Genetic Missense Variants at the EGLN1 Locus Associated with High‐Altitude Adaptation in Tibetans are Rare in Andeans

Abstract

High‐altitude populations have been challenged by chronic hypoxia for many generations and demonstrate some of the most rapid evolution observed in humans. Genome‐wide scans have brought to light numerous hypoxic‐response candidate genes that are associated with distinct traits in these populations. One example is EGLN1, which shows signals of selection in Tibetan and Andean populations and has been linked to hemoglobin concentration in Tibetans living at high altitude. EGLN1 encodes the hypoxia‐inducible factor (HIF) prolyl hydroxylase 2 (PHD2) protein, which serves as an oxygen‐sensitive regulator of HIF transcription factor activity. We examined the frequencies of two single nucleotide polymorphisms (SNPs) (rs186996510, rs12097901) in the first exon of EGLN1, previously identified at high frequencies and having a gain‐of‐function effect in Tibetans, in a cohort of Quechua Andeans resident at high altitude and individuals of Himalayan (Tibetan, Nepali) ancestry resident at sea level. The minor C allele of rs186996510 is rare among Andeans (0.95%; 1/105) and Nepalese (5.9%; 1/17) but present in 50% (3/6) of Tibetans (X2=36.6, p<0.0001). The minor G allele of rs12097901 was found at 6.6% (7/106) in Andeans, 11.8% (2/17) in Nepalese, and 50% (3/6) in Tibetans (X2=12.8, p<0.002). Two female sea‐level, Tibetan participants with the minor C allele rs186996510 both had significantly lower hematocrit values than the other sea‐level women (F(1,7)=8.8, p=0.025). These genomic differences suggest that despite the identification of an adaptive genetic signal at this locus in both Andean and Tibetan populations, the EGLN1 variants previously reported in Tibetans are very rare in Andeans.Support or Funding InformationThis study was supported by an NIH NRSA Individual Postdoctoral Fellowship (Parent F32) to ECH (F32HL131218), NIH TL1TR001443 to LW, a University of California, San Diego Ledell Family Undergraduate Research Scholarship award for Science and Engineering to ESL, and NIH R00HL118215 and American Physiological Society Giles F. Filley Memorial Award to TSS. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The UPCH team was supported by a Wellcome Trust PHTM grant (107544/Z/15/Z) to FCV.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.