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Abstract

As researchers have sought to understand the genetic architecture of complex traits, including disease, it has become apparent that the majority of the signal originates outside protein coding regions of the genome. These results, obtained through many genome wide association studies (GWAS), have led most to conclude that changes in the regulation rather than structure of genes is the driving force behind variation in complex traits. Therefore, many hundreds if not thousands of genetic variants with small effects drive variation in complex traits, making it difficult to identify meaning genetic variants. This has led many researches to focus on the effects of genetic variation on gene regulation as an intermediate phenotype. Here I present three works focused on improving our ability to understand the mechanisms underlying inter-individual variation in gene regulation and building a better systems to study these phenomena in disease relevant cell-types. In my second chapter I will describe the effect of genetic variation on changes in DNA methylation levels and how these changes result in coordinate changes in histone modifications, transcription factor binding, and gene expression. My third chapter will focus on testing the fidelity of a new system, induced pluripotent stem cells, in which we can study gene regulation. Finally my fourth chapter will focus on characterizing inter-individual variation in gene regulation across three cell-types (induced pluripotent stem cells, cardiomyocytes derived from induced pluripotent stem cells, and lymphoblastoid cell lines from which the induce pluripotent stem cells were derived).

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