Droma, Y. | bioRxiv Science

bioRxiv2024

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

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 SpO2 in Sherpa highlanders, EPO concentrations did not elevate at high altitudes. The EPAS1 and EGLN1 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.

genetics↗

bioRxiv2020

Hypoxia-tolerant vascular endothelial growth factor-A (VEGF-A) and the genetic variations of VEGFA in Sherpa highlanders

Sherpa highlanders demonstrate extraordinary tolerance to hypoxia at high altitudes, partly by one of the adaptation mechanisms promoting increases of microcirculatory blood flow and capillary density at high altitude for restoring oxygen supply to tissues. Hypoxia stimulates vascular endothelial growth factor (VEGF), which is an important signaling protein involved in hypoxia-stimulated vasculogenesis and angiogenesis. Our present study included 51 Sherpas dwelling in Namche Bazaar village (3440 m) and 76 non-Sherpa lowlanders residing in Kathmandu (1300 m) in Nepal. In these participants, we measured plasma VEGF-A concentrations and genotyped five single-nucleotide polymorphisms (SNPs) of VEGFA: rs699947, rs8333061, rs1570360, and rs2010963 in the 5'-untranslated region (5'-UTR); and rs3025039 in the 3'-UTR. The average circulating VEGF-A level in Sherpas did not respond to hypoxia at the high altitude in 3440 m, remaining equivalent to the level in non-Sherpa lowlanders at low altitude. Allele discriminations for the analyzed SNPs revealed significant genetic divergences of rs699947, rs8333061, and rs2010963 in Sherpa highlanders compared with non-Sherpa lowlanders, East Asians, South Asians, and the global population; however, consistency with the indigenous Tibetan highlanders from the Tibet Plateau. On the other hand, the SNP rs3025039 in the 3'-UTR presented constant preserved genetic variation among global populations. Our findings indicated that the physiological sea-level VEGF-A concentration in Sherpa highlanders at high altitude was probably linked with the significant variations of VEGFA in Sherpas that regulate the gene expression in a manner of tolerance to hypoxia through production of the optimal biological level of VEGF-A at high altitudes. Precise angiogenesis at high altitude contributes to the adaptive levels of capillary density and microcirculation, providing efficient and effective diffusion of oxygen to tissues and representing human adaptation to high-altitude hypoxia environment. Author summarySherpa highlanders demonstrate extraordinary tolerance to hypoxia at high altitudes, partly by one of the adaptation mechanisms promoting increases of microcirculatory blood flow and capillary density at high altitude for restoring oxygen supply to tissues. Vascular endothelial growth factor (VEGF) is mainly stimulated by hypoxia, and is an important signaling protein involved in hypoxia-stimulated vasculogenesis and angiogenesis. Interestingly, we found that the circulating VEGF-A level in Sherpa highlanders did not respond to hypoxia at high altitude. Furthermore, allele discrimination of the single nucleotide polymorphisms (SNPs) of VEGFA revealed significant divergences of rs699947, rs8333061, and rs2010963 within the VEGFA regulation region in Sherpa highlanders compared to the non-Sherpa lowlanders, East Asians, South Asians, and the global population; however, consistency with Tibetan highlanders from the Tibet Plateau. We propose that the hypoxia-tolerant circulating VEGF-A level in Sherpa highlanders is linked with the genetic variations of VEGFA, contributing to human adaptation to high-altitude hypoxic environments.

genetics↗