Project Summary / Abstract Genetic variation among individuals shapes important phenotypes, including the risk for common human diseases such as cardiovascular, autoimmune, and neurological disease. In particular, regulatory genetic variation causes inter-individual differences in gene expression. The resulting gene expression differences account for a substantial portion of variation in many genetically complex traits. In spite of the critical importance of regulatory variation, many fundamental questions remain open. First, most DNA differences in a given genome likely have no effect. The nature of the specific variants that do have effects remains poorly understood. Second, genetic variation can specifically affect the protein abundance of a given gene without altering the abundance of the mRNA of the same gene. The mechanisms that are responsible for these protein-specific effects remain unclear. Third, we only have a crude understanding of how the differences in gene expression that result from regulatory variation affect organismal phenotypes. Over the next five years, research in my laboratory will focus on addressing these critical gaps in knowledge. Specifically, we seek to identify and characterize causal DNA variants, study the impact of genetic variation on protein degradation, and examine quantitatively how the precise abundance of a given gene can shape organismal traits. Our work combines computational biology, quantitative and statistical genetics with experimental genome-wide approaches. We use the yeast Saccharomyces cerevisiae as a powerful and tractable model system for regulatory variation, while pursuing related approaches in human cells. Our long-term vision is to improve our understanding of regulatory variation to the point at which it becomes possible to accurately predict the consequences of the DNA variants in an individual’s genome. This ability will be valuable for fundamental research and personalized approaches for improving human health.

Project Narrative This project will address fundamental questions about the causes, molecular mechanisms, and phenotypic consequences of regulatory genetic variation. Regulatory variation arises from inter-individual differences in DNA sequence that alter gene expression and underpin much of the genetic risk for common human diseases. A better understanding about the causes and consequences of regulatory variation will improve our ability to predict genetic disease risk from individual genomes.