Human Molecular Genetics Advance Access originally published online on February 24, 2006
Human Molecular Genetics 2006 15(7):1143-1150; doi:10.1093/hmg/ddl029
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Strength of the purifying selection against different categories of the point mutations in the coding regions of the human genome
1Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA, 2Department of Statistics, Rice University, Houston, TX, USA and 3System Engineering Group, Silesian Institute of Technology, Akademicka 16, 44-100 Gliwice, Poland
* To whom correspondence should be addressed at: Department of Epidemiology, Unit 340, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Tel: +1 7135634951; Fax: +1 7137928261; Email: ipgorlov{at}mdanderson.org
Received November 10, 2005; Revised December 29, 2005; Accepted February 10, 2006
Using available Information on the total absolute size of the coding region of the human genome, data on codon usage and pseudogene-derived mutation rates for different single nucleotide substitutions we have estimated, for the human genome, the potential numbers of mutation events capable to produce: (1) nonsense; (2) missense (radical and conservative); (3) silent; (4) splice; and (5) protein-elongating (those changing wild-type stop codon into an amino acid encoding codon) mutations. We used the NCBI dbSNP database to retrieve data on the observed number of polymorphisms of each category. The fraction of polymorphisms in each category among all potential events in the genome depends on the strength of selection: the higher the rate of polymorphism, the weaker the selection. We used nonsense mutations as a referent group. Compared with nonsense mutations, we found that the relative selection coefficient against protein-elongating mutations was 21%, and the relative selection was 12% against missense mutations. Radical missense mutations were found to be four times more deleterious compared to conservative ones. Surprisingly, we found that silent mutations on average are not neutral; with the average harmfulness of 3% of nonsense mutations. Silent mutations may be deleterious when they affect splicing by creating cryptic donor-acceptor sites or by disturbing exonic splicing enhancers (ESESs). The average selection coefficient against splice mutations was 48% of that against nonsense mutations. Converting the relative selection coefficients into absolute ones using data on loss-of-function mutations in Saccharomyces cerevisiae and Caenorhabditis elegans, or by analysis of the expected frequency of mutations in the human genome, suggested that genetic drift could play a role in population dynamics of conservative missense and silent mutations.