Journal Article

Human Enhancers Are Fragile and Prone to Deactivating Mutations

Shan Li and Ivan Ovcharenko

in Molecular Biology and Evolution

Published on behalf of Society for Molecular Biology and Evolution

Volume 32, issue 8, pages 2161-2180
Published in print August 2015 | ISSN: 0737-4038
Published online May 2015 | e-ISSN: 1537-1719 | DOI:
Human Enhancers Are Fragile and Prone to Deactivating Mutations

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  • Evolutionary Biology
  • Molecular and Cell Biology


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To explore the underlying mechanisms whereby noncoding variants affect transcriptional regulation, we identified nucleotides capable of disrupting binding of transcription factors and deactivating enhancers if mutated (dubbed candidate killer mutations or KMs) in HepG2 enhancers. On average, approximately 11% of enhancer positions are prone to KMs. A comparable number of enhancer positions are capable of creating de novo binding sites via a single-nucleotide mutation (dubbed candidate restoration mutations or RSs). Both KM and RS positions are evolutionarily conserved and tend to form clusters within an enhancer. We observed that KMs have the most deleterious effect on enhancer activity. In contrast, RSs have a smaller effect in increasing enhancer activity. Additionally, the KMs are strongly associated with liver-related Genome Wide Association Study traits compared with other HepG2 enhancer regions. By applying our framework to lymphoblastoid cell lines, we found that KMs underlie differential binding of transcription factors and differential local chromatin accessibility. The gene expression quantitative trait loci associated with the tissue-specific genes are strongly enriched in KM positions. In summary, we conclude that the KMs have the greatest impact on the level of gene expression and are likely to be the causal variants of tissue-specific gene expression and disease predisposition.

Keywords: enhancers; causal mutations; transcription factor binding sites; gene regulation

Journal Article.  13764 words.  Illustrated.

Subjects: Evolutionary Biology ; Molecular and Cell Biology

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