Research Summary South Asians account for nearly 25% of the global population, displaying unique and complex genetic and social structures. South Asians also exhibit a high burden of infectious and non-infectious diseases. Yet, the paucity of modern and ancient genomics data deriving from individuals of South Asian ancestry, result in a fragmented picture of the origins and evolution of the genetic and socio-cultural diversity of this region. Over the next five years, one of primary research programs in the Raghavan lab will leverage our expertise in ancient and modern genomics to address three crucial themes to promote our understanding of the genetics of South Asians and their diseases: (i) the regional demographic history over the last ~8,000 years, (ii) the prehistoric occurrence of infectious diseases and the evolution of pathogens and infectious diseases in this region, and (iii) the impact of dietary transitions on the gut microbiome composition and health of Indian populations. Since present-day gene pools and disease landscapes are products of long-acting evolutionary processes, we will jointly generate and analyze ancient and modern human genomic datasets in order to achieve Themes 1 and 2 that focus on the evolution of modern human populations, including reconstructing past migrations and admixture events, and infectious diseases, including the detection and phylogenetic characterization of ancient pathogens in human skeletal materials, respectively. Theme 3 will additionally benefit from my group’s growing networks with Indigenous populations across India to study the impact of dietary and subsistence transitions – so-called ‘westernization’ of traditionalist diets - on the gut microbiome. Ultimately, through the implementation of these complementary themes set within the context of South Asian populations, this research program will contribute towards our overall understanding of the evolutionary mechanisms that underlie health and disease among human populations. Importantly, data and results from our research will address critical representational gaps in the genomics literature and make precision medicine efforts more universal and diverse in their application, especially for a region that, in light of being one of the most populous regions with the largest diaspora, contributes substantially to the global disease burden.