Establishing the precise evolutionary history of a gene improves prediction of disease-causing missense mutations.
Establishing the precise evolutionary history of a gene improves prediction of disease-causing missense mutations.
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DOI：
10.1038/gim.2015.208
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发表时间：
2016-10
期刊：
影响因子：
--
通讯作者：
Zhulin IB
中科院分区：
文献类型：
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作者：
Adebali O;Reznik AO;Ory DS;Zhulin IB
预测突变的表型效应已成为临床遗传诊断的重要应用。计算工具评估变异在进化过程中的行为，并假设在进化过程中看到的变异对于人类来说可能是良性的。然而，当前的工具没有考虑直系同源/旁系同源关系。旁系同源物在孟德尔疾病中具有显着不同的作用。例如，NPC1 基因的失活突变会导致神经退行性疾病 Niemann-Pick C，而其旁系同源物 NPC1L1 的失活突变不会导致疾病，而且还与预防冠心病有关。我们确定了 NPC1 进化中的主要事件，并通过系统发育和蛋白质序列分析揭示和比较了人类 NPC1 基因的直系同源物和旁系同源物。我们预测氨基酸替代是否会通过降低生物体的适应性来影响蛋白质功能。去除旁系同源物和远距离同源物提高了对致病和良性氨基酸取代进行分类的整体性能。结果表明，进行彻底的进化分析并鉴定直系同源物可以提高预测致病错义突变的准确性。我们预计这种方法也将被用作解释其他遗传疾病变异的参考。基因医学 18 10, 1029–1036。
Predicting the phenotypic effects of mutations has become an important application in clinical genetic diagnostics. Computational tools evaluate the behavior of the variant over evolutionary time and assume that variations seen during the course of evolution are probably benign in humans. However, current tools do not take into account orthologous/paralogous relationships. Paralogs have dramatically different roles in Mendelian diseases. For example, whereas inactivating mutations in the NPC1 gene cause the neurodegenerative disorder Niemann-Pick C, inactivating mutations in its paralog NPC1L1 are not disease-causing and, moreover, are implicated in protection from coronary heart disease. We identified major events in NPC1 evolution and revealed and compared orthologs and paralogs of the human NPC1 gene through phylogenetic and protein sequence analyses. We predicted whether an amino acid substitution affects protein function by reducing the organism’s fitness. Removing the paralogs and distant homologs improved the overall performance of categorizing disease-causing and benign amino acid substitutions. The results show that a thorough evolutionary analysis followed by identification of orthologs improves the accuracy in predicting disease-causing missense mutations. We anticipate that this approach will be used as a reference in the interpretation of variants in other genetic diseases as well. Genet Med 18 10, 1029–1036.