Genetic changes in the EPAS1 gene between Tibetan and Han ethnic groups and adaptation to the plateau hypoxic environment

In the Chinese Han population, prolonged exposure to hypoxic conditions can promote compensatory erythropoiesis which improves hypoxemia. However, Tibetans have developed unique phenotypes, such as downregulation of the hypoxia-inducible factor pathway through EPAS1 gene mutation, thus the mechanism of adaption of the Han population should be further studied. The results indicated that, under plateau hypoxic conditions, the plains population was able to acclimate rapidly to hypoxia through increasing EPAS1 mRNA expression and changing the hemoglobin conformation. Furthermore, the mutant genotype frequencies of the rs13419896, rs1868092 and rs4953354 loci in the EPAS1 gene were significantly higher in the Tibetan population than in the plains population. The EPAS1 gene expression level was lowest in the Han population carrying the A-A homozygous mutant of the rs13419896 locus but that it increased rapidly after these individuals entered the plateau. At this time, the hemoglobin content was lower in the homozygous mutant Han group than in the wild-type and heterozygous mutant populations, and the viscosity of blood was reduced in populations carrying the A-A haplotypes in rs13419896 and rs1868092 Among Tibetans, the group carrying homozygous mutations of the three SNPs also had lower hemoglobin concentrations than the wild-type. The Raman spectroscopy results showed that exposure of the Tibetan and Han population to hypoxic conditions changed the spatial conformation of hemoglobin and its binding ability to oxygen. The Tibetan population has mainly adapted to the plateau through genetic mutations, whereas some individuals adapt through changes in hemoglobin structure and function.