Wide distribution and altitude correlation of an archaic high-altitude-adaptive EPAS1 haplotype in the Himalayas.

Sophie Hackinger,Mark A Jobling,Peter De Knijff,Massimo Mezzavilla,George Van Driem,Chris Tyler-Smith,Thirsa Kraaijenbrink,Yali Xue,Asan Asan,Qasim Ayub

doi:10.1007/s00439-016-1641-2

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-016-1641-2) contains supplementary material, which is available to authorized users.

Highlights

Genetic, biochemical and morphological changes have enabled humans to survive, adapt and reproduce in hostile high-altitude environments in Africa, Asia and South America
A follow-up study showed that this single nucleotide polymorphism (SNP) lay within an extended haplotype in Tibetans, and a 32.7-kb region matched the genome of an archaic Denisovan hominin (Meyer et al 2012), but few other modern humans (Huerta-Sanchez et al 2014), suggesting that this haplotype might have been introduced into the Tibetan gene pool by archaic DNA introgression (Racimo et al 2015)
While our primary goal was to investigate the presence of the core Denisovan haplotype in the Himalayas, we included samples from China, India, Mongolia, Pakistan and Russia to gain a better understanding of the geographical distribution of this haplotype

Summary

Introduction

Biochemical and morphological changes have enabled humans to survive, adapt and reproduce in hostile high-altitude environments in Africa, Asia and South America. Previous studies have identified several genetic variants within EPAS1 that are associated with high-altitude adaptation in Tibetans and have been shown to correlate with lower haemoglobin levels in Tibetans as well as in the Nepalese Sherpa (Beall and Reichsman 1984; Samaja et al 1979; Yi et al 2010) One of these was rs150877473, where the derived G allele showed a 78 % higher frequency in Tibetans than in Han Chinese “representing the fastest allele frequency change observed at any human gene to date” according to the authors (Yi et al 2010). A parallel study compared genome-wide SNP data of Nepalese Sherpa with Tibetans and suggested that they shared a common ancestor and the high-altitude-adaptive haplotype (Jeong et al 2014)

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Results

Conclusion