Effects of natural selection on interpopulation divergence at polymorphic sites in human protein-coding Loci.
ABSTRACT To develop new strategies for searching for genetic associations with complex human diseases, we analyzed 2784 single-nucleotide polymorphisms (SNPs) in 396 protein-coding genes involved in biological processes relevant to cancer and other complex diseases, with respect to gene diversity within samples of individuals representing the three major historic human populations (African, European, and Asian) and with respect to interpopulation genetic distance. Reduced levels of both intrapopulation gene diversity and interpopulation genetic distance were seen in the case of SNPs located within the 5'-UTR and at nonsynonymous SNPs, causing radical changes to protein structure. Reduction of gene diversity at SNP loci in these categories was evidence of purifying selection acting at these sites, which in turn causes a reduction in interpopulation divergence. By contrast, a small number of SNP sites in these categories revealed unusually high genetic distances between the two most diverged populations (African and Asian); these loci may have historically been subject to divergent selection pressures.
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ABSTRACT: The nearly neutral theory contends that the interaction of drift and selection is important and occurs at various levels, including synonymous and nonsynonymous substitutions in protein coding regions and sequence turnover of regulatory elements. Recent progress of the theory is reviewed, and the interaction between drift and selection is suggested to differ at these different levels. Weak selective force on synonymous changes is stable, whereas its consequence on nonsynonymous changes depends on environmental factors. Selection on differentiation of regulatory elements is even more dependent on environmental factors than on amino acid changes. Of particular significance is the role of drift in the evolution of gene regulation that directly participates in morphological evolution. The range of near neutrality depends on the effective size of the population that is influenced by selected linked loci. In addition to the effective population size, molecular chaperones such as heat shock protein 90 have significant effects on the range of near neutrality.Proceedings of the National Academy of Sciences 01/2003; 99(25):16134-7. · 9.68 Impact Factor
Article: Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease.[show abstract] [hide abstract]
ABSTRACT: The past two decades have witnessed an explosion in the identification, largely by positional cloning, of genes associated with mendelian diseases. The roughly 1,200 genes that have been characterized have clarified our understanding of the molecular basis of human genetic disease. The principles derived from these successes should be applied now to strategies aimed at finding the considerably more elusive genes that underlie complex disease phenotypes. The distribution of types of mutation in mendelian disease genes argues for serious consideration of the early application of a genomic-scale sequence-based approach to association studies and against complete reliance on a positional cloning approach based on a map of anonymous single nucleotide polymorphism haplotypes.Nature Genetics 04/2003; 33 Suppl:228-37. · 35.53 Impact Factor
Article: Unusual haplotypic structure of IL8, a susceptibility locus for a common respiratory virus.[show abstract] [hide abstract]
ABSTRACT: Interleukin-8 (IL8) is believed to play a role in the pathogenesis of bronchiolitis, a common viral disease of infancy, and a recent U.K. family study identified an association between this disease and the IL8-251A allele. In the present study we report data, from a different set of families, which replicate this finding; combined analysis of 194 nuclear families through use of the transmission/disequilibrium test gives P = .001. To explore the underlying genetic cause, we identified nine single-nucleotide polymorphisms (SNPs) in a 7.6-kb segment spanning the IL8 gene and its promoter region and used six of these SNPs to define the haplotypic structure of the IL8 locus. The IL8-251A allele resides on two haplotypes, only one of which is associated with disease, suggesting that this may not be the functional allele. Europeans show an unusual haplotype genealogy that is dominated by two common haplotypes differing at multiple sites, whereas Africans have much greater haplotypic diversity. These marked haplotype-frequency differences give an F(ST) of.25, and, in the European sample, both Tajima's D statistic (D = 2.58, P = .007) and the Hudson/Kreitman/Aguade test (chi(2) = 4.9, P = .03) reject neutral equilibrium, suggesting that selective pressure may have acted on this locus.The American Journal of Human Genetics 09/2001; 69(2):413-9. · 10.60 Impact Factor