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

Author(s): Sunyaev, Shamil R; Kondrashov, Fyodor A; Bork, Peer; Ramensky, Vasily
Article Title: Impact of selection, mutation rate and genetic drift on human genetic variation
Abstract: 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.
Journal Title: Human Molecular Genetics
Volume: 12
Issue 24
ISSN: 0964-6906
Publisher: Oxford University Press  
Date Published: 2003-12-15
Start Page: 3325
End Page: 3330
DOI: 10.1093/hmg/ddg359
Notes: We are grateful to Alexey Kondrashov and Alison Wellman for the careful reading of the manuscript and providing us with their valuable comments.
Open access: no