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Population history and natural selection shape patterns of genetic variation in 132 genes.

ABSTRACT: Identifying regions of the human genome that have been targets of natural selection will provide important insights into human evolutionary history and may facilitate the identification of complex disease genes. Although the signature that natural selection imparts on DNA sequence variation is difficult to disentangle from the effects of neutral processes such as population demographic history, selective and demographic forces can be distinguished by analyzing multiple loci dispersed throughout the genome. We studied the molecular evolution of 132 genes by comprehensively resequencing them in 24 African-Americans and 23 European-Americans. We developed a rigorous computational approach for taking into account multiple hypothesis tests and demographic history and found that while many apparent selective events can instead be explained by demography, there is also strong evidence for positive or balancing selection at eight genes in the European-American population, but none in the African-American population. Our results suggest that the migration of modern humans out of Africa into new environments was accompanied by genetic adaptations to emergent selective forces. In addition, a region containing four contiguous genes on Chromosome 7 showed striking evidence of a recent selective sweep in European-Americans. More generally, our results have important implications for mapping genes underlying complex human diseases.

SUBMITTER: Akey JM

PROVIDER: S-EPMC515367 | biostudies-literature | 2004 Oct

REPOSITORIES: biostudies-literature

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Population history and natural selection shape patterns of genetic variation in 132 genes.

Akey Joshua M JM Eberle Michael A MA Rieder Mark J MJ Carlson Christopher S CS Shriver Mark D MD Nickerson Deborah A DA Kruglyak Leonid L

PLoS biology 20040907 10

Identifying regions of the human genome that have been targets of natural selection will provide important insights into human evolutionary history and may facilitate the identification of complex disease genes. Although the signature that natural selection imparts on DNA sequence variation is difficult to disentangle from the effects of neutral processes such as population demographic history, selective and demographic forces can be distinguished by analyzing multiple loci dispersed throughout ...[more]

PMID: 15361935

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Project description:Levels of sex differences for human body size and shape phenotypes are hypothesized to have adaptively reduced following the agricultural transition as part of an evolutionary response to relatively more equal divisions of labor and new technology adoption. In this study, we tested this hypothesis by studying genetic variants associated with five sexually differentiated human phenotypes: height, body mass, hip circumference, body fat percentage, and waist circumference. We first analyzed genome-wide association (GWAS) results for UK Biobank individuals (~194,000 females and ~167,000 males) to identify a total of 114,199 single nucleotide polymorphisms (SNPs) significantly associated with at least one of the studied phenotypes in females, males, or both sexes (P<5x10-8). From these loci we then identified 3,016 SNPs (2.6%) with significant differences in the strength of association between the female- and male-specific GWAS results at a low false-discovery rate (FDR<0.001). Genes with known roles in sexual differentiation are significantly enriched for co-localization with one or more of these SNPs versus SNPs associated with the phenotypes generally but not with sex differences (2.73-fold enrichment; permutation test; P = 0.0041). We also confirmed that the identified variants are disproportionately associated with greater phenotype effect sizes in the sex with the stronger association value. We then used the singleton density score statistic, which quantifies recent (within the last ~3,000 years; post-agriculture adoption in Britain) changes in the frequencies of alleles underlying polygenic traits, to identify a signature of recent positive selection on alleles associated with greater body fat percentage in females (permutation test; P = 0.0038; FDR = 0.0380), directionally opposite to that predicted by the sex differences reduction hypothesis. Otherwise, we found no evidence of positive selection for sex difference-associated alleles for any other trait. Overall, our results challenge the longstanding hypothesis that sex differences adaptively decreased following subsistence transitions from hunting and gathering to agriculture.

Dataset Information

Population history and natural selection shape patterns of genetic variation in 132 genes.

Publications

Population history and natural selection shape patterns of genetic variation in 132 genes.

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