Project Summary/Abstract: Large-scale population genomic studies have failed to provide a full picture of the genetic variation harbored in human populations, largely overlooking entire regions of the world. Indeed, of the human genomes currently available, only ~3% are from Oceania, a region that harbors unique population-specific genetic variation, including the largest amounts of DNA inherited from archaic hominin such as Neanderthals and the enigmatic Denisovans. Thus, a fundamental knowledge gap exists regarding human genetic variation and archaic hominin introgression in Oceania. A better understanding of the full spectrum of human genomic variation in Oceania is critical for reconstructing our evolutionary past and disentangling the genetic basis of phenotypic variation and disease susceptibility. In this context, my lab aims to discover and characterize human genetic variation in Oceania at unprecedented resolution. Upon establishing my lab in July 2020, we have spearheaded two large- scale genome sequencing projects which aim to characterize the full spectrum of human genetic variation in Oceania, from single nucleotide polymorphisms to large, complex structural variants. Using an integrative approach that combines insights from population genomics, molecular biology, genome sequencing, computational biology and anthropology, my lab seeks to understand how migrations, admixture, genetic drift, cultural barriers, and natural selection influence patterns in population genetic structure. One fundamental question we seek to address is how archaic hominin introgression contributes to phenotypic variation. While several lines of evidence exist for both adaptive and deleterious effects of Neandertal introgressed variants, our understanding of the impact of Denisovan introgression on fitness in modern humans is limited by the few available Oceanic genomes available. Our proposal offers an unprecedented opportunity to map Denisovan introgressed variants that remain undiscovered at present and make inference about their fitness and functional consequences. Importantly, motivated by the recent discovery of Oceanic-specific adaptive introgressed structural variants (SVs), my lab will explore the role that SVs played in human evolution and adaptation by generating the first panel of fully phased de novo assemblies of Oceanic genomes, and will comprehensively characterize SVs by integrating them into the latest human pangenome graph. Overall, my research program will empower the discovery of previously unknown human genetic variation, including novel candidates for adaptive introgression, and address fundamental questions about our evolutionary history.