Downregulations of mRNA expressions in the EPAS1and EGLN1: Unraveling a genetic mechanism for high-altitude hypoxia adaptation in Sherpa highlanders

Abstract Sherpa highlanders exhibit unique hypoxia-tolerant traits, likely evolved through natural selection in response to high-altitude conditions. Previous research has implicated EPAS1 and EGLN1 in this adaptation, but their functional mechanisms remain unclear. This study aims to elucidate these mechanisms by exploring mRNA expressions of EPAS1 and EGLN1 in 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, EPAS1 and EGLN1 mRNA expression analyses, and genotyping of single nucleotide polymorphisms (SNPs) rs13419896 and rs4953354 in EPAS1 , as well as rs1435166 and rs2153364 SNPs in EGLN1. Comparative analyses were conducted on these elements between highlanders and lowlanders. Despite decreased SpO 2 in Sherpa highlanders, EPO concentrations did not elevate at high altitudes. The EPAS1 and EGLN 1 mRNA expressions were significantly lower in Sherpa highlanders compared to non-Sherpa lowlanders. Moreover, genotype distributions and allele frequencies of rs13419896 and rs4953354 in EPAS1 , as well as rs1435166 and rs2153364 in EGLN1 , differed significantly between Sherpa highlanders and non-Sherpa lowlanders. Analyses of the relative mRNA expressions of EPAS1 and EGLN1 by the SNPs suggested that the rs13419896/G and rs4953354/A alleles in EPAS1 , as well as the rs1435166/G and rs2153364/A alleles in EGLN1, 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 in EPAS1 and EGLN1 genes. 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.