The Road From Variants To Traits: How Regulatory Variants Affect Gene Expression & Organismal Phenotypes

Abstract

Nature hosts an incredible amount of diversity and beneath such diversity lies fascinating genetics that we have spent years trying to decode. Differences in our DNA sequences lead to variation in organismal traits. Most of these variants have been found to reside in noncoding portions of the genome, implying that a lot of organismal trait variation arises from variation in gene expression levels. Advances in sequencing technology have over the years allowed us to map hundreds of genomic loci underlying gene expression variation, and these loci are called expression quantitative trait loci (eQTLs). These eQTLs are of two types, local and trans, depending on their proximity to the genes they regulate. Local eQTLs regulate expression of genes in close genomic proximity while trans eQTLs regulate distant genes. Today, we possess a vast catalog of eQTLs across multiple taxa. Yet, we don’t fully understand the mechanisms by which eQTLs affect organismal traits. In this dissertation, I computationally dissect the mechanisms connecting genetic variation, gene expression and organismal traits in yeast Saccharomyces cerevisiae. As the first eukaryotic organism to have its genome fully sequenced, S.cerevisiae has over the years been a workhorse for understanding the genetics underlying complex traits. We today have comprehensive sets of QTLs underlying traits like gene expression and growth in yeast that account for most of heritable variation in these traits, allowing us to investigate the mechanisms by which eQTLs lead to organismal trait variation. In this dissertation, I characterize causal variants underlying local eQTLs in yeast (Chapter II) and the mechanisms by which eQTLs influence growth in different conditions (Chapter III). My work unravels fundamental principles by which eQTLs influence complex organismal traits.