Selective pressures at a codon-level predict deleterious mutations in human disease genes.
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 (omega) is a measure of selective pressure on amino acid replacement mutations for protein-coding genes. Different methods have been developed in order to predict non-synonymous 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 (omega<0.1) are significantly associated (p<0.01) with human disease. We hypothesize that non-synonymous change on amino acids showing omega<0.1 will most likely affect protein function. The application of this evolutionary prediction at a genomic scale will provide an a priori hypothesis of the phenotypic effect of non-synonymous coding single nucleotide polymorphisms (SNPs) in the human genome.
Pharmacogenomics and Comparative Genomics Unit, Centro de Investigación Príncipe Felipe (CIPF), Autopista del Saler 16-3, 46013 Valencia, Spain.
Leonardo
L
Arbiza
Serena
S
Duchi
David
D
Montaner
Jordi
J
Burguet
David
D
Pantoja-Uceda
Antonio
A
Pineda-Lucena
Joaquín
J
Dopazo
Hernán
H
Dopazo
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D003062:Codon / Q000235:genetics*; D030541:Databases, Genetic; D019143:Evolution, Molecular; D016158:Genes, p53; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D015894:Genome, Human; D006801:Humans; D008957:Models, Genetic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009369:Neoplasms / Q000235:genetics; D011506:Proteins / Q000235:genetics; D012641:Selection, Genetic; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics
D003062:Codon; D011506:Proteins; D016159:Tumor Suppressor Protein p53