Burk-Herrick Angela, Scally Mark, Amrine-Madsen Heather, Stanhope Michael J, Springer Mark S
Biology Department, University of California, Riverside, 92521, USA.
Mamm Genome. 2006 Mar;17(3):257-70. doi: 10.1007/s00335-005-0067-2. Epub 2006 Mar 3.
Comparison of orthologous gene sequences is emerging as a powerful approach to elucidating functionally important positions in human disease genes. Using a diverse array of 132 mammalian BRCA1 (exon 11) sequences, we evaluated the functional significance of specific sites in the context of selection information (purifying, neutral, or diversifying) as well as the ability to extract such information from alignments that index varying degrees of mammalian diversity. Small data sets of either closely related taxa (Primates) or divergent placental taxa were unable to distinguish sites conserved due to purifying selection from sites conserved due to chance (false-positive rate = 65%-99%). Increasing the number of placental taxa to 57 greatly reduced the potential false-positive rate (0%-1.5%). Using the larger data set, we ranked the oncogenic risk of human missense mutations using a novel method that incorporates site-specific selection level and severity of the amino acid change evaluated against the amino acids present in other mammalian taxa. In addition to sites undergoing positive selection in Marsupialia, Laurasiatheria, Euarchontoglires, and Primates, we identified sites most likely to be undergoing divergent selection pressure in different lineages and six pairs of potentially interacting sites. Our results demonstrate the necessity of including large numbers of sequences to elucidate functionally important sites of a protein when using a comparative evolutionary approach.
直系同源基因序列的比较正逐渐成为一种强有力的方法，用于阐明人类疾病基因中功能重要的位点。我们使用了132种哺乳动物BRCA1（第11外显子）序列的多样阵列，在选择信息（纯化、中性或多样化）的背景下评估了特定位点的功能意义，以及从索引不同程度哺乳动物多样性的比对中提取此类信息的能力。亲缘关系密切的分类群（灵长目）或分歧的胎盘类分类群的小数据集无法区分因纯化选择而保守的位点和因偶然因素而保守的位点（假阳性率 = 65% - 99%）。将胎盘类分类群的数量增加到57个大大降低了潜在的假阳性率（0% - 1.5%）。使用更大的数据集，我们采用一种新方法对人类错义突变的致癌风险进行了排名，该方法结合了位点特异性选择水平和针对其他哺乳动物分类群中存在的氨基酸评估的氨基酸变化的严重程度。除了有袋类、劳亚兽总目、灵长总目和灵长目中经历正选择的位点外，我们还确定了不同谱系中最有可能经历分歧选择压力的位点以及六对潜在的相互作用位点。我们的结果表明，在使用比较进化方法阐明蛋白质的功能重要位点时，纳入大量序列的必要性。
