title: Wide distribution and altitude correlation of an archaic high-altitude-adaptive EPAS1 haplotype in the Himalayas.
abstract: High-altitude adaptation in Tibetans is influenced by introgression of a 32.7-kb haplotype from the Denisovans, an extinct branch of archaic humans, lying within the endothelial PAS domain protein 1 (EPAS1), and has also been reported in Sherpa. We genotyped 19 variants in this genomic region in 1507 Eurasian individuals, including 1188 from Bhutan and Nepal residing at altitudes between 86 and 4550 m above sea level. Derived alleles for five SNPs characterizing the core Denisovan haplotype (AGGAA) were present at high frequency not only in Tibetans and Sherpa, but also among many populations from the Himalayas, showing a significant correlation with altitude (Spearman's correlation coefficient = 0.75, p value 3.9 × 10(-11)). Seven East- and South-Asian 1000 Genomes Project individuals shared the Denisovan haplotype extending beyond the 32-kb region, enabling us to refine the haplotype structure and identify a candidate regulatory variant (rs370299814) that might be interacting in an additive manner with the derived G allele of rs150877473, the variant previously associated with high-altitude adaptation in Tibetans. Denisovan-derived alleles were also observed at frequencies of 3-14% in the 1000 Genomes Project African samples. The closest African haplotype is, however, separated from the Asian high-altitude haplotype by 22 mutations whereas only three mutations, including rs150877473, separate the Asians from the Denisovan, consistent with distant shared ancestry for African and Asian haplotypes and Denisovan adaptive introgression.
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Sophie
authors.initials: S
authors.lastname: Hackinger
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Thirsa
authors.initials: T
authors.lastname: Kraaijenbrink
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Yali
authors.initials: Y
authors.lastname: Xue
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.|Division of Experimental Genetics, Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Massimo
authors.initials: M
authors.lastname: Mezzavilla
authors.affiliation: BGI-Shenzhen, Shenzhen, 518083, China.
authors.lastname: Asan
authors.affiliation: Institute of Linguistics, University of Bern, Bern, CH 3012, Switzerland.
authors.forename: George
authors.initials: G
authors.lastname: van Driem
authors.affiliation: Department of Genetics, University of Leicester, Leicester, UK.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jobling
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: de Knijff
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Tyler-Smith
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK. qa1@sanger.ac.uk.
authors.forename: Qasim
authors.initials: Q
authors.lastname: Ayub
mesh_terms: D000531:Altitude; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1