title: MtDNA analysis reveals enriched pathogenic mutations in Tibetan highlanders.
abstract: Tibetan highlanders, including Tibetans, Monpas, Lhobas, Dengs and Sherpas, are considered highly adaptive to severe hypoxic environments. Mitochondrial DNA (mtDNA) might be important in hypoxia adaptation given its role in coding core subunits of oxidative phosphorylation. In this study, we employed 549 complete highlander mtDNA sequences (including 432 random samples) to obtain a comprehensive view of highlander mtDNA profile. In the phylogeny of a total of 36,914 sequences, we identified 21 major haplogroups representing founding events of highlanders, most of which were coalesced in 10 kya. Through founder analysis, we proposed a three-phase model of colonizing the plateau, i.e., pre-LGM Time (30 kya, 4.68%), post-LGM Paleolithic Time (16.8 kya, 29.31%) and Neolithic Time (after 8 kya, 66.01% in total). We observed that pathogenic mutations occurred far more frequently in 22 highlander-specific lineages (five lineages carrying two pathogenic mutations and six carrying one) than in the 6,857 haplogroups of all the 36,914 sequences (P = 4.87 × 10(-8)). Furthermore, the number of possible pathogenic mutations carried by highlanders (in average 3.18 ± 1.27) were significantly higher than that in controls (2.82 ± 1.40) (P = 1.89 × 10(-4)). Considering that function-altering and pathogenic mutations are enriched in highlanders, we therefore hypothesize that they may have played a role in hypoxia adaptation.
authors: Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region; Key Laboratory of High Altitude Environment and Gene Related to Disease of Tibet Ministry of Education, School of Medicine, Xizang University for Nationalities, Xianyang, China.
authors: Longli
authors: L
authors: Kang
authors: Ministry of Education Key Laboratory of Contemporary Anthropology and Center for Evolutionary Biology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
authors: Hong-Xiang
authors: HX
authors: Zheng
authors: Ministry of Education Key Laboratory of Contemporary Anthropology and Center for Evolutionary Biology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
authors: Menghan
authors: M
authors: Zhang
authors: Ministry of Education Key Laboratory of Contemporary Anthropology and Center for Evolutionary Biology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
authors: Shi
authors: S
authors: Yan
authors: Ministry of Education Key Laboratory of Contemporary Anthropology and Center for Evolutionary Biology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
authors: Lei
authors: L
authors: Li
authors: Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region; Key Laboratory of High Altitude Environment and Gene Related to Disease of Tibet Ministry of Education, School of Medicine, Xizang University for Nationalities, Xianyang, China.
authors: Lijun
authors: L
authors: Liu
authors: Tibet Occupational College of Technology, Lhasa, Tibet, China.
authors: Kai
authors: K
authors: Liu
authors: Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region; Key Laboratory of High Altitude Environment and Gene Related to Disease of Tibet Ministry of Education, School of Medicine, Xizang University for Nationalities, Xianyang, China.
authors: Kang
authors: K
authors: Hu
authors: Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region; Key Laboratory of High Altitude Environment and Gene Related to Disease of Tibet Ministry of Education, School of Medicine, Xizang University for Nationalities, Xianyang, China.
authors: Feng
authors: F
authors: Chen
authors: Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region; Key Laboratory of High Altitude Environment and Gene Related to Disease of Tibet Ministry of Education, School of Medicine, Xizang University for Nationalities, Xianyang, China.
authors: Lifeng
authors: L
authors: Ma
authors: Ministry of Education Key Laboratory of Contemporary Anthropology and Center for Evolutionary Biology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
authors: Zhendong
authors: Z
authors: Qin
authors: Ministry of Education Key Laboratory of Contemporary Anthropology and Center for Evolutionary Biology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
authors: Yi
authors: Y
authors: Wang
authors: Ministry of Education Key Laboratory of Contemporary Anthropology and Center for Evolutionary Biology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
authors: Xiaofeng
authors: X
authors: Wang
authors: Ministry of Education Key Laboratory of Contemporary Anthropology and Center for Evolutionary Biology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
authors: Li
authors: L
authors: Jin
mesh_terms: D000222:Adaptation, Physiological; D044466:Asian People / Q000235:genetics; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D019143:Evolution, Molecular; D018703:Founder Effect; D014644:Genetic Variation; D006239:Haplotypes; D063426:Human Migration; D006801:Humans; D008928:Mitochondria / Q000235:genetics; D009154:Mutation; D010802:Phylogeny; D018609:Tibet
chemical_list: D004272:DNA, Mitochondrial