Quantifying deleterious effects of regulatory variants #MMPMID27980060
Li S; Alvarez RV; Sharan R; Landsman D; Ovcharenko I
Nucleic Acids Res 2017[Mar]; 45 (5): 2307-17 PMID27980060show ga
The majority of genome-wide association study (GWAS) risk variants reside in non-coding DNA sequences. Understanding how these sequence modifications lead to transcriptional alterations and cell-to-cell variability can help unraveling genotype?phenotype relationships. Here, we describe a computational method, dubbed CAPE, which calculates the likelihood of a genetic variant deactivating enhancers by disrupting the binding of transcription factors (TFs) in a given cellular context. CAPE learns sequence signatures associated with putative enhancers originating from large-scale sequencing experiments (such as ChIP-seq or DNase-seq) and models the change in enhancer signature upon a single nucleotide substitution. CAPE accurately identifies causative cis-regulatory variation including expression quantitative trait loci (eQTLs) and DNase I sensitivity quantitative trait loci (dsQTLs) in a tissue-specific manner with precision superior to several currently available methods. The presented method can be trained on any tissue-specific dataset of enhancers and known functional variants and applied to prioritize disease-associated variants in the corresponding tissue.
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Nucleic+Acids+Res 2017 ; 45 (5): 2307-17
