Human Molecular Genetics Advance Access originally published online on October 21, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 24 3325-3330
DOI: 10.1093/hmg/ddg359
© 2003 Oxford University Press
Impact of selection, mutation rate and genetic drift on human genetic variation
1Genetics Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA, 2European Molecular Biology Laboratory (EMBL), Meyerhofstr. 1, 69117 Heidelberg, Germany, 3National Center for Biotechnology Information, National Institutes of Health, Bethesda, MD 20894, USA, 4Section of Evolution and Ecology, University of California at Davis, Davis, CA 95616, USA, 5Max-Delbrueck Center for Molecular Medicine, Robert-Roessle-Strasse 10, 13122 Berlin, Germany and 6Engelhardt Institute of Molecular Biology, Vavilova 32, 119991 Moscow, Russia
Received August 5, 2003; Accepted October 17, 2003
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 non-synonymous variability within human genes with their divergence from murine orthologs. We separately analyzed the non-synonymous 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 non-synonymous, benign variability and non-synonymous 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 non-synonymous single-nucleotide polymorphisms reduces fitness and never reaches fixation. Evolutionary and medical implications of the impact of selection on human polymorphisms are discussed.
* To whom correspondence should be addressed. Tel: +1 6175256675; Fax: +1 6177325123; Email: ssunyaev{at}rics.bwh.harvard.edu
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