Selective pressures at a codon-level predict deleterious mutations in human disease genes

TitleSelective pressures at a codon-level predict deleterious mutations in human disease genes
Publication TypeJournal Article
Year of Publication2006
AuthorsArbiza, L, Duchi, S, Montaner, D, Burguet, J, Pantoja-Uceda, D, Pineda-Lucena, A, Dopazo, J, Dopazo, H
JournalJ Mol Biol
KeywordsAmino Acid Sequence Amino Acid Substitution Codon/*genetics Databases; Genetic Evolution; Genetic Models; Human Humans Models; Inborn/*genetics Genome; Molecular Genes; Molecular Molecular Sequence Data *Mutation Neoplasms/genetics Proteins/genetics *Selection (Genetics) Tumor Suppressor Protein p53/chemistry/genetics; p53 Genetic Diseases

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.


Arbiza, Leonardo Duchi, Serena Montaner, David Burguet, Jordi Pantoja-Uceda, David Pineda-Lucena, Antonio Dopazo, Joaquin Dopazo, Hernan Research Support, Non-U.S. Gov’t England Journal of molecular biology J Mol Biol. 2006 May 19;358(5):1390-404. Epub 2006 Mar 15.