PROJECT SUMMARY As modern human expanded worldwide, they settled in different environments that subjected them to selective pressure, driving genetic adaptations to varied local conditions. The origin of modern adaptive variants is intricately intertwined with population history and local adaptations that shaped the phenotypic diversity among human population today including health related traits. The investigation of the functions of adaptive genetic variants provides important insights into the mechanisms of human evolution and facilitate the identification of complex disease genes. Nonetheless, current strategies for establishing connections between genetic variants and functions face several limitations and new approach are needed. This proposal describes my plan to use ancient human DNA to explore the origin of adaptive variants and the strength of selection that has influenced their occurrences over time. Up to now, the use of ancient DNA (aDNA) to investigate adaptation events was challenged by the scarcity of human fossils. To overcome this barrier, I leverage on a new approach, I and others pioneered, to retrieve human aDNA from archaeological sediment independent of skeletal remains. This breakthrough technology allows us to generate genomic time-series data at a previously unachievable scale in any locations where human have once lived. I will apply this innovative approach to investigate the evolution of recent human phenotypes in East Asia. I propose to extract aDNA from a collection of sediment samples from the Tsagaan Agui cave, an archaeological site in Mongolia with evidence of ancient human occupation spanning the last 500,000 years. Mongolia, with its rich archaeological records is an ideal location not only to retrieve aDNA from modern humans but also from now-extinct archaic humans that once thrived in the region and were adapted to local environmental conditions hundreds of thousands of years before the arrival of modern human. I will use target sequencing to infer the ancestry of past individuals that occupied the site and genotype them across thousands of adaptive loci. By combining these data to the archaeological and past ecological records of the region, I will contextualize the emergence of specific adaptive variants in both archaic and modern humans. This project will significantly enhance our understanding of past environmental conditions that contributed to the acquisition of specific adaptive variants in modern human populations and holds the promise of addressing fundamental queries about our evolutionary history by defining the genetic basis of human adaptation to local environments, diets, and modern diseases.