TY - JOUR
T1 - Wide distribution and altitude correlation of an archaic high-altitude-adaptive EPAS1 haplotype in the Himalayas
AU - Hackinger, Sophie
AU - Kraaijenbrink, Thirsa
AU - Xue, Yali
AU - Mezzavilla, Massimo
AU - Asan, null
AU - van Driem, George
AU - Jobling, Mark A.
AU - de Knijff, Peter
AU - Tyler-Smith, Chris
AU - Ayub, Qasim
N1 - Funding Information:
We thank the sample donors for making this study possible. We also thank the Sanger Institute’s core Sample Logistics Facility and Suzannah Bumpstead and Sam Taylor for the Sequenom genotyping. SH, YX, MM, CTS and QA were supported by The Wellcome Trust (098051), and MAJ by a Wellcome Trust Senior Fellowship (087576).
Publisher Copyright:
© 2016, The Author(s).
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2016/4
Y1 - 2016/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84958741842&partnerID=8YFLogxK
U2 - 10.1007/s00439-016-1641-2
DO - 10.1007/s00439-016-1641-2
M3 - Article
C2 - 26883865
AN - SCOPUS:84958741842
VL - 135
SP - 393
EP - 402
JO - Human Genetics
JF - Human Genetics
SN - 0340-6717
IS - 4
ER -