Highlight talk – Theme: Data
Abstract
In this study, we identified nucleotides capable of disrupting binding of transcription factors and deactivating enhancers (dubbed killer mutations or KMs). On average, ~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 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 while RSs could boost enhancer activity. Additionally, HepG2 KMs are strongly associated with liver-related GWAS traits. By applying our framework to lymphoblastoid cell lines, we found that KMs underlie differential binding of transcription factors and differential local chromatin accessibility. In summary, 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.
Authors
Shan Li, NIH, United States
Ivan Ovcharenko, NIH, United States