Strength of the purifying selection against different categories of the point mutations in the coding regions of the human genome

Abstract

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.

Relative effects of mutability and selection on single nucleotide polymorphisms in transcribed regions of the human genome

“…After adjusting PSSs by mutation rates, we found that functional type had a significant effect on SNP density ( P = 0.02), suggesting that selection also plays a role in SNP density. This result is consistent with those of other studies [11,14,17,19,42]. …”

Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics

“…In addition, one must be aware in this context that synonymous (''silent'') mutations, although not altering the amino acid sequence of the encoded protein directly, can still influence splicing accuracy or efficiency [Cartegni et al, 2002;Gorlov et al, 2006;Hunt et al, 2009;Sanford et al, 2009;Wang and Cooper, 2007]. Recently, it has been realized that apparently silent SNPs may also become distinctly ''audible'' in the context of mRNA stability or even protein structure and function.…”

Evolutionary evidence of the effect of rare variants on disease etiology

“…A number of investigators have suggested that purifying selection affects SNP frequencies (24–28). One of the first such studies, conducted by Hellmann and colleagues, sequenced more than 5000 expressed sequence tags from the chimpanzee and compared them with their human counterparts (29).…”