Fleming Melissa A, Potter John D, Ramirez Christina J, Ostrander Gary K, Ostrander Elaine A
Divisions of Clinical Research and Human Biology, and Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1151-6. doi: 10.1073/pnas.0237285100. Epub 2003 Jan 16.
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.
乳腺癌易感基因BRCA1中错义突变的作用一直难以确定。我们采用比较进化方法来识别第11外显子中潜在的功能重要氨基酸位点以及可能破坏基因功能的错义突变，比对了57种真兽类哺乳动物的序列，并根据保守程度对氨基酸位点进行分类。我们使用贝叶斯系统发育分析来确定直系同源基因之间的关系，并识别在正选择下进化的密码子。大多数保守残基位于蛋白质相互作用结构域浓度最高的区域。快速进化的残基集中在与RAD51相互作用的结构域中，这表明选择对BRCA1在DNA修复中的作用影响最大。对乳腺癌易感性中错义突变功能作用的研究应集中在第11外显子保守区域的38个错义突变和快速进化区域的3个错义突变上。
