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Understanding missense mutations in the BRCA1 gene: an evolutionary approach.

ABSTRACT: The role of missense changes in BRCA1 in breast cancer susceptibility has been difficult to establish. We used comparative evolutionary methods to identify potential functionally important amino acid sites in exon 11 and missense changes likely to disrupt gene function, aligning sequences from 57 eutherian mammals and categorizing amino acid sites by degree of conservation. We used Bayesian phylogenetic analyses to determine relationships among orthologs and identify codons evolving under positive selection. Most conserved residues occur in a region with the highest concentration of protein-interacting domains. Rapidly evolving residues are concentrated in the RAD51-interacting domain, suggesting that selection is acting most strongly on the role of BRCA1 in DNA repair. Investigation of the functional role of missense changes in breast-cancer susceptibility should focus on 38 missense changes in conserved and 3 in rapidly evolving regions of exon 11.

SUBMITTER: Fleming MA 

PROVIDER: S-EPMC298742 | biostudies-literature | 2003 Feb

REPOSITORIES: biostudies-literature

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Understanding missense mutations in the BRCA1 gene: an evolutionary approach.

Fleming Melissa A MA   Potter John D JD   Ramirez Christina J CJ   Ostrander Gary K GK   Ostrander Elaine A EA  

Proceedings of the National Academy of Sciences of the United States of America 20030116 3

The role of missense changes in BRCA1 in breast cancer susceptibility has been difficult to establish. We used comparative evolutionary methods to identify potential functionally important amino acid sites in exon 11 and missense changes likely to disrupt gene function, aligning sequences from 57 eutherian mammals and categorizing amino acid sites by degree of conservation. We used Bayesian phylogenetic analyses to determine relationships among orthologs and identify codons evolving under positi  ...[more]

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