Genome-wide detection and characterization of positive selection in human populations

With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used ‘long-range haplotype’ methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 nonsynonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population: LARGE and DMD, both related to infection by the Lassa virus, in West Africa; SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia. An increasing amount of information about genetic variation, together with new analytical methods, is making it possible to explore the recent evolutionary history of the human population. The first phase of the International Haplotype Map, including ,1 million single nucleotide polymorphisms (SNPs), allowed preliminary examination of natural selection in humans. Now, with the publication of the Phase 2 map (HapMap2) in a companion paper, over 3 million SNPs have been genotyped in 420 chromosomes from three continents (120 European (CEU), 120 African (YRI) and 180 Asian from Japan and China (JPT 1 CHB)). In our analysis of HapMap2, we first implemented two widely used tests that detect recent positive selection by finding common alleles carried on unusually long haplotypes. The two, the Long-Range Haplotype (LRH) and the integrated Haplotype Score (iHS) tests, rely on the principle that, under positive selection, an allele may rise to high frequency rapidly enough that long-range association with nearby polymorphisms—the long-range haplotype—will not have time to be eliminated by recombination. These tests control for local variation in recombination rates by comparing long haplotypes to other alleles at the same locus. As a result, they lose power as selected alleles approach fixation (100% frequency), because there are then few alternative alleles in the population (Supplementary Fig. 2 and Supplementary Tables 1–2). We next developed, evaluated and applied a new test, Cross Population Extended Haplotype Homozogysity (XP-EHH), to detect selective sweeps in which the selected allele has approached or achieved fixation in one population but remains polymorphic in the human population as a whole (Methods, and Supplementary Fig. 2 and Supplementary Tables 3–6). Related methods have recently also been described. Our analysis of recent positive selection, using the three methods, reveals more than 300 candidate regions(Supplementary Fig. 3 and Supplementary Table 7), 22 of which are above a threshold such that no similar events were found in 10 Gb of simulated neutrally evolving sequence (Methods). We focused on these 22 strongest signals (Table 1), which include two well-established cases, SLC24A5 and LCT, and 20 other regions with signals of similar strength. The challenge is to sift through genetic variation in the candidate regions to identify the variants that were the targets of selection. Our candidate regions are large (mean length, 815 kb; maximum length, 3.5 Mb) and often contain multiple genes (median, 4; maximum, 15). A typical region harbours ,400–4,000 common SNPs (minor allele frequency .5%), of which roughly three-quarters are represented in current SNP databases and half were genotyped as part of HapMap2 (Supplementary Table 8). We developed three criteria to help highlight potential targets of selection (Supplementary Fig. 1): (1) selected alleles detectable by our tests are likely to be derived (newly arisen), because long-haplotype tests have little power to detect selection on standing (pre-existing) variation; we therefore focused on derived alleles, as identified by comparison to primate outgroups; (2) selected alleles are likely to be highly differentiated between populations, because recent selection is probably a local environmental adaptation; we thus looked for alleles common in only the population(s) under selection; (3) selected alleles must have biological effects. On the basis of current knowledge, we therefore focused on non-synonymous coding SNPs and SNPs in evolutionarily conserved sequences. These criteria are intended as heuristics, not absolute requirements. Some targets of selection may not satisfy them, and some will not be in current SNP databases. Nonetheless, with ,50% of common SNPs in these populations genotyped in HapMap2, a search for causal variants is timely. We applied the criteria to the regions containing SLC24A5 and LCT, each of which already has a strong candidate gene, mutation and trait. At SLC24A5, the 600 kb region contains 914 genotyped