Dataset Information

Genetic variants at the EGLN1 locus associated with high-altitude adaptation in Tibetans are absent or found at low frequency in highland Andeans.

ABSTRACT: EGLN1 encodes the hypoxia-inducible factor (HIF) pathway prolyl hydroxylase 2 (PHD2) that serves as an oxygen-sensitive regulator of HIF activity. The EGLN1 locus exhibits a signature of positive selection in Tibetan and Andean populations and is associated with hemoglobin concentration in Tibetans. Recent reports provide evidence for functional roles of protein-coding variants within the first exon of EGLN1 (rs186996510, rs12097901) that are linked to an adaptive signal in Tibetans, yet whether these same variants are present and contribute to adaptation in Andean highlanders is unknown. We determined the frequencies of these adaptive Tibetan alleles in Quechua Andeans resident at high altitude (4,350 m) in addition to individuals of Nepali ancestry resident at sea level. The rs186996510 C (minor) allele previously found at high frequency in Tibetans is absent in Andean (G: 100%) and rare among Nepali (C: 11.8%, G: 88.2%) cohorts. The minor G allele of rs12097901 is found at similarly low frequencies in Andeans (G: 12.7%, C: 87.3%) and Nepalis (G: 23.5%, C: 76.5%) compared to Tibetans. These results suggest that adaptation involving EGLN1 in Andeans involves different mechanisms than those described in Tibetans. The precise Andean adaptive variants remain to be determined.

SUBMITTER: Heinrich EC

PROVIDER: S-EPMC7920394 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Genetic variants at the EGLN1 locus associated with high-altitude adaptation in Tibetans are absent or found at low frequency in highland Andeans.

Heinrich Erica C EC Wu Lu L Lawrence Elijah S ES Cole Amy M AM Anza-Ramirez Cecilia C Villafuerte Francisco C FC Simonson Tatum S TS

Annals of human genetics 20190204 3

EGLN1 encodes the hypoxia-inducible factor (HIF) pathway prolyl hydroxylase 2 (PHD2) that serves as an oxygen-sensitive regulator of HIF activity. The EGLN1 locus exhibits a signature of positive selection in Tibetan and Andean populations and is associated with hemoglobin concentration in Tibetans. Recent reports provide evidence for functional roles of protein-coding variants within the first exon of EGLN1 (rs186996510, rs12097901) that are linked to an adaptive signal in Tibetans, yet whether ...[more]

PMID: 30719713

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Project description:Since their arrival in the Tibetan Plateau during the Neolithic Age, Tibetans have been well-adapted to extreme environmental conditions and possess genetic variation that reflect their living environment and migratory history. To investigate the origin of Tibetans and the genetic basis of adaptation in a rigorous environment, we genotyped 30 Tibetan individuals with more than one million SNP markers. Our findings suggested that Tibetans, together with the Yi people, were descendants of Tibeto-Burmans who diverged from ancient settlers of East Asia. The valleys of the Hengduan Mountain range may be a major migration route. We also identified a set of positively-selected genes that belong to functional classes of the embryonic, female gonad, and blood vessel developments, as well as response to hypoxia. Most of these genes were highly correlated with population-specific and beneficial phenotypes, such as high infant survival rate and the absence of chronic mountain sickness. Genetic features of Tibetans have been broadly investigated, but the properties of copy number variation (CNV) have not been well examined. To get a preliminary view of CNV in Tibetans, we scanned 29 Tibetan genomes with the Illumina Human-1 M high-resolution genotyping microarray and identified 139 putative copy number variable regions (CNVRs), consisting of 70 deletions, 61 duplications, and 8 multi-allelic loci. Thirty-four of the 139 CNVRs showed differential allele frequencies versus other East-Asian populations, with P values ,0.0001. These results indicated a distinct pattern of CNVR allele frequency distribution in Tibetans. The Tibetan CNVRs are enriched for genes in the disease class of human reproduction (such as genes from the DAZ, BPY2, CDY, and HLA-DQ and -DR gene clusters) and biological process categories of ‘‘response to DNA damage stimulus’’ and ‘‘DNA repair’’ (such as RAD51, RAD52, and MRE11A). These genes are related to the adaptive traits of high infant birth weight and darker skin tone of Tibetans, and may be attributed to recent local adaptation. Our results provide a different view of genetic diversity in Tibetans and new insights into their high-altitude adaptation.

Dataset Information

Genetic variants at the EGLN1 locus associated with high-altitude adaptation in Tibetans are absent or found at low frequency in highland Andeans.

Publications

Genetic variants at the EGLN1 locus associated with high-altitude adaptation in Tibetans are absent or found at low frequency in highland Andeans.

Similar Datasets

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