Signatures of natural selection on genetic variants affecting complex human traits

Abstract

It has recently been hypothesized that polygenic adaptation, resulting in modest allele frequency changes at many loci, could be a major mechanism behind the adaptation of complex phenotypes in human populations. Here we leverage the large number of variants that have been identified through genome-wide association (GWA) studies to comprehensively study signatures of natural selection on genetic variants associated with complex traits. Using population differentiation based methods, such as FST and phylogenetic branch length analyses, we systematically examined nearly 1300 SNPs associated with 38 complex phenotypes. Instead of detecting selection signatures at individual variants, we aimed to identify combined evidence of natural selection by aggregating signals across many trait associated SNPs. Our results have revealed some general features of polygenic selection on complex traits associated variants. First, natural selection acting on standing variants associated with complex traits is a common phenomenon. Second, characteristics of selection for different polygenic traits vary both temporarily and geographically. Third, some studied traits (e.g. height and urate level) could have been the primary targets of selection, as indicated by the significant correlation between the effect sizes and the estimated strength of selection in the trait associated variants; however, for most traits, the allele frequency changes in trait associated variants might have been driven by the selection on other correlated phenotypes. Fourth, the changes in allele frequencies as a result of selection can be highly stochastic, such that, polygenic adaptation may accelerate differentiation in allele frequencies among populations, but generally does not produce predictable directional changes. Fifth, multiple mechanisms (pleiotropy, hitchhiking, etc) may act together to govern the changes in allele frequencies of genetic variants associated with complex traits.

Fast and robust detection of ancestral selective sweeps

“…Although no functional study has linked its variants with specific phenotypes yet, a previous association study by Zhang et al. () identified this gene to have high iHS scores in East Asians, as well as significant correlations with type I diabetes, menarche and height.…”

“…In addition to SLC35F3, the other significant candidate, CENPW (Table 1; Figures S10A and S12A), which encodes a centromere-related protein, may also reflect potential adaptation to energy metabolism in East Asians. Although no functional study has linked its variants with specific phenotypes yet, a previous association study by Zhang et al (2013) Consistent with Mathieson et al (2015), the lactase gene LCT and the pigmentation gene SLC45A2 exhibit the highest ABS scores in both the scans with EF (Table 3; Figure S15A) and with SA (Table 3; Figure 5) as the close outgroup. Furthermore, the most extreme score is not located within LCT, but instead within MCM6, a gene immediately upstream of LCT (Table 3; Figure 6a).…”

Human genetic adaptation to high altitudes: Current status and future prospects

“…Since gene flow would affect all alleles or loci in the same way whereas natural selection would be expected to act on specific gene regions, Lewontin and Krakauer proposed that natural selection could be measured as the heterogeneity between genetic loci, termed the F value (Lewontin and Krakauer, 1973). In the intervening years various tests have been developed for detecting different kinds of natural selection producing, for example, increased variation, decreased variation, or increased linkage disequilibrium (i.e., the nonrandom association of alleles usually due to being situated on the same chromosome; for review see (Zhang et al, 2013)).…”

A method for genome-wide genealogy estimation for thousands of samples

“…In particular, we find strongest enrichment for GWAS hits, across all considered populations, encouragingly supporting a link between evidence of selection and SNPs with detectable influences on phenotypes at the organism level. Multiple previous studies [46][47][48][49] have attempted to test individual polygenic traits for evidence of directional polygenic selection, but confounding due to population stratification 50,51 is potentially problematic in practice. To leverage potential power gains of the Relate Selection Test for this purpose, we tested whether derived mutations that increase (or decrease) a trait show increased evidence of directional selection relative to randomly sampled control mutations of the same frequency (Wilcoxon test; Methods).…”