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Enhancer redundancy predicts gene pathogenicity and informs complex disease gene discovery

View ORCID ProfileXinchen Wang, David B. Goldstein
doi: https://doi.org/10.1101/459123
Xinchen Wang
1Institute for Genomic Medicine, Columbia University Medical Center, Hammer Health Sciences, 1408, 701 West 168th Street, New York, New York 10032, USA.
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  • For correspondence: xw2553@cumc.columbia.edu dg2875@cumc.columbia.edu
David B. Goldstein
1Institute for Genomic Medicine, Columbia University Medical Center, Hammer Health Sciences, 1408, 701 West 168th Street, New York, New York 10032, USA.
2Department of Genetics & Development, Columbia University Medical Center, Hammer Health Sciences, 1602, 701 West 168th Street, New York, New York 10032, USA.
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  • For correspondence: xw2553@cumc.columbia.edu dg2875@cumc.columbia.edu
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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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Posted November 01, 2018.
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Enhancer redundancy predicts gene pathogenicity and informs complex disease gene discovery
Xinchen Wang, David B. Goldstein
bioRxiv 459123; doi: https://doi.org/10.1101/459123
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Enhancer redundancy predicts gene pathogenicity and informs complex disease gene discovery
Xinchen Wang, David B. Goldstein
bioRxiv 459123; doi: https://doi.org/10.1101/459123

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