Xiang Zhu, of the Department of Statistics at Penn State, will present:
“Applying an Enhancer Lens to Human Disease Genetics”
Over the past two decades, genome-wide association studies (GWAS) have advanced the discovery and interpretation of numerous genetic variants influencing complex human diseases. Notably, more than 90% of disease-associated variants are located within non-coding regions of the human genome, thereby complicating their translation to biological knowledge and clinical practice. Enhancers, non-coding elements that interact with transcription factors to increase gene expression levels, can provide crucial insights into the regulatory mechanisms underpinning GWAS discoveries. In this seminar, I will present three studies to illustrate how enhancers, when coupled with new statistical methods and computational tools, can improve the discovery and interpretation in GWAS. First, we develop a scalable strategy to identify non-coding elements exhibiting both high levels of cross-species sequence conservation and enhancer-like biochemical activity. Through Bayesian hierarchical modeling of these elements in GWAS, we further showcase the real-world utility of sequence-conserved enhancers in identifying heritability enrichments, likely causal variants, and effector genes for complex diseases. Second, we employ multiplexed CRISPR interference and machine learning to reveal a multi-layer enhancer network that maintains robust gene expression against non-coding mutations. Building on this enhancer network, we further develop an analytical framework to identify non-additive effects of genetic interactions on disease risk beyond standard additivity-only GWAS. Third, we develop a Bayesian variable selection method to infer target genes of enhancers from transcriptomic and epigenomic data across diverse tissues and cell types. By combining the identified enhancer-gene linkages with GWAS, we further pinpoint disease associations in the non-coding genome to putative regulatory mechanisms for experimental interrogation. Together, these studies demonstrate the promise of enhancers to elucidate human disease genetics, and offer several generalizable strategies to deliver on this promise.
A seminar tea will be held at 11:00 a.m. in University Office Plaza, Room 240. All are Welcome.
