Impact of selection, mutation rate and genetic drift on human genetic variation

Human Molecular Genetics Advance Access published online ahead of print October 21, 2003
Human Molecular Genetics, 10.1093/hmg/ddg359

Shamil Sunyaev et al.

The accumulation of genome-wide information on single nucleotide polymorphisms in humans provides an unprecedented opportunity to detect the evolutionary forces responsible for heterogeneity of the level of genetic variability across loci. Previous studies have shown that history of recombination events has produced long haplotype blocks in the human genome, which contribute to this heterogeneity. Other factors, however, such as natural selection or the heterogeneity of mutation rates across loci may also lead to heterogeneity of genetic variability. We compared synonymous and nonsynonymous variability within human genes to their divergence from murine orthologues. We separately analysed the nonsynonymous variants predicted to damage protein structure or function and the variants predicted to be functionally benign. The predictions were based on comparative sequence analysis and, in some cases, on the analysis of protein structure. A strong correlation between nonsynonymous, benign variability and nonsynonymous human-mouse divergence suggests that selection played an important role in shaping the pattern of variability in coding regions of human genes. However, the lack of correlation between deleterious variability and evolutionary divergence shows that a substantial proportion of the observed nonsynonymous single nucleotide polymorphisms reduce fitness and never reach fixation. Evolutionary and medical implications of the impact of selection on human polymorphisms are discussed.

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