Understanding missense mutations in the BRCA1 gene: an evolutionary approach.
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.
Fleming
Melissa A
MA
Divisions of Clinical Research and Human Biology, and Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
Potter
John D
JD
Ramirez
Christina J
CJ
Ostrander
Gary K
GK
Ostrander
Elaine A
EA
D000465:Algorithms; D000595:Amino Acid Sequence; D000818:Animals; D001499:Bayes Theorem; D017124:Conserved Sequence; D004249:DNA Damage; D004260:DNA Repair; D019143:Evolution, Molecular; D005091:Exons; D019398:Genes, BRCA1; D006801:Humans; D008957:Models, Genetic; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010802:Phylogeny; D017386:Sequence Homology, Amino Acid; D012984:Software