale study of gene conversion tracts associated with noncrossover (NCO) recombination events in humans (Williams et al 2015). Their analysis identified 103 NCOs and provided the first genome-wide quantification of GC-biased transmission distortion in humans: Among the AT/GC heterozygous SNPs that were involved in a NCO gene conversion, the GC allele was transmitted at a frequency F S = 68% (95% confidence interval: 58%-78%).…”

“…The gBGC coefficient (conditional to the fact that the SNP is affected by a NCO event) is b i = 2 × F S − 1. Given the rate of NCO gene conversion (r NCO = 5.7 × 10 −6 /bp/ generation; CI: 4.5 × 10 −6 -7.3 × 10 −6 ) (Williams et al 2015), and assuming an effective population size of 10,000-20,000, this implies that the population-scaled gBGC coefficient associated with NCOs (B NCO = 4 N e × r NCO × b i ) is ∼0.08-0.16. In humans and mice, crossover recombination events (COs) are ∼5-15 times less frequent than NCOs, but their conversion tracts are ∼2-8 times longer (Jeffreys and May 2004;Cole et al 2014).…”

Chromosome-wide distribution and characterization of intersubspecific meiotic noncrossovers in mice

“…Another difference from the human studies is an almost complete absence of complex NCO gene conversions in our dataset. Only one out of 94 NCO events was a 231 bp long complex conversion interrupted by one nonconverted SNP in contrast to 46% or 65% of complex events found in human studies 30,53 .…”

“…The NCO gene conversion tracts were much shorter, 50–300 bp at the mouse Psmb9 hotspot and two hotspots on chromosome 1 51,52 and 55–290 bp at the MHC hotspot in human chromosome 6 18 . More recently, a human genome-wide study based on Illumina SNP arrays indicated the multiple-SNP NCO gene conversion tract length in the range of 100–1000 bp 53 , while most of NCO events involved only one SNP due to low SNP density. Thus our estimate, 32 bp, based on the screen of 10 mouse chromosomes is much shorter than reported previously for individual hotspots but close to another recent mouse study showing 30 bp and 41 bp for two different Prdm9 alleles 48 .…”