The 89th Annual Meeting of the American Association of Physical Anthropologists (2020)


Population-genetic and functional investigation of high altitude adaptation in the Himalayan populations

ELENA ARCIERO1, MARC HABER1,8, THIRSA KRAAIJENBRINK2, . ASAN3, MICHAŁ SZPAK1,10, PILLE HALLAST1,11, NIKOLAOS PANOUSIS1, YUAN CHEN1, SHANE MCCARTHY1, IRENE GALLEGO ROMERO9, HUANMING YANG3, MARK JOBLING4, GEORGE VAN DRIEM5, PETER DE KNIJFF2, QASIM AYUB6,7, YALI XUE1 and CHRIS TYLER-SMITH1.

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 Add to calendar

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).