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bioRxiv · 10.1101/459123

Enhancer redundancy predicts gene pathogenicity and informs complex disease gene discovery

Wang, X.·Goldstein, D. B.
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Abstract

Non-coding transcriptional regulatory elements are critical for controlling the spatiotemporal expression of genes. Here, we demonstrate that the number of bases in enhancers linked to a gene reflects its disease pathogenicity. Moreover, genes with redundant enhancer domains are depleted of cis-acting genetic variants that disrupt gene expression, and are buffered against the effects of disruptive non-coding mutations. Our results demonstrate that dosage-sensitive genes have evolved robustness to the disruptive effects of genetic variation by expanding their regulatory domains. This resolves a puzzle in the genetic literature about why disease genes are depleted of cis-eQTLs, suggesting that eQTL information may implicate the wrong genes at genome-wide association study loci, and establishes a framework for identifying non-coding regulatory variation with phenotypic consequences.

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Wang, X., Goldstein, D. B.. 2018-11-01. Enhancer redundancy predicts gene pathogenicity and informs complex disease gene discovery. https://doi.org/10.1101/459123

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