Pervasive Hitchhiking at Coding and Regulatory Sites in Humans

Abstract

Much effort and interest have focused on assessing the importance of natural selection, particularly positive natural selection, in shaping the human genome. Although scans for positive selection have identified candidate loci that may be associated with positive selection in humans, such scans do not indicate whether adaptation is frequent in general in humans. Studies based on the reasoning of the MacDonald–Kreitman test, which, in principle, can be used to evaluate the extent of positive selection, suggested that adaptation is detectable in the human genome but that it is less common than in Drosophila or Escherichia coli. Both positive and purifying natural selection at functional sites should affect levels and patterns of polymorphism at linked nonfunctional sites. Here, we search for these effects by analyzing patterns of neutral polymorphism in humans in relation to the rates of recombination, functional density, and functional divergence with chimpanzees. We find that the levels of neutral polymorphism are lower in the regions of lower recombination and in the regions of higher functional density or divergence. These correlations persist after controlling for the variation in GC content, density of simple repeats, selective constraint, mutation rate, and depth of sequencing coverage. We argue that these results are most plausibly explained by the effects of natural selection at functional sites—either recurrent selective sweeps or background selection—on the levels of linked neutral polymorphism. Natural selection at both coding and regulatory sites appears to affect linked neutral polymorphism, reducing neutral polymorphism by 6% genome-wide and by 11% in the gene-rich half of the human genome. These findings suggest that the effects of natural selection at linked sites cannot be ignored in the study of neutral human polymorphism.

Heterozygote advantage as a natural consequence of adaptation in diploids

“…Although our model also predicts such fast fixation events, it additionally predicts that many adaptive mutations will initially only sweep to intermediate frequencies, where they are then maintained for a period of time by balancing selection, before continuing on to either fixation or loss. Both models thus predict an elevated rate of fixation at functional sites compared with the neutral expectation and a local reduction of genetic diversity around adaptive sites, as have been observed in a range of organisms (27)(28)(29)(30). However, in contrast to the classic model, we also expect the presence of many incomplete selective sweeps.…”

A coalescent model of background selection with recombination, demography and variation in selection coefficients

“…The simulations reveal several patterns that are readily testable using DNA sequence polymorphisms: (1) a positive correlation between neutral diversity and recombination rates (Figure 3; Shapiro et al, 2007;Cai et al, 2009;Cutter and Choi, 2010); (2) a positive correlation between neutral diversity and the distance to regions subject to background selection (Figure 4b; McVicker et al, 2009); (3) a deficit of diversity in the middle of a selected region (Figures 3 and 4b; Comeron and Guthrie, 2005); (4) a negative correlation between the prevalence of singletons (or low-frequency variants) and recombination rates (Figure 3; Shapiro et al, 2007;Lohmueller et al, 2011); (5) a negative correlation between the prevalence of singletons and the distance to regions subject to background selection (Figure 4c; Lohmueller et al, 2011); (6) an excess of singletons in the middle of a selected region (Figures 3 and 4c). Encouragingly, these patterns exist in the presence of recent demographic changes (Figure 4; Supplementary Figures S1 to S3), suggesting that previous analyses based on these correlations are likely to be robust.…”

“…Such a relationship has been found in many organisms such as Drosophila (Begun and Aquadro, 1992), humans (Cai et al, 2009) and Caenorhabditis (Cutter and Choi, 2010). Two population genetic models, selective sweeps and background selection, have been widely perceived as potential explanations for this correlation Charlesworth, 2012a).…”

Patterns of Neutral Diversity Under General Models of Selective Sweeps

“…Moreover, levels of diversity are also lower in regions that a priori are expected to have a higher rate of functional mutations, e.g., near genes and conserved elements (Cai et al 2009;McVicker et al 2009;Hernandez et al 2011). Since the rate of neutral genetic drift is independent of recombination rate, this positive correlation between recombination rates and diversity offers good evidence that linked selection plays a substantial role in the fate of alleles, especially in lowrecombination regions.…”

“…Under the neutral theory of molecular evolution this stochasticity is thought to result mostly from genetic drift (Kimura 1983), the random resampling that occurs in finite populations, an effect that is exaggerated by fluctuating population size and large variation in reproductive success among individuals (see Charlesworth 2009, for a recent review). However, selection at linked sites may provide a major source of stochasticity as the dynamics of a neutral allele can be strongly influenced by the random genetic background on which selected alleles arise (Maynard Smith and Haigh 1974;Kaplan et al 1989;Charlesworth et al 1995;Hudson and Kaplan 1995b).In many species examined to date, levels of diversity are substantially lower in regions of low recombination, as found in multiple species of Drosophila (Aguade et al 1989;Berry et al 1991;Begun and Aquadro 1992;Begun et al 2007;Shapiro et al 2007), Caenorhabditis (Cutter and Payseur 2003;Cutter and Choi 2010), humans (Hellmann et al 2008;Cai et al 2009), and Saccharomyces cerevisiae (Cutter and Moses 2011), but not in all species, e.g., Arabidopsis (Nordborg et al 2005; Wright et al 2006). Moreover, levels of diversity are also lower in regions that a priori are expected to have a higher rate of functional mutations, e.g., near genes and conserved elements (Cai et al 2009;McVicker et al 2009;Hernandez et al 2011).…”