High-Altitude Andean H194R HIF2A Allele Is a Hypomorphic Allele

Abstract

For over 10,000 years, Andeans have resided at high altitude where the partial pressure of oxygen challenges human survival. Recent studies have provided evidence for positive selection acting in Andeans on the HIF2A (also known as EPAS1) locus, which encodes for a central transcription factor of the Hypoxia Inducible Factor pathway. However, the precise mechanism by which this allele might lead to altitude-adaptive phenotypes, if any, is unknown. By analyzing whole genome sequencing data from 46 high-coverage Peruvian Andean genomes, we confirm evidence for positive selection acting on HIF2A, and a unique pattern of variation surrounding the Andean specific SNV, rs570553380, which encodes for an H194R amino acid substitution in HIF-2α. Genotyping the Andean-associated SNV rs570553380 in a group of 299 Peruvian Andeans from Cerro de Pasco, Peru (4,338 m) reveals a positive association with increased fraction of exhaled nitric oxide, a marker of nitric oxide biosynthesis. In vitro assays show that the H194R mutation impairs binding of HIF-2α to its heterodimeric partner, ARNT. A knockin mouse model bearing the H194R mutation in the Hif2a gene displays decreased levels of hypoxia-induced pulmonary Endothelin-1 transcripts and protection against hypoxia-induced pulmonary hypertension. We conclude the Andean H194R HIF2A allele is a hypomorphic (partial loss of function) allele.

Functional EPAS1 / HIF2A missense variant is associated with hematocrit in Andean highlanders

“…S9). The observed down-regulation of canonical HIF targets in cells with the Andean-specific missense variant parallels the loss-of-function phenotype similarly observed in studies of this variant ( 10 ) and Tibetan-specific noncoding variants in EPAS1 ( 11 , 53 , 54 ). While these findings provide insight into altered transcriptional activity as a result of this missense variant in vitro, previous EPAS1 loss-of-function studies in animal models suggest a protective effect against chronic hypoxia, in which heterozygous knockout mice ( Epas1 +/− ) exhibit lower [Hb] and reduced risk of pulmonary hypertension and right ventricular hypertrophy relative to wild-type mice following exposure to sustained hypoxia ( 54 ).…”

“…Although the allele frequency of rs570553380 (A>G) is modest among Andean highlanders [Quechua: 10% in this study; Quechua: 9% ( 10 ); Colla: 32% ( 25 )], rs570553380 (G) is nearly absent in publicly available genome data with a global frequency of only 0.20% [attributed solely to the Peruvian subpopulation (PEL) = 7.1%] (1000 Genomes, Phase III). The estimated age of rs570553380 is ~9845 years (Genealogical Estimation of Variant Age (GEVA), based on 1000 Genomes data) and ~13,027 years (based off calculations of haplotype heterozygosity in the 40 Andean whole genomes) (table S1).…”

“…Only a few of these traits have been linked to genetic factors, including relatively lower hemoglobin concentration ([Hb]) ( 3 – 5 ) and altered metabolic function within Tibetans ( 6 , 7 ) and increased uterine artery diameter, birth weight ( 8 ), and exercise capacity within Andeans ( 9 ). However, the extent of adaptation involving the same genetic regions across continental highland populations remains an ongoing area of research ( 10 , 11 ).…”

“…Although Tibetans demonstrate lower average [Hb] than Andeans, Andean highlanders exhibit substantial intrapopulation variation in this phenotype ( 1 ), with values ranging from sea level to excessively high levels ( 33 ). While many of the same candidate gene regions studied in Tibetans have been identified as potential targets of selection in Andeans ( 12 ), including EPAS1 ( 10 , 25 ), adaptations upon the same genes and associated phenotypes have not been found.…”

“…Here, we examine a previously identified EPAS1 missense variant (rs570553380, A>G, p.[His194Arg]) ( 10 , 25 ) within a cohort of Andean highlanders (Cerro de Pasco, Peru, 4340 m). Through genotype-phenotype analyses and in vitro functional assessments, we show evidence of genotypic-phenotypic, cross-continental convergence between Andean and Tibetan highland groups.…”