Characterizing genomic variation in Neanderthals and Denisovans and its functional impact on modern human populations

There are now hundreds of ancient genomes available from a wide range of species, including extinct archaic humans: Neanderthals and Denisovans. Such data provide a direct window into the history of demography and natural selection in the recent past, and have greatly contributed to the understanding of how humans adapted to new environments after expanding outside of Africa. Direct comparisons of archaic and modern human genomes have revealed a complex landscape of genetic admixture, where living humans today carry a small but significant proportion of archaic DNA. This archaic inheritance affects the fitness and health of living people. While bioinformatics methods for identifying archaic genome variants are very advanced, functional validation of how archaic genome variants differ from modern human equivalents in vitro lags behind. The proposed research will close this gap by performing functional validation experiments leveraging state-of-the-art cellular assays that take advantage of high-throughput DNA sequencing. Moreover, the focus of these experiments is in understanding the evolutionary history and medical consequences of archaic ancestry in underrepresented populations: in particular, Indigenous American and Latino individuals, whose genome ancestry is complex following 500 years of European colonization. We will focus on pharmacogenes, genes responsible for the metabolizing of exotic substances, which have a direct link to both adaptation to novel environments, and metabolizing of plant-derived medical drugs in modern medicine. By working with collaborators who specialize in the health consequences of pharmacogene variation in Indigenous populations, we will produce and disseminate knowledge in an ethical, responsible, and inclusive manner. We will also develop methodology to elucidate details of how modern humans and archaic humans, such as Neandertals interbred. By leveraging patterns of variation in Neandertal DNA sharing within and among European, East Asian, and Southeast Asian populations, we will determine the number of times that humans and Neandertals interbred, with the particular research question did Neanderthals interbred with modern humans in the Indian subcontinent.