A Neutral Explanation for the Correlation of Diversity with Recombination Rates in Humans

Abstract

One of the most striking findings to emerge from the study of genomic patterns of variation is that regions with lower recombination rates tend to have lower levels of intraspecific diversity but not of interspecies divergence. This uncoupling of variation within and between species has been widely interpreted as evidence that natural selection shapes patterns of genetic variability genomewide. We revisited the relationship between diversity, divergence, and recombination in humans, using data from closely related species and better estimates of recombination rates than previously available. We show that regions that experience less recombination have reduced divergence to chimpanzee and to baboon, as well as lower levels of diversity. This observation suggests that mutation and recombination are associated processes in humans, so that the positive correlation between diversity and recombination may have a purely neutral explanation. Consistent with this hypothesis, diversity levels no longer increase significantly with recombination rates after correction for divergence to chimpanzee.

No effect of recombination on the efficacy of natural selection in primates

“…While this scenario is possible, it would require a very specific distribution of selection coefficients, which ensures that HRI is sufficiently strong to prevent the fixation of any beneficial mutations in 60-70 Myr, and yet not strong enough to allow for the fixation of any weakly deleterious mutations by drift. A simpler explanation for most of these d N = 0 genes may be that genes with a lower recombination rate tend to have a lower substitution rate (Hellmann et al 2003a(Hellmann et al , 2005. Consistent with this hypothesis, d S is much lower in genes with d N = 0 (broad-scale: P = 4 ‫ן‬ 10 ‫8מ‬ ; fine-scale: P = 1 ‫ן‬ 10 ‫9מ‬ by a two-tailed t-test).…”

“…The correlation between recombination rate and d S (and d N ) could reflect a mutagenic effect of recombination (Hellmann et al 2003a(Hellmann et al , 2005 or could reflect nonequilibrium GC content, e.g., caused by biased gene conversion Webster et al 2003;Spencer et al 2006). Regardless of the reason, measuring the rate of protein evolution using the ratio d N /d S should control at least partially for mutation rate variation, assuming d S is largely a reflection of the fixation of neutral alleles.…”

Genomic Regionality in Rates of Evolution Is Not Explained by Clustering of Genes of Comparable Expression Profile

“…The rate of synonymous evolution covaries with regional GC content (Smith and Hurst 1999;Bielawski et al 2000;Hurst and Williams 2000;Castresana 2002b;Hardison et al 2003), although the exact form and strength of this relationship is still a matter of debate, and seems to depend on methodology Bierne and Eyre-Walker 2003). There is also evidence of a positive correlation between K 4 and meiotic recombination rate (Perry and Ashworth 1999;Filatov 2003;Filatov and Gerrard 2003;Hellmann et al 2003), possibly indicating a mutagenic effect of recombination. GC and recombination rates are known to covary (Eyre-Walker 1993; Fullerton et al 2001), and it has recently been argued that substitutional GC biases are directly associated with recombination events (Meunier and Duret 2004).…”

“…Aside from transcription, other possibilities to explain the local variation in the synonymous substitution rate include (1) heterogeneity in the activity of repair enzymes (Matassi et al 1999), (2) recombination-associated mutational and/or repair hotspots (Perry and Ashworth 1999;Filatov and Gerrard 2003;Hellmann et al 2003), and (3) GCassociated mutation or fixation biases (Lercher et al 2001;Castresana 2002b;Yi et al 2002;Hardison et al 2003). We examine the last two of these together, as it has been argued that they are not independent (Meunier and Duret 2004).…”

Recent developments in genetic data analysis: what can they tell us about human demographic history?

“…Given this perspective, it does not aim to be an exhaustive treatment of the genetic evidence for past human demographic history, which has been well covered recently (Harpending and Rogers, 2000;Relethford, 2001;Goldstein and Chikhi, 2002;CavalliSforza and Feldman, 2003). The motivation behind this review is that the connection between genetic data and demographic history appears rather more complicated than hitherto appreciated, and, as evidence of the widespread effects of selection in the human genome continues to mount Nachman, 2001;Payseur and Nachman, 2002; but see Hellmann et al, 2003), and with increasing concerns of the subtle effects of ascertainment and population structure (Wakeley, 1999;Wakeley et al, 2001;Ptak and Przeworski, 2002), it is from a rigorous model-based perspective that progress may be best made. Humans are an ideal model organism for this research programme because of the wide availability of genetic markers, background historical information and general availability of funding.…”