Biostatistics Weekly Seminar

Interpretation of regulatory variants towards deciphering of disease risk

Jing Wang, PhD
Vanderbilt University School of Medicine

The goal of precision medicine is to treat patients with drugs that target the specific genetic mutations in their tumors, regardless of where the tumors are found. Although variants in protein-coding regions have received the most attention, recent genome-wide association studies (GWAS) have found >88% of disease-risk variants lie in non-coding regions, especially enriched in enhancers. Sequence variants within enhancers can alter transcription factor binding and/or disrupt enhancer-promoter interactions, resulting in gene expression dysregulation and disease. To identify, interpret, and prioritize such risk variants in enhancers, we must identify the enhancers active in disease-relevant cell types, their upstream TF binding, and their downstream target genes. To address this need, we describe NRSA and built HACER. NRSA (nascent RNA sequencing analysis) is a novel bioinformatics tool dedicated to analyze nascent transcription profiles generated by PRO-seq and GRO-seq data. NRSA not only outperforms existing methods for enhancer identification, but also enables annotation and quantification of active enhancers, and prediction of their target genes. Furthermore, NRSA smoothly integrates other genomic data to prioritize enhancers. HACER is an atlas of Human ACtive Enhancers to interpret Regulatory variants. The HACER atlas catalogues and annotates in-vivo transcribed cell-type-specific enhancers, as well as placing enhancers within transcriptional regulatory networks by integrating ENCODE TF ChIP-Seq and predicted/validated chromatin interaction data. We demonstrate the utility of HACER in (i) offering mechanistic hypothesis to explain the association of SNP with disease risk, (ii) exploring tumor-specific enhancers in target gene dysregulation, and (iii) prioritizing non-coding regulatory regions. HACER provides a valuable resource for studies of GWAS, non-coding variants, and enhancer-mediated regulation.

2525 WEA, 10th Floor VICTR Conference Room
8 February 2019

Topic revision: r1 - 18 Jan 2019, TawannaPeters

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