Exploring the Regulatory Genome and Functional Genetic Variation

A substantial fraction of SNPs associated with human traits and diseases through genome-wide association studies (GWAS) are likely regulatory variants as they tend to be located within enhancers and associated with differential gene expression. Thus, as a key step in implementing personalized medicine, it is important to identify regulatory variants in the human genome, and characterize their underlying molecular mechanisms. However, identifying and elucidating the functions of regulatory variants is currently challenging as these variants show similar associations with many other neutral variants due to linkage disequilibrium, can be quite far from the gene(s) they regulate, and often have cell type-specific effects. In order to overcome these challenges and interrogate the function of these regulatory variants, it could be possible to examine and integrate epigenetic information in a cell type dependent manner. Here, I present three studies which focus on the functionality of the epigenome – specifically chromatin looping and co-accessibility – in the context of gene regulation, genetics, and disease. I present a tool for computationally working with chromatin loop data, and utilize this tool to show that genetic variation is not associated with large changes in chromatin looping, but rather small modulation in contact propensity which are associated with large changes in gene expression. I then examine chromatin co-accessibility, and show that genetic variants may be able to mediate long range effects on genes and accessible sites hundreds of megabases away – across entire chromosomes – which are associated with cell type relevant genes and diseases