Enhancer Domains Predict Gene Pathogenicity and Inform Gene Discovery in Complex Disease

Abstract

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.

Keywords: EDS; Mendelian disease; causal gene; eQTLs; enhancer; enhancer domains; gene regulation; intolerance; pathogenicity.