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Abstract

Gene regulation is context-specific and dynamic, changing between cell types and states, and during processes like differentiation and development. To more deeply understand the genetic architecture of human traits and diseases, it is necessary to characterize genetic effects on gene regulation in the relevant cell types and in dynamic contexts. In this thesis, I addressed this goal using in vitro differentiations of human induced pluripotent stem cells (iPSCs) to study dynamic regulation of gene expression. In Chapter 2, I differentiated a panel of iPSCs to cardiomyocytes and collected timecourse RNA-seq data at regular intervals throughout the differentiation. I used this data to identify dynamic eQTLs, or genetic loci whose effect on gene expression changes through time. I found that dynamic eQTLs acting during cardiomyocyte differentiation are associated with heart phenotypes and cardiovascular disease risk. In Chapter 3, I characterized patterns of gene expression in embryoid bodies (EBs), a differentiation system that enables the simultaneous study of a multitude of cell types and differentiation trajectories. I found that EBs are composed of functionally and temporally diverse cells, including cells with similar transcriptomes to primary fetal cell types. This work provides a foundation of knowledge of the EB system that will enable future studies of dynamic eQTLs. In chapter 4, I generated EBs from human and chimpanzee lines to compare gene expression between species across many cell types, including early developmental cell types which have previously been inaccessible. I identified patterns of conserved and diverged gene expression between species. Overall, these studies leverage iPSC differentiations to study dynamic gene regulation and provide new insight into the genetics of human development, complex traits, and disease.

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