¹Human Genetics, The Wellcome Sanger Institute,Wellcome Genome Campus, Hinxton, United Kingdom, ²MGC Department of Human and Clinical Genetics, Leiden University Medical Centre, Leiden, the Netherlands, ³BGI-Shenzhen, Shenzen 518083, China, ⁴Department of Genetics, University of Leicester, United Kingdom, ⁵Himalayan Languages Project, Institut für Sprachwissenschaft, University of Bern, Bern, Switzerland, ⁶Monash University Malaysia Genomics Facility, Tropical Medicine and Biology Multidisciplinary Platform, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia, ⁷School of Science, Monash University Malaysia, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia, ⁸Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom, ⁹Melbourne Integrative Genomics, University of Melbourne, Parkville, VIC, 3013, Australia, ¹⁰EMBL-European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, United Kingdom, ¹¹Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia

April 17, 2020 9:30AM, Diamond 4

The Himalayas provide a diversity of environments for humans, some of which have required substantial genetic adaptation. We have used a combination of SNP-chip data, genome sequences and functional studies to explore the demographic history, genetic structure and signatures of adaptation in the Himalayan populations. We previously genotyped ~600,000 genome-wide SNPs in 883 Himalayan individuals from 49 different autochthonous groups from Nepal, Bhutan, North India and the Tibetan Plateau in China, and have now generated whole-genome sequences of 100 individuals from a subset of these populations plus four additional ones. We find that the Himalayan populations share a genetic component derived from a common ancestral population, followed by the development of local fine structure correlating with language and geographical distribution, with variable gene flow from neighbouring populations. High-altitude adaptation seems to have originated in a single ancestral population and spread widely across the Himalayas: We find a major demographic expansion taking place only 3,000-4,000 years ago, coinciding with the archaeological evidence of permanent settlements above 2,500 m. We find signatures of adaptation to high altitude in EPAS1 and other genes involved in the hypoxic response. We performed in vitro functional validation of variants in the EPAS1 region that have been previously reported to result from introgression of DNA from the Denisovans using cell lines with and without the adaptive haplotype. We find that EPAS1 expression in normoxia or hypoxia remains constant in cultured cells with the Denisovan introgressed haplotype, unlike cells with the lowland haplotype where it increases in hypoxia.

Our work was funded by Wellcome (grant 098051).