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. 2004 Oct;2(10):e286.
doi: 10.1371/journal.pbio.0020286. Epub 2004 Sep 7.

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

Joshua M Akey  1 , Michael A Eberle, Mark J Rieder, Christopher S Carlson, Mark D Shriver, Deborah A Nickerson, Leonid Kruglyak
Affiliations

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

Joshua M Akey et al. PLoS Biol. 2004 Oct.

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.

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Conflict of interest statement

The authors have declared that no conflicts of interest exist.

Figures

Figure 1
Figure 1. Scatter Plot of Neutrality Test Statistics in European- and African-Americans
Genes that are nominally significant (p < 0.05) in European-Americans (EA), African-Americans (AA), or both populations are denoted by red, blue, and green circles, respectively. Genes that are not significant are shown as black dots. Two-sided tests were used for Tajima's D, Fu and Li's D*, and Fu and Li's F*, and a one-sided test was used for Fay and Wu's H.
Figure 2
Figure 2. Summary of the Four Demographic Models Considered in Each Population
(A) Schematic diagram of each demographic model and its associated parameters (see Materials and Methods for details). Parameter values that match the observed data most closely for European-Americans (EA) and African-Americans (AA) are shown below the diagrams. (B) Average and 95% confidence intervals of Tajima's D (blue bars), Fu and Li's D* (red bars), and Fu and Li's F* (pale yellow bars) for the observed data and each demographic model (using the parameters that most closely match the empirical data). Results from the standard neutral model (Constant) are also shown.
Figure 3
Figure 3. The Influence of Demographic History on Tests of Selection
(A and B) The significance of observed values of Tajima's D (red), Fu and Li's D* (pale yellow), Fu and Li's F* (pale blue), and Fay and Wu's H (dark blue) were reassessed for each best-fit demographic model in European-Americans (A) and African-Americans (B). Results from the standard neutral model (Constant) are shown for comparison. The number of significant genes for each demographic model is noted above each category in (A) and (B). For example, there were a total of 19 significant test statistics across all four tests of neutrality assuming a bottleneck model for Europeans, which define ten unique genes. Therefore, each gene is supported by approximately two (19/10) tests of neutrality. (C) The distribution of the number of significant genes across the five demographic models in European-Americans and African-Americans. For example, in European-Americans, 40 genes were significant in at least one of the demographic models, and 27 genes were significant in at least two of the demographic models.
Figure 4
Figure 4. A Strong Signature of Positive Selection Spanning 115 kb on Chromosome 7q
(A–D) Exons for EPHB6, TRPV6, TRPV5, and KEL are shown as gray vertical lines. A dashed black line indicates the boundary between EPHB6 and TRPV6 exons, which are approximately 1 kb apart. Transcriptional orientation is indicated by the arrows below exon positions. SNPs found in European-Americans and African-Americans are shown below. Noncoding, synonymous, and nonsynonymous SNPs are denoted as black, blue, and red vertical bars, respectively. The positions of three nonsynonymous SNPs in TRPV6 are shown with asterisks. For each of the resulting nonsynonymous amino acid changes, the most frequent amino acid in European-Americans is given first. The frequency of derived alleles, PD (B), sliding window plots of Tajima's D (C), and nucleotide diversity, π (D), are shown across the entire region. Gaps in the sliding window plots indicate positions where sequence data were not obtained. In (B–D), European- and African-American data are shown in red and black, respectively. (E) The distribution of FST across the 115-kb region. The average FST for all SNPs across the 132 genes is shown as a dashed red line. The dashed green line indicates the threshold for significantly (p < 0.01) large values of FST, determined by coalescent simulations.
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