Downregulations of mRNA expressions in theEPAS1andEGLN1: Unraveling a genetic mechanism for high-altitude hypoxia adaptation in Sherpa highlanders

Abstract

AbstractSherpa highlanders exhibit unique hypoxia-tolerant traits, likely evolved through natural selection in response to high-altitude conditions. Previous research has implicatedEPAS1andEGLN1in this adaptation, but their functional mechanisms remain unclear. This study aims to elucidate these mechanisms by exploring mRNA expressions ofEPAS1andEGLN1in Sherpa highlanders. Field investigations enrolled 54 healthy Sherpa highlanders and 25 non-Sherpa lowlanders in Namche Bazaar (3,440 m) and Kathmandu (1,300 m), respectively. Venous blood was collected for erythropoietin (EPO) measurements,EPAS1andEGLN1mRNA expression analyses, and genotyping of single nucleotide polymorphisms (SNPs) rs13419896 and rs4953354 inEPAS1, as well as rs1435166 and rs2153364 SNPs inEGLN1.Comparative analyses were conducted on these elements between highlanders and lowlanders. Despite decreased SpO2in Sherpa highlanders, EPO concentrations did not elevate at high altitudes. TheEPAS1andEGLN1 mRNA expressions were significantly lower in Sherpa highlanders compared to non-Sherpa lowlanders. Moreover, genotype distributions and allele frequencies of rs13419896 and rs4953354 inEPAS1, as well as rs1435166 and rs2153364 inEGLN1, differed significantly between Sherpa highlanders and non-Sherpa lowlanders. Analyses of the relative mRNA expressions ofEPAS1andEGLN1by the SNPs suggested that the rs13419896/G and rs4953354/A alleles inEPAS1, as well as the rs1435166/G and rs2153364/A alleles inEGLN1,have down-regulatory effects on the gene mRNA expressions in Sherpa highlanders, contributing to inhibiting the EPO hypoxia response and exhibiting hypoxia-tolerant EPO levels in Sherpa highlanders. Natural selection, driven by high-altitude hypoxia, has encouraged adaptive evolution in Sherpa highlanders, including modifications inEPAS1andEGLN1genes. This evolutionary process leads to the downregulation of gene mRNA expressions, effectively tempering EPO responses to hypoxia and thereby enabling adaptation to high-altitude environments.