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Access Type
WSU Access
Date of Award
January 2025
Degree Type
Dissertation
Degree Name
Ph.D.
Department
Molecular Biology and Genetics
First Advisor
Roger Pique-Regi
Second Advisor
Francesca Luca
Abstract
Noncoding variants contribute to the regulation of gene expression, largely by disrupting regulatory sequences. Both genome-wide association studies (GWAS) and expression quantitative trait loci (eQTLs) have highlighted the importance of studying noncoding regulatory variants, as many GWAS variants are noncoding, and eQTLs directly regulate gene expression. These findings increase our understanding of human health and molecular mechanisms respectively; however we do not fully understand the complexities of gene regulation and their relation to complex disease. GWAS and eQTLs largely ignore contexts that could impact gene regulatory activity, such as environmental stimuli. Explicitly considering environmental context can uncover regulatory gene-environment interactions, where allelic effects are not observed in one environment, but are observed in a different environment, making the gene regulatory activity context-dependent. Furthermore, these gene-environment interactions have important phenotypic consequences and underlie variation in complex traits. Thus, gene-environment interactions are a crucial area of study, as results may uncover important information regarding human health and evolution.In chapter 2 I utilized a massively parallel reporter assay to identify genotype-environment interactions (GxE) in vascular endothelial cells exposed to caffeine. This work demonstrates that we can elucidate potential mechanisms explaining the inter-individual response to caffeine and its implications for cardiovascular health. In chapter 3 I investigated the role of BPA and phthalate exposure related to cardiovascular health. This work demonstrates that these ubiquitous plastic contaminants alter gene expression in vascular endothelial cells. In chapter 4 I investigated the role of GxE in human evolution by identifying instances of GxE for Neanderthal-introgressed and fixed variants. This work found differences in the gene regulatory activity of these fixed and introgressed variants and expands on the evolutionary implications of this finding. This work also identifies GxE for adaptively introgressed variants, contributing to the field by identifying sun exposure as a potential selective pressure as humans migrated out of Africa. Altogether, my PhD research demonstrates the importance of considering environmental context when studying gene regulatory activity and the downstream effects of genotype-environment interactions on human health and evolution.
Recommended Citation
Boye, Carly, "Genotype-Environment Interactions For Non-Coding Variants In Disease And Evolution" (2025). Wayne State University Dissertations. 4220.
https://digitalcommons.wayne.edu/oa_dissertations/4220