RT Journal Article
SR Electronic
T1 Enhancer redundancy predicts gene pathogenicity and informs complex disease gene discovery
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 459123
DO 10.1101/459123
A1 Xinchen Wang
A1 David B. Goldstein
YR 2018
UL http://biorxiv.org/content/early/2018/11/01/459123.abstract
AB 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.