Identification of cis-suppression of human disease mutations by comparative genomics
Identification of cis-suppression of human disease mutations by comparative genomics
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DOI：
10.1038/nature14497
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发表时间：
2015-08-13
期刊：
影响因子：
64.8
通讯作者：
Katsanis, Nicholas
中科院分区：
文献类型：
--
作者：
Jordan, Daniel M.;Frangakis, Stephan G.;Katsanis, Nicholas
氨基酸保守模式已成为理解蛋白质进化的工具（1）。同样的原理也在人类基因组学中得到了广泛的应用，这是由于需要解释患者变异的致病潜力（2）。在这里，我们对导致人类疾病的错义变体进行了系统的比较基因组学分析。我们发现，相当一部分致病等位基因固定在其他物种的基因组中，这表明基因组背景的作用。我们开发了一个遗传相互作用的模型，预测其中大部分是简单的成对补偿。该模型在两个已知的人类疾病基因上的功能测试（3，4）揭示了离散的顺式氨基酸残基，尽管其本身是良性的，但可以在体内挽救人类突变。这种方法也被应用于从头基因发现，以支持在超过50个物种中进行保护性顺式修饰的BTG 2中的从头疾病驱动因子的鉴定。最后，在我们的数据和模型的基础上，我们开发了一个计算工具来预测候选残基受到补偿。总之，我们的数据突出了顺式基因组背景作为蛋白质进化贡献者的重要性;它们提供了对等位基因对表型影响的复杂性的洞察;并且它们可能有助于预测等位基因致病性的方法（5，6）。
Patterns of amino acid conservation have served as a tool for understanding protein evolution(1). The same principles have also found broad application in human genomics, driven by the need to interpret the pathogenic potential of variants in patients(2). Here we performed a systematic comparative genomics analysis of human disease-causing missense variants. We found that an appreciable fraction of disease-causing alleles are fixed in the genomes of other species, suggesting a role for genomic context. We developed a model of genetic interactions that predicts most of these to be simple pairwise compensations. Functional testing of this model on two known human disease genes(3,4) revealed discrete cis amino acid residues that, although benign on their own, could rescue the human mutations in vivo. This approach was also applied to ab initio gene discovery to support the identification of a de novo disease driver in BTG2 that is subject to protective cis-modification in more than 50 species. Finally, on the basis of our data and models, we developed a computational tool to predict candidate residues subject to compensation. Taken together, our data highlight the importance of cis-genomic context as a contributor to protein evolution; they provide an insight into the complexity of allele effect on phenotype; and they are likely to assist methods for predicting allele pathogenicity(5,6).