Identifying Genes Whose Mutant Transcripts Cause Dominant Disease Traits by Potential Gain-of-Function Alleles
Identifying Genes Whose Mutant Transcripts Cause Dominant Disease Traits by Potential Gain-of-Function Alleles
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DOI：
10.1016/j.ajhg.2018.06.009
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发表时间：
2018-08-02
影响因子：
9.8
通讯作者：
Carvalho, Claudia M. B.
中科院分区：
文献类型：
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作者：
Coban-Akdemir, Zeynep;White, Janson J.;Carvalho, Claudia M. B.
携带提前终止密码子（PTC）的转录物通常被无义介导的衰变（NMD）降解，导致功能丧失（LoF）等位基因。然而，并非所有PTC都导致LoF突变，即，一些这样的转录物逃避NMD并被翻译成截短的肽产物，其由于功能获得（GoF）效应而导致疾病。由于PTC的位置是决定转录物命运的主要因素，我们假设在对照数据库中预测逃避NMD的基因区域内的蛋白质截短变体（PTV）的耗尽可以通过GoF与LoF提供疾病的基因易感性的排名。我们开发了NMD逃避不耐受评分，以基于PTV的消耗对基因进行排名，这将使它们能够使用社区研究中的动脉粥样硬化风险（ARIC）和外显子组聚集联盟（ExAC）对照数据库逃避NMD，其进一步用于筛选Baylor-Center for Mendelian Genomics疾病数据库。该分析揭示了1，996个基因对于预测逃离NMD的PTV显著耗尽，即，进一步的研究提供了证据，揭示了一个子集作为候选基因的孟德尔表型。重要的是，这些基因具有典型的低pLI评分，这可能导致它们被忽视为显性疾病的候选者。总的来说，我们证明了这种NMD逃避不耐受评分是一种有效的和高效的工具，基因发现孟德尔疾病，由于生产的截断或改变的蛋白质。更重要的是，我们提供了一个互补的分析工具，以帮助识别与显性性状相关的基因，通过一个不同于LoF的机制。
Premature termination codon (PTC)-bearing transcripts are often degraded by nonsense-mediated decay (NMD) resulting in loss-of-function (LoF) alleles. However, not all PTCs result in LoF mutations, i.e., some such transcripts escape NMD and are translated to truncated peptide products that result in disease due to gain-of-function (GoF) effects. Since the location of the PTC is a major factor determining transcript fate, we hypothesized that depletion of protein-truncating variants (PTVs) within the gene region predicted to escape NMD in control databases could provide a rank for genic susceptibility for disease through GoF versus LoF. We developed an NMD escape intolerance score to rank genes based on the depletion of PTVs that would render them able to escape NMD using the Atherosclerosis Risk in Communities Study (ARIC) and the Exome Aggregation Consortium (ExAC) control databases, which was further used to screen the Baylor-Center for Mendelian Genomics disease database. This analysis revealed 1,996 genes significantly depleted for PTVs that are predicted to escape from NMD, i.e., PTVesc; further studies provided evidence that revealed a subset as candidate genes underlying Mendelian phenotypes. Importantly, these genes have characteristically low pLI scores, which can cause them to be overlooked as candidates for dominant diseases. Collectively, we demonstrate that this NMD escape intolerance score is an effective and efficient tool for gene discovery in Mendelian diseases due to production of truncated or altered proteins. More importantly, we provide a complementary analytical tool to aid identification of genes associated with dominant traits through a mechanism distinct from LoF.