Selective pressures at a codon-level predict deleterious mutations in human disease genes.
J Mol Biol
; 358(5): 1390-404, 2006 May 19.
Article
em En
| MEDLINE
| ID: mdl-16584746
ABSTRACT
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Seleção Genética
/
Códon
/
Doenças Genéticas Inatas
/
Mutação
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
J Mol Biol
Ano de publicação:
2006
Tipo de documento:
Article
País de afiliação:
Espanha