Natural selection and mammalian BRCA1 sequences:: elucidating functionally important sites relevant to breast cancer susceptibility in humans
Natural selection and mammalian BRCA1 sequences:: elucidating functionally important sites relevant to breast cancer susceptibility in humans
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DOI：
10.1007/s00335-005-0067-2
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发表时间：
2006-03-01
期刊：
影响因子：
2.5
通讯作者：
Springer, MS
中科院分区：
文献类型：
--
作者：
Burk-Herrick, A;Scally, M;Springer, MS
正向同源基因序列的比较是阐明人类疾病基因重要功能位置的有力手段。使用132个哺乳动物BRCA 1（外显子11）序列的多样化阵列，我们评估了特定位点在选择信息（纯化，中性或多样化）的背景下的功能意义，以及从不同程度的哺乳动物多样性的索引对齐中提取这些信息的能力。密切相关的分类群（灵长类动物）或不同的胎盘分类群的小数据集无法区分由于纯化选择而保守的位点与由于偶然而保守的位点（假阳性率= 65%-99%）。将胎盘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，我们排名致癌风险的人类错义突变使用一种新的方法，结合位点特异性选择水平和严重程度的氨基酸变化评估对其他哺乳动物类群中存在的氨基酸。除了网站进行积极的选择在有袋类，Laurasiatheria，Euarchontoglires，灵长类动物，我们确定了网站最有可能正在经历不同的选择压力在不同的血统和6对潜在的相互作用的网站。我们的研究结果表明，包括大量的序列，以阐明功能上重要的网站的蛋白质时，使用比较进化的方法的必要性。
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.