PT  - JOURNAL ARTICLE
AU  - Xinchen Wang
AU  - David B. Goldstein
TI  - Enhancer redundancy predicts gene pathogenicity and informs complex disease gene discovery
AID  - 10.1101/459123
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 459123
4099  - http://biorxiv.org/content/early/2018/11/01/459123.short
4100  - http://biorxiv.org/content/early/2018/11/01/459123.full
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.