Van Dyke, Krisna2024-01-192024-01-192023-11https://hdl.handle.net/11299/260148University of Minnesota Ph.D. dissertation. November 2023. Major: Molecular, Cellular, Developmental Biology and Genetics. Advisor: Frank Albert. 1 computer file (PDF); viii, 139 pages + 1 supplementary .ZIP file.Differences in non-coding regions of genomes explain the majority of heritable differences between individuals such as disease heritability. These non-coding differences are thought to largely act by altering gene expression, positioning regulatory variation as a key bridge between DNA variation and differences in traits. Expression quantitative trait loci (eQTLs) are regions of the genome containing one or more variants that alter the expression of a gene. In a cross between two strains of Saccharomyces cerevisiae, most heritable variation in gene expression acted in trans, with 90% of these trans-eQTLs overlapping only 102 “hotspot” loci. The large amount of heritable variation in gene expression that hotspots account for, and their discovery across the tree of life suggest they are a critical and ubiquitous feature of genome architecture. Classifying the structure of genetic variation underlying hotspots and learning what mechanisms allow hotspots to affect such large numbers of genes is critical to understanding how genetic variation gives rise to phenotypic variation. The following chapters describe a dissection of the variation underlying a hotspot and the uncovering of a new framework for how hotspots affect such numerous genes. Chapter II details how hotspots can co-opt the cellular mechanisms that cause adjacent genes to be coexpressed to extend their effect in cis. Chapter III dissects a hotspot with a complex epistatic basis to demonstrate how variants and groups of variants within a gene can interact to have wide-reaching impacts on the expression of many genes.enepistasisgeneticsgenomicspleiotropytrans-eQTLyeastThesis or Dissertation