Genetic Variants in EPAS1 Contribute to Adaptation to High-Altitude Hypoxia in Sherpas

Masayuki Hanaoka,Nobumitsu Kobayashi,Michiko Ito,Keishi Kubo,Buddha Basnyat,Masao Ota,Yunden Droma,Yoshihiko Katsuyama

doi:10.1371/journal.pone.0050566

Abstract

Sherpas comprise a population of Tibetan ancestry in the Himalayan region that is renowned for its mountaineering prowess. The very small amount of available genetic information for Sherpas is insufficient to explain their physiological ability to adapt to high-altitude hypoxia. Recent genetic evidence has indicated that natural selection on the endothelial PAS domain protein 1 (EPAS1) gene was occurred in the Tibetan population during their occupation in the Tibetan Plateau for millennia. Tibetan-specific variations in EPAS1 may regulate the physiological responses to high-altitude hypoxia via a hypoxia-inducible transcription factor pathway. We examined three significant tag single-nucleotide polymorphisms (SNPs, rs13419896, rs4953354, and rs4953388) in the EPAS1 gene in Sherpas, and compared these variants with Tibetan highlanders on the Tibetan Plateau as well as with non-Sherpa lowlanders. We found that Sherpas and Tibetans on the Tibetan Plateau exhibit similar patterns in three EPAS1 significant tag SNPs, but these patterns are the reverse of those in non-Sherpa lowlanders. The three SNPs were in strong linkage in Sherpas, but in weak linkage in non-Sherpas. Importantly, the haplotype structured by the Sherpa-dominant alleles was present in Sherpas but rarely present in non-Sherpas. Surprisingly, the average level of serum erythropoietin in Sherpas at 3440 m was equal to that in non-Sherpas at 1300 m, indicating a resistant response of erythropoietin to high-altitude hypoxia in Sherpas. These observations strongly suggest that EPAS1 is under selection for adaptation to the high-altitude life of Tibetan populations, including Sherpas. Understanding of the mechanism of hypoxia tolerance in Tibetans is expected to provide lights to the therapeutic solutions of some hypoxia-related human diseases, such as cardiovascular disease and cancer.

Highlights

Sherpas are originally Tibetans who emigrated from eastern Tibet to the Everest region of Nepal 500 years ago in order to be close to the mountain they hold sacred, Mt
The patterns of the predominant alleles of three tag single nucleotide polymorphisms (SNPs; rs13419896, rs4953354, and rs4953388) in Sherpas were very similar to those in Tibetans on the Tibetan Plateau, but were the reverse of those in non-Sherpa populations including Nepalese subjects, Japanese high-altitude pulmonary edema (HAPE)-susceptible subjects (J-HAPE-s, a group of Japanese individuals that were susceptible to high-altitude pulmonary edema due to genetic mutations [23,24,25]), Japanese HAPE-resistant subjects (J-HAPE-r, a group of Japanese individuals resistant to high-altitude pulmonary edema due to a nonmutated genetic background [23,24,25]), Japanese subjects in Tokyo (JPT), Han Chinese in Beijing (CHB), Utah residents with ancestry from northern and western Europe (CEU), and Yoruba from Ibadan (YRI; Table 1, Figure 1)
This observation indicates that the high-altitude populations (Sherpas in the Himalayan region in Nepal and Tibetans on the Tibetan Plateau) and low-altitude populations (JPT, CHB, CEU, YRI) are clearly separated into two genetic clusters by the distributions of the major alleles of endothelial PAS domain protein 1 (EPAS1) gene

Summary

Introduction

Sherpas are originally Tibetans who emigrated from eastern Tibet to the Everest region of Nepal 500 years ago in order to be close to the mountain they hold sacred, Mt. Everest according to the evidences of the history of Sherpas and linguistics [1,2]. Most Sherpas reside at elevations above 3000 m in the Himalayan region in Nepal. Their mountaineering prowess and power of endurance has brought them prominence in adventure mountaineering and has attracted the interest of anthropologists, physiologists, mountain medicine researchers, and sports scientists. The present available genetic evidences are insufficient to explain the Sherpas’ powerful adaptation to highaltitude hypoxia at genetic level

Objectives

Methods

Results

Conclusion