DESCRIPTION (provided by applicant): Project Summary Recent technological advances in genome sequencing have enabled numerous large-scale association studies aimed at discovering genetic variants underlying a wide array of complex diseases. It has become increasingly evident that the majority of these associations stem from a perturbation of regulatory function. While the ENCODE project and related efforts have strengthened our ability to comprehensively identify regulatory elements, our ability to decipher the impact of individual variants within these elements has not kept step. To address this gap, I aim to develop and apply the massively parallel reporter assay (MPRA) to empirically test the regulatory potential of thousands of individual variant sites for a wide range of roles. My specific aims are to: (1) Demonstrate the utility of MPRA by applying the method to loci in the human genome with evidence of recent positive selection and those identified in published genome wide association studies; (2) Modify MPRA to capture a more comprehensive array of regulatory mechanisms; and (3) Transition the current MPRA episomal vector to a viral delivery platform, allowing for chromosomal integration. I anticipate that these methods will provide the broader research community with a catalog of biologically meaningful regulatory variants and a valuable toolkit for understanding the role that regulatory variation plays in human health and disease.