Non-coding transcriptional regulatory elements are critical for controlling the spatiotemporal expression of genes. Here, we demonstrate that the sizes and number of enhancers linked to a gene reflect its disease pathogenicity. Moreover, genes with redundant enhancer domains are depleted of cis-acting genetic variants that disrupt gene expression, and they are buffered against the effects of disruptive non-coding mutations. Our results demonstrate that dosage-sensitive genes have evolved a robustness to the disruptive effects of genetic variation by expanding their regulatory domains. This solves a puzzle about why genes associated with human disease are depleted of cis-eQTLs (cis-expression quantitative trait loci), suggesting that this relationship might complicate gene identification in causal genome-wide association studies (GWASs) using eQTL information, and establishes a framework for identifying non-coding regulatory variation with phenotypic consequences.

中文翻译：

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增强子结构域预测复杂疾病中的基因致病性并通知基因发现。

非编码转录调控元件对于控制基因的时空表达至关重要。在这里，我们证明了与基因连接的增强子的大小和数量反映了其疾病的致病性。此外，具有冗余增强子结构域的基因中缺失了破坏基因表达的顺式作用遗传变异，并且缓冲了它们免受破坏性非编码突变的影响。我们的结果表明，剂量敏感性基因通过扩展其调控域，已发展出对遗传变异破坏作用的鲁棒性。这解决了一个关于为什么与人类疾病相关的基因被耗尽了顺式eQTL（顺式表达定量性状基因座）的难题，