Neutral and weakly nonneutral sequence variants may define individuality
Neutral and weakly nonneutral sequence variants may define individuality
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DOI：
10.1073/pnas.1216613110
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发表时间：
2013-08-27
影响因子：
11.1
通讯作者：
Rost, Burkhard
中科院分区：
文献类型：
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作者：
Bromberg, Yana;Kahn, Peter C.;Rost, Burkhard
对日益丰富的基因组变异数据的大规模计算分析始终讲述了两个截然不同的故事。第一个是预期的：在疾病相关数据库中报告的编码变体显著改变了受影响蛋白质的功能。第二个是令人惊讶的：健康个体的基因组似乎携带许多变异，这些变异被预测会对功能产生一些影响。只要对所有人类基因组变异进行完整的实验分析仍然是不可能的，计算方法，如PolyPhen，SNAP和SIFT，可能会提供重要的见解。这些方法可以很好地捕捉特定变异的影响，并可以突出变异群体的趋势。可以说，疾病是极端的表型变异，通常可归因于一个或几个严重的功能破坏性变异。我们的研究结果表明，不同的非疾病表型的基因组基础。预测方法表明，看似健康的个体中的变异对蛋白质分子功能往往是中性的或弱破坏性的。预计这些变异效应在很大程度上要么是实验无法检测到的，要么被认为不足以发表。这可能表明，非疾病表型的出现，通过许多变体的组合，其影响是弱非中性（破坏或增强）的分子蛋白质功能，但属于野生型范围内的整体生理功能。
Large-scale computational analyses of the growing wealth of genome-variation data consistently tell two distinct stories. The first is expected: coding variants reported in disease-related databases significantly alter the function of affected proteins. The second is surprising: the genomes of healthy individuals appear to carry many variants that are predicted to have some effect on function. As long as the complete experimental analysis of all human genome variants remains impossible, computational methods, such as PolyPhen, SNAP, and SIFT, might provide important insights. These methods capture the effects of particular variants very well and can highlight trends in populations of variants. Diseases are, arguably, extreme phenotypic variations and are often attributable to one or a few severely functionally disruptive variants. Our findings suggest a genomic basis of the different nondisease phenotypes. Prediction methods indicate that variants in seemingly healthy individuals tend to be neutral or weakly disruptive for protein molecular function. These variant effects are predicted to be largely either experimentally undetectable or are not deemed significant enough to be published. This may suggest that nondisease phenotypes arise through combinations of many variants whose effects are weakly nonneutral (damaging or enhancing) to the molecular protein function but fall within the wild-type range of overall physiological function.