title: Identification of a Tibetan-specific mutation in the hypoxic gene EGLN1 and its contribution to high-altitude adaptation.
abstract: Tibetans are well adapted to high-altitude hypoxic conditions, and in recent genome-wide scans, many candidate genes have been reported involved in the physiological response to hypoxic conditions. However, the limited sequence variations analyzed in previous studies would not be sufficient to identify causal mutations. Here we conducted resequencing of the entire genomic region (59.4 kb) of the hypoxic gene EGLN1 (one of the top candidates from the genome-wide scans) in Tibetans and identified 185 sequence variations, including 13 novel variations (12 substitutions and 1 insertion or deletion). There is a nonsynonymous mutation (rs186996510, D4E) showing surprisingly deep divergence between Tibetans and lowlander populations (Fst = 0.709 between Tibetans and Han Chinese). It is highly prevalent in Tibetans (70.9% on average) but extremely rare in Han Chinese, Japanese, Europeans, and Africans (0.56-2.27%), suggesting that it might be the causal mutation of EGLN1 contributing to high-altitude hypoxic adaptation. Neutrality test confirmed the signal of Darwinian positive selection on EGLN1 in Tibetans. Haplotype network analysis revealed a Tibetan-specific haplotype, which is absent in other world populations. The estimated selective intensity (0.029 for the C allele of rs186996510) puts EGLN1 among the known genes that have undergone the strongest selection in human populations, and the onset of selection was estimated to have started at the early Neolithic (∼8,400 years ago). Finally, we detected a significant association between rs186996510 and hemoglobin levels in Tibetans, suggesting that EGLN1 contributes to the adaptively low hemoglobin level of Tibetans compared with acclimatized lowlanders at high altitude.
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Xiang
authors.lastname: Ouzhuluobu
authors.forename: Yi
authors.initials: Y
authors.lastname: Peng
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Yang
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhang
authors.forename: Chaoying
authors.initials: C
authors.lastname: Cui
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Zhang
authors.lastname: Bianba
authors.lastname: Gonggalanzi
authors.lastname: Basang
authors.lastname: Ciwangsangbu
authors.forename: Tianyi
authors.initials: T
authors.lastname: Wu
authors.forename: Hua
authors.initials: H
authors.lastname: Chen
authors.forename: Hong
authors.initials: H
authors.lastname: Shi
authors.forename: Xuebin
authors.initials: X
authors.lastname: Qi
authors.forename: Bing
authors.initials: B
authors.lastname: Su
mesh_terms: D000064:Acclimatization / Q000235:genetics*; D000328:Adult; D000483:Alleles; D000531:Altitude; D044466:Asian People / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D006239:Haplotypes; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000235:genetics*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010101:Oxygen Consumption; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012641:Selection, Genetic; D018609:Tibet
chemical_list: D006454:Hemoglobins; C490190:EGLN1 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases
keywords: EGLN1; Tibetans; hypoxic adaptation; positive selection