Natural Variation in Gene Expression Modulates the Severity of Mutant Phenotypes
Natural Variation in Gene Expression Modulates the Severity of Mutant Phenotypes
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DOI：
10.1016/j.cell.2015.06.037
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发表时间：
2015-07-16
期刊：
影响因子：
64.5
通讯作者：
Fraser, Andrew G.
中科院分区：
文献类型：
--
作者：
Vu, Victoria;Verster, Adrian J.;Fraser, Andrew G.
许多突变会导致遗传疾病。然而，两个遗传相同突变的人通常会有不同的症状严重程度，这在一定程度上是遗传的。遗传背景对突变表型的影响知之甚少，但预测突变表型对个性化药物至关重要。为了全面系统地研究这一现象，我们利用RNAi技术比较了两个线虫分离株中类似1400个基因的功能丧失表型，发现在这两个遗传背景中，大约20%的基因的表型严重程度不同。重要的是，遗传背景对RNAi和突变表型的严重程度的影响可以从受影响基因表达水平的变化中预测出来。在哺乳动物细胞中也是如此，这表明这是遗传网络的一种普遍属性。我们认为，突变表型在个体之间的表现差异很大程度上是基因表达的自然差异的结果。
Many mutations cause genetic disorders. However, two people inheriting the same mutation often have different severity of symptoms, and this is partly genetic. The effects of genetic background on mutant phenotypes are poorly understood, but predicting them is critical for personalized medicine. To study this phenomenon comprehensively and systematically, we used RNAi to compare loss-of-function phenotypes for similar to 1,400 genes in two isolates of C. elegans and find that similar to 20% of genes differ in the severity of phenotypes in these two genetic backgrounds. Crucially, this effect of genetic background on the severity of both RNAi and mutant phenotypes can be predicted from variation in the expression levels of the affected gene. This is also true in mammalian cells, suggesting it is a general property of genetic networks. We suggest that differences in the manifestation of mutant phenotypes between individuals are largely the result of natural variation in gene expression.