PROJECT SUMMARY Population genomic data carry a detailed record of evolutionary history, but this record is simultaneously impacted by multiple evolutionary forces making interpretation extremely challenging. Methods development and increasing accessibility of large-scale genomic datasets have led to more powerful strategies to disentangle the effects of natural selection and identify loci underlying recent adaptation. Yet we still lack understanding of many aspects of adaptive processes, including the types of genetic variation (e.g., point mutations vs. structural variants), numbers of loci, and selective regimes by which it occurs. Over the next five years, research in the Leffler lab aims to probe the genetics of adaptation by developing new approaches and datasets to study loci under recent pathogen-driven selective pressures in humans and non-human primates. Pathogens have a severe impact on host fitness and survival and consequently are a driving force for evolutionary change and an effective model system for learning about selective processes. We will combine approaches in computational, population and evolutionary genomics to explore a range of signatures that host- pathogen interactions leave in our genomes, organized in three project areas. First, we will characterize population genomic variation in the Arabian Peninsula, developing a new sequence-based approach to identify adaptive gene flow post-admixture and test for enrichment related to infectious disease, particularly focusing on blood group variation. Second, we will analyze copy number variation in paralogous gene clusters, developing new methods for inference of both copy number and selection, in order to test whether they may be frequent targets of pathogen-driven selection. Finally, we will investigate evolutionary genomics of wild macaques in southeast Asia. We will assess evidence for pathogen-driven selection by comparing allele frequencies in populations with a range of pathogen burdens and different levels of admixture with closely related species living in the absence of these pathogens. Together, the results of these research projects will provide new tools, datasets, and significant insight into the impact of host-pathogen co-evolution across populations, gene families, and primate species.