Date of Award
7-10-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Genetic sequences and epigenetic features work together to regulate gene expression, which can vary across species, individuals, and cell-types. Understanding this relationship between genetics and epigenetics is a key step to revealing the connection between genotype and phenotype on a systematic, genome-wide level. The first chapter of my thesis outlines the ways genetic variation and epigenetic variation may interact to shape gene regulation across scales, as well as how we can question it further. One of the most studied mechanisms is genetic variation that has a direct impact on epigenetic variation. At the species level, it is documented that species-specific sequence and assembly differences, can result in major differences in genome folding. Interestingly, transposable elements (TEs), often referred to as junk DNA, often harbor CTCF binding motifs which often play a major role in shaping the genome. In Chapter 2 of my thesis, I show that TEs contributed to species-specific three-dimensional genome folding, potentially impacting species-specific gene regulation. Zooming into variation at an individual level, we see further examples of genetic variation directly overlapping epigenetic variation. However, it is still critical to know in what genomic contexts genetic variation might impact on epigenetic variation, or even vice versa. In Chapter 3, I propose that human induced Pluripotent Stem Cells (iPSCs) can be used as a model to study the relationship between genetic variation and epigenetic variation while controlling for consistent environmental factors. I quantified the association between genetic and epigenetic variation in iPSCs from three donors, as well as the cell-type-specific relationships in monocytes, neuronal stem cells (NSCs) and motor neurons derived from the respective iPSCs via directed differentiation. I discovered that epigenetic variation is most strongly associated with genetic variation at the iPSC stage, and that this relationship weakens as epigenetic variation increases in the differentiated cells, shedding light on how genetic variation may impact human cellular function in a cell-type-specific manner.
Language
English (en)
Chair and Committee
Ting Wang
Committee Members
Andrew Yoo; Nancy Lim Saccone; Tychele Turner; Xiaoxia Cui
Recommended Citation
Quaid, Kara, "Understanding the Relationship between Genetic and Epigenetic Variation at a Species and Individual Level" (2024). Arts & Sciences Electronic Theses and Dissertations. 3319.
https://openscholarship.wustl.edu/art_sci_etds/3319