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Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1151-6. Epub 2003 Jan 16.

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

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  • 1Divisions of Clinical Research and Human Biology, and Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.

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.

PMID:
12531920
[PubMed - indexed for MEDLINE]
PMCID:
PMC298742
Free PMC Article
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