Project summary This research project bridges the gap between evolutionary genetics and genetic epidemiology. In the past few years, a large number of genome-wide association studies have identified thousands of disease susceptibility loci. However, the vast majority of these studies have focused on individuals with European ancestry. Many disease loci have yet to be discovered, and disease-associations that are presently known suffer from ascertainment bias. A major public health challenge is to accurately predict hereditary disease risks in other populations. Previous work has revealed that hereditary disease risks have evolved over human history and that disease risks are correlated with different genetic ancestries. This proposed research plan combines multiple approaches: analysis of ancient and modern genomes, mathematical modeling, and bioinformatics tool development. It examines the evolutionary causes of differences in genetic disease risks across populations, and it will help extend precision medicine to individuals who have diverse ancestries. By applying genomic medicine approaches to ancient DNA, this project will be result in a better understanding of how health and disease have evolved in the recent past. Mathematical models and computer simulations will be used to generate testable predictions about what sorts of genetic architectures contribute the most to health inequities. This project includes development of a novel ancestry painting approach that will improve predictions of hereditary disease risks for individuals whose genomes contain a mix of different ancestries. This project also involves generating improved genetic risk scores that correct for ascertainment bias and evolutionary history while incorporating details of molecular cell biology. The effectiveness of this approach will be assessed using phenotypic data from multiple populations. A major goal of this project is to understand how disease risks have come to vary across the globe, and this work will help extend the benefits of genomic medicine to individuals who have diverse ancestries.