Genome-wide signals of positive selection in human evolution

The rate and patterns of positive selection are of fundamental interest for the study of human evolution. Population genomic studies should, in principle, allow us to quantify positive selection from its expected signatures in sequence polymorphism and divergence data. Surprisingly, despite the sequencing of thousands of human genomes (The 1000 Genomes Project Consortium 2012) and the availability of whole-genome sequences of closely related species, the extent to which adaptation has left identifiable signatures in the patterns of polymorphism in the human genome remains highly controversial (Akey 2009; Hernandez et al. 2011). On the one hand, recent studies have identified a large number of loci showing signatures of recent selective sweeps (Voight et al. 2006; Sabeti et al. 2007; Williamson et al. 2007; Pickrell et al. 2009; Grossman et al. 2013), and McDonald-Kreitman (MK) analyses inferred that ∼10%–20% of amino acid changes have been adaptive in human evolution (Boyko et al. 2008; Messer and Petrov 2013). Consistently, regions of high functional density, high rate of amino acid substitutions, and low recombination all show reduced levels of neutral diversity (Cai et al. 2009; Lohmueller et al. 2011), as expected under recurrent selective sweeps in functional regions. On the other hand, there are reasons to question the notion that adaptation left clear signatures in the human genome. First, different scans for positive selection have identified largely nonoverlapping sets of candidates (Akey 2009), which could be due to a high rate of false positives. Second, MK analyses can be confounded by a number of factors, such as perturbations left by demographic events and by the presence of slightly deleterious mutations (Eyre-Walker and Keightley 2009; Messer and Petrov 2013), and some MK analyses have failed to find evidence for adaptation in the human lineage (Eyre-Walker and Keightley 2009). Finally, it has been shown that background selection (BGS) (Charlesworth et al. 1993), a process in which deleterious mutations remove linked neutral variation from the population, reduces levels of polymorphism in regions of higher functional density and low recombination, providing an alternative explanation for the observation of these correlations in the human genome. One signature of positive selection—lower levels of neutral variation near functional substitutions (Andolfatto 2007; Macpherson et al. 2007; Cai et al. 2009)—is not generally expected under BGS and should therefore provide the clearest genomic evidence for the action of positive selection. While this signature was found in the human genome by Cai et al. (2009), it could not be detected by two recent studies using the newest large-scale data sets of human diversity (Hernandez et al. 2011; Lohmueller et al. 2011). In particular, Hernandez et al. (2011) searched for lower levels of neutral diversity near functional substitutions by contrasting levels of neutral diversity near nonsynonymous compared with synonymous substitutions. They did not find this signature in the human genome and, moreover, found that diversity might in fact be marginally higher near nonsynonymous substitutions. Simulations showed that this puts sharp limits on the amount of adaptation by classic selective sweeps in recent human evolution (Hernandez et al. 2011). However, it is likely that the study design of Hernandez et al. (2011) (also implemented in Drosophila by Sattath et al. 2011) is strongly biased against finding signatures of positive selection in the human genome and all other genomes with sharply variable levels of genomic constraint. This is because, as we show in the Results, nonsynonymous substitutions in the human genome tend to be located in regions of weaker constraint and thus weaker BGS compared with synonymous substitutions. These differences in levels of BGS should elevate neutral diversity near nonsynonymous compared with synonymous substitutions. The approach of Hernandez et al. (2011) would thus detect positive selection only if the reduction of diversity due to positive selection near nonsynonymous substitutions happens to be greater than the initial difference in the opposite direction due to BGS. Here we utilize a number of more sensitive approaches in the search for signatures of positive selection while attempting to reduce the confounding effects of BGS to the greatest extent possible. Our results suggest that positive selection was frequent in human history and might have involved adaptive mutations of substantial selective effect. We estimate that a few hundred strong adaptive events are likely to be detectable in the human genome, consistent with the latest scan for positive selection (Grossman et al. 2013). Moreover, we provide evidence that the majority of adaptive substitutions were due to cis-regulatory rather than protein-coding changes, consistent with the King and Wilson (1975) hypothesis that adaptive divergence is primarily driven by regulatory changes.