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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增强子结构域预测基因致病性并为复杂疾病中的基因发现提供信息。


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，我们证明与基因相关的增强子的大小和数量反映了其疾病致病性。此外，具有冗余增强子结构域的基因消除了破坏基因表达的顺式作用遗传变异，并且它们可以缓冲破坏性非编码突变的影响。我们的结果表明，剂量敏感基因通过扩大其调控域，进化出了对遗传变异破坏性影响的鲁棒性。这解决了为什么与人类疾病相关的基因缺乏 cis-eQTL（顺式表达数量性状位点）的难题，表明这种关系可能会使使用 eQTL 信息的因果全基因组关联研究 (GWAS) 中的基因识别变得复杂，并建立了用于识别具有表型后果的非编码调控变异的框架。