Selective Pressures at a Codon-Level Predict Deleterious Mutations in Human Disease Genes

HERNÁN DOPAZO

Valencia. España

Congreso; II Congreso de la Sociedad Española de Farmacogenética y Farmacogenómica; 2006

Sociedad Española de Farmacogenética y Farmacogenómica

Deleterious mutations affecting biological function of proteins are constantly being rejected by purifying selection from the gene pool. The non-synonymous/synonymous substitution rate ratio (ω) is a measure of selective pressure on amino acid replacement mutations for protein-coding genes. Different methods have been developed in order to predict nonsynonymous changes affecting gene function. However, none has considered the estimation of selective constraints acting on protein residues. Here, we have used codon-based maximum likelihood models in order to estimate the selective pressures on the individual amino acid residues of a well-known model protein: p53. We demonstrate that the number of residues under strong purifying selection in p53 is much higher than those that are strictly conserved during the evolution of the species. In agreement with theoretical expectations, residues that have been noted to be of structural relevance, or in direct association with DNA, were among those showing the highest signals of purifying selection. Conversely, those changing according to a neutral, or nearly neutral mode of evolution, were observed to be irrelevant for protein function. Finally, using more than 40 human disease genes, we demonstrate that residues evolving under strong selective pressures (ω