The Himalayas in South Asia provide a diversity of environments for humans, some of which have required substantial genetic adaptation. There is, however, little understanding of the genetic history of the Himalayans and how culture, geography and genetic selection have shaped Himalayan genomes. In this study, we are using a combination of population-genetic and functional analyses to explore these topics. We analysed ~600,000 genome-wide SNPs in 948 Himalayan individuals from 49 different autochthonous groups from Nepal, Bhutan, North India and Tibetan Plateau in China. We find that the Himalayan populations share a component derived from a common ancestral population, followed by the development of local fine genetic structure correlating with language and geographical distribution. High altitude adaptation phenotype seems to have originated in a single ancestral population and spread across several areas in Himalaya. Genetic signatures of adaptation to high altitude are observed in EPAS1 and ATP6V1E2. We find signatures of adaptation to low altitude within the TRIM67 region, possibly associated with anti-microbial activity in the tropical forest. We are exploring functional validation of variants in the EPAS1 region using 1000 Genomes Project lymphoblastoid cell lines with and without the Denisovan introgressed haplotype under both normoxia and hypoxic conditions and analysing expression of candidate hypoxia responsive genes in order to characterize the response of cell lines with the introgressed haplotype. We are also investigating whether this haplotype confers resistance to the DNA damage experienced at high altitude through induction of DNA strand breakage and oxidative DNA damage in cultured cells.