ORCID
https://orcid.org/0000-0002-6340-6791
Date of Award
5-8-2025
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Deciphering the “genotype to phenotype” map is a crucial goal of biology. We will not improve our ability to predict phenotypes from DNA sequences until we better incorporate epigenetic and environmental variation into our models of human health and disease. Genes are typically presumed to express both parental alleles equally, but genetic and epigenetic factors can cause one allele to function differently than the other (e.g. expressed or silenced more). These allele-specific imbalances can alter the final composition of a gene’s transcriptional product and ultimately shape phenotypes. Allele-specific effects have widespread impacts on complex traits, but how environmental signals contribute to this phenomenon remains unclear. This thesis unravels the causes and consequences of allele-specific gene regulation on metabolic phenotypes related to obesity and diabetes. First, I explored how DNA sequence, parent-of-origin, tissue, sex, and dietary nutrition simultaneously govern allele-specific gene expression (ASE) biases. I used a simple, yet powerful, F1 reciprocal cross of the LG/J and SM/J mouse strains to distinguish between two ASE classes: parent-of-origin dependent (unequal expression based on parental origin) and sequence dependent (unequal expression based on haplotype sequence). I constructed a genome-wide map of ASE patterns in thousands of genes across three metabolic tissues and nine environmental contexts. The magnitudes and directions of these expression biases are highly sensitive to tissue type and environmental factors. Second, I probed how those same factors influence both classes of allele-specific DNA methylation (ASM) biases. Parent-of-origin ASM sites are enriched in the promoters of genes with parental expression biases, while sequence ASM sites are enriched in intergenic regions with unclear relevance to gene expression. Third, I integrated my allele-specific findings with quantitative trait loci (QTL) data from published intercrosses of these same strains. Tissue-specific ASE genes are enriched in QTLs for metabolic and musculoskeletal traits yet comprise a small number of all genes within those QTL. I demonstrate how this orthogonal approach can pinpoint actionable candidates for functional validation. Collectively, my thesis work provides novel insights into how genetic, epigenetic, and environmental variation modulate allele-specific gene regulation in metabolic phenotypes. Finally, I outlined my work with the Young Scientist Program, a K-12 STEM outreach program. I described the curriculum for a science communication course that introduces crucial science literacy skills to high school students. After completing the course, students reported significant improvements in their self-confidence to read, interpret, and communicate scientific data. This chapter also renders visible my contributions to improving how we train and support the next generation of diverse scientists.
Language
English (en)
Chair and Committee
Heather Lawson
Committee Members
Ting Wang; Arpana Agrawal; Barak Cohen; Michael Province
Recommended Citation
St. Pierre, Celine Louise, "Parental Guidance Suggested: Genetic, Epigenetic, and Environmental Factors Shape Allele-Specific Gene Regulation in Metabolic Traits" (2025). Arts & Sciences Theses and Dissertations. 3537.
https://openscholarship.wustl.edu/art_sci_etds/3537