Research Article: Population History and Natural Selection Shape Patterns of Genetic Variation in 132 Genes

Date Published: October 7, 2004

Publisher: Public Library of Science

Author(s): Joshua M Akey, Michael A Eberle, Mark J Rieder, Christopher S Carlson, Mark D Shriver, Deborah A Nickerson, Leonid Kruglyak

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.

Partial Text: Despite intense study and interest, a detailed understanding of the evolutionary and demographic forces that have shaped extant patterns of human genomic variation remains elusive. An important goal in studies of DNA sequence variation is to identify loci that have been targets of natural selection and thus contribute to differences in fitness between individuals in a population. Identifying regions of the human genome that have been subject to natural selection will provide important insights into recent human history (Sabeti et al. 2002; Tishkoff and Verrelli 2003), the function of genes (Akey et al. 2002), and the mechanisms of evolutionary change (Otto 2000), and it may also facilitate the identification of complex disease genes (Jorde et al. 2001; Nielsen 2001).

In summary, we have found that both population demographic history and natural selection shaped patterns of DNA sequence variation in the 132 genes studied here. By studying multiple unlinked loci dispersed throughout the genome, we were able to develop a rigorous computational approach to distinguish between the confounding effects of natural selection and demographic history on patterns of genetic variation. Using this strategy, we found that approximately two-thirds of the genes that were initially significant could be accounted for by population demographic history. Thus, our analyses clearly demonstrate the importance of considering both neutral and nonneutral forces when interpreting DNA sequence variation.



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