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PMID: 12531920 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 100 ·No. 3 ·2003-02-04 ·Pages 1151-6

Fleming MA, Potter JD, Ramirez CJ, Ostrander GK, Ostrander EA

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.

MeSH Terms
Algorithms Amino Acid Sequence Animals Bayes Theorem Conserved Sequence DNA Damage DNA Repair Evolution, Molecular Exons Genes, BRCA1 Humans Models, Genetic Molecular Sequence Data Mutation, Missense Phylogeny Sequence Homology, Amino Acid Software
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Fleming Melissa A
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
Ramirez Christina J
Ostrander Gary K
Ostrander Elaine A
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0237285100
Published
2003-02-04
Epub
2003-00-16
Pages
1151-6
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC298742
Subset
IM
Grants
NCI NIH HHS · K05 CA090754 · United States
NCI NIH HHS · U24 CA078164 · United States
NCI NIH HHS · K05 CA-90754-01 · United States
NCI NIH HHS · U24 CA-78164 · United States
External Links
PubMed source DOI: 10.1073/pnas.0237285100 PMC Full Text View journal details
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