Interrogating a High-Density SNP Map for Signatures of Natural Selection

Abstract

Identifying genomic regions that have been targets of natural selection remains one of the most important and challenging areas of research in genetics. To this end, we report an analysis of 26,530 single nucleotide polymorphisms (SNPs) with allele frequencies that were determined in three populations. Specifically, we calculated a measure of genetic differentiation, FST, for each locus and examined its distribution at the level of the genome, the chromosome, and individual genes. Through a variety of analyses, we have found statistically significant evidence supporting the hypothesis that selection has influenced extant patterns of human genetic variation. Importantly, by contrasting the FST of individual SNPs to the empirical genome-wide distribution of FST, our results are not confounded by tenuous assumptions of population demographic history. Furthermore, we have identified 174 candidate genes with distribution of genetic variation that indicates that they have been targets of selection. Our work provides a first generation natural selection map of the human genome and provides compelling evidence that selection has shaped extant patterns of human genomic variation

Sequence diversity and haplotype structure at the human CYP3A cluster

“…The F ST statistic summarizes allele frequency differentiation between samples, and a genome-wide survey of 25 549 autosomal SNPs revealed an average worldwide F ST value of 0.123. 31 Our estimates of F ST values for each site between the African-American sample and each non-African sample confirmed that many sites at the CYP3A locus are characterized by large differences in allele frequency across populations. Our F ST findings are consistent with the observed large differences in allele frequency between populations and strong haplotype structure across samples, and might be expected if a specific haplotype class was driven quickly to high frequency by natural selection in one of the populations.…”

A population genetics study of the Familial Mediterranean Fever gene: evidence of balancing selection under an overdominance regime

“…In particular, lower F ST values are expected at loci under balancing selection compared with neurally evolving ones. 26,27 F ST among AA, EA and AS was 0.021, much lower than the genome average of 0.123 27 and not significantly different from 0 (P ¼ 0.10); consistently, an F ST value of 0.021 corresponds to the 0.034 percentile in the distribution of 232 F ST values calculated for 5 kb windows from NIEHS genes among the same three populations.…”

Haplotype tagging efficiency in worldwide populations in CTLA4 gene

“…39 Although differences among populations in allele frequencies have been found in the CTLA4 gene, none of the SNPs analyzed presented significantly higher F ST values compared to an SNP genomewide distribution of F ST . 35,36 This fact stresses that the differences among populations are not unexpectedly large and points to a lack of local selective pressures across human populations on the CTLA4 gene, at least in recent times.…”

“…7 However, F ST values are not significantly different between disease-related and nondisease-related SNPs (Mann-Whitney test, P ¼ 0.494). In order to evaluate the significance of the F ST values, the F ST for each SNP was compared to the F ST distributions provided by genomewide studies: Akey et al 35 for a large set of SNPs in three populations and Kidd et al 36 for gene-centred SNPs in a similar set of populations than Table 2) fall close to the mean for 369 markers. 36 This suggests that the geographic stratification shown by CTLA4 is well below a genomewide average and points to the absence of strong geographically specific selective pressures.…”