Environmental and genetic regulation of gene expression via exercise and ancestry

Differential gene expression contributes to variation in complex traits and disease. The regulation of gene expression is dynamic and multifactorial, governed by the genome, epigenome, environment, and interactions between these levels. Genetic association studies link phenotypic differences to specific genetic factors, identifying putative genetic mechanisms underlying disease. Ancestry contributes to genetic and environmental factors that manifest in population differences ranging from gene expression to disease incidence. Therefore, ancestry must be carefully accounted for when performing genetic association studies in heterogeneous cohorts to avoid spurious results arising from confounding population structure. In Chapter 2, an admixed subcohort of the Genotype-Tissue Expression (GTEx) Project is leveraged to compare variant-specific local and genome-wide global ancestry adjustments in the context of genetic association studies. We provide a local ancestry map of the admixed GTEx subcohort and report generally concordant results between local and global ancestry-based adjustments, identifying distinct advantages and disadvantages of each approach. Among environmental factors impacting gene expression, exercise elicits strong but transient effects that reflect a coordinated, whole-body response. Regular exercise promotes wide-ranging health benefits, substantially reducing the risk of cardiovascular, metabolic, and neurological pathologies, among others. However, the multi-tissue molecular mechanisms underlying these adaptive responses are incompletely understood. To address this gap, the Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to develop multi-omic molecular maps of the acute and chronic endurance and/or resistance exercise responses across tissues in rats and accessible tissues in humans. All MoTrPAC data will be made publicly available (https://motrpac-data.org/). Chapter 3 presents MoTrPAC's complete multi-tissue, multi-omic endurance exercise training data resource from young adult male and female rats, encompassing 211 datasets across 19 tissues, 25 molecular assays, and 4 training time points. We identify 35,439 molecular features that respond to training in at least one sex over the training time course and perform integrative analyses to describe alterations in whole-body homeostasis, mitochondrial biogenesis, metabolism, immune responses, and tissue structure. The benefits of regular exercise necessarily manifest through repeated acute exercise bouts. Therefore, Chapter 4 presents preliminary analyses of multi-tissue gene expression data from an acute endurance exercise study in young adult male and female rats, representing a fraction of what will be another powerful MoTrPAC data resource. The work presented in Chapter 2 will be relevant for future genetic analyses of the diverse MoTrPAC clinical cohort. In totality, this work contributes to our understanding of the interplay between genetics, exercise, and disease

Keywords: Genetics.
Advisor: Montgomery Stephen
Engreitz Jesse
Snyder Michael
Wheeler Matthew B.
Wyss-Coray Anton