title: Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA.
abstract: As modern humans migrated out of Africa, they encountered many new environmental conditions, including greater temperature extremes, different pathogens and higher altitudes. These diverse environments are likely to have acted as agents of natural selection and to have led to local adaptations. One of the most celebrated examples in humans is the adaptation of Tibetans to the hypoxic environment of the high-altitude Tibetan plateau. A hypoxia pathway gene, EPAS1, was previously identified as having the most extreme signature of positive selection in Tibetans, and was shown to be associated with differences in haemoglobin concentration at high altitude. Re-sequencing the region around EPAS1 in 40 Tibetan and 40 Han individuals, we find that this gene has a highly unusual haplotype structure that can only be convincingly explained by introgression of DNA from Denisovan or Denisovan-related individuals into humans. Scanning a larger set of worldwide populations, we find that the selected haplotype is only found in Denisovans and in Tibetans, and at very low frequency among Han Chinese. Furthermore, the length of the haplotype, and the fact that it is not found in any other populations, makes it unlikely that the haplotype sharing between Tibetans and Denisovans was caused by incomplete ancestral lineage sorting rather than introgression. Our findings illustrate that admixture with other hominin species has provided genetic variation that helped humans to adapt to new environments.
authors.affiliation: 1] BGI-Shenzhen, Shenzhen 518083, China [2] Department of Integrative Biology, University of California, Berkeley, California 94720 USA [3] School of Natural Sciences, University of California, Merced, California 95343 USA [4].
authors.forename: Emilia
authors.initials: E
authors.lastname: Huerta-Sánchez
authors.affiliation: 1] BGI-Shenzhen, Shenzhen 518083, China [2] School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China [3].
authors.forename: Xin
authors.initials: X
authors.lastname: Jin
authors.affiliation: 1] BGI-Shenzhen, Shenzhen 518083, China [2] Binhai Genomics Institute, BGI-Tianjin, Tianjin 300308, China [3] Tianjin Translational Genomics Center, BGI-Tianjin, Tianjin 300308, China [4].
authors.lastname: Asan
authors.affiliation: 1] The People's Hospital of Lhasa, Lhasa 850000, China [2].
authors.forename: Zhuoma
authors.initials: Z
authors.lastname: Bianba
authors.affiliation: Department of Integrative Biology, University of California, Berkeley, California 94720 USA.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Peter
authors.affiliation: Department of Integrative Biology, University of California, Berkeley, California 94720 USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vinckenbosch
authors.affiliation: 1] BGI-Shenzhen, Shenzhen 518083, China [2] Binhai Genomics Institute, BGI-Tianjin, Tianjin 300308, China [3] Tianjin Translational Genomics Center, BGI-Tianjin, Tianjin 300308, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liang
authors.affiliation: 1] BGI-Shenzhen, Shenzhen 518083, China [2] Binhai Genomics Institute, BGI-Tianjin, Tianjin 300308, China [3] Tianjin Translational Genomics Center, BGI-Tianjin, Tianjin 300308, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Yi
authors.affiliation: 1] BGI-Shenzhen, Shenzhen 518083, China [2] Bioinformatics and Computational Biology Program, Iowa State University, Ames, Iowa 50011, USA.
authors.forename: Mingze
authors.initials: M
authors.lastname: He
authors.affiliation: Department of Biological Sciences, Middle East Technical University, 06800 Ankara, Turkey.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Somel
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Peixiang
authors.initials: P
authors.lastname: Ni
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Ou
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.lastname: Huasang
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Jiangbai
authors.initials: J
authors.lastname: Luosang
authors.affiliation: The Second People's Hospital of Tibet Autonomous Region, Lhasa 850000, China.
authors.forename: Zha Xi Ping
authors.initials: ZX
authors.lastname: Cuo
authors.affiliation: The People's Hospital of the Tibet Autonomous Region, Lhasa 850000, China.
authors.forename: Kui
authors.initials: K
authors.lastname: Li
authors.affiliation: The hospital of XiShuangBanNa Dai Nationalities, Autonomous Jinghong, 666100 Yunnan, China.
authors.forename: Guoyi
authors.initials: G
authors.lastname: Gao
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Yin
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: 1] BGI-Shenzhen, Shenzhen 518083, China [2] The Guangdong Enterprise Key Laboratory of Human Disease Genomics, BGI-Shenzhen, 518083 Shenzhen, China [3] Shenzhen Key Laboratory of Transomics Biotechnologies, BGI-Shenzhen, 518083 Shenzhen, China.
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Zhang
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Xun
authors.initials: X
authors.lastname: Xu
authors.affiliation: 1] BGI-Shenzhen, Shenzhen 518083, China [2] Princess Al Jawhara Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia [3] James D. Watson Institute of Genome Science, 310008 Hangzhou, China.
authors.forename: Huanming
authors.initials: H
authors.lastname: Yang
authors.affiliation: BGI-Shenzhen, Shenzhen 518083, China.
authors.forename: Yingrui
authors.initials: Y
authors.lastname: Li
authors.affiliation: 1] BGI-Shenzhen, Shenzhen 518083, China [2] James D. Watson Institute of Genome Science, 310008 Hangzhou, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: 1] BGI-Shenzhen, Shenzhen 518083, China [2] Princess Al Jawhara Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia [3] Department of Biology, University of Copenhagen, Ole MaaløesVej 5, 2200 Copenhagen, Denmark [4] Macau University of Science and Technology, AvenidaWai long, Taipa, Macau 999078, China [5] Department of Medicine, University of Hong Kong 999077, Hong Kong.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: 1] BGI-Shenzhen, Shenzhen 518083, China [2] Department of Integrative Biology, University of California, Berkeley, California 94720 USA [3] Department of Statistics, University of California, Berkeley, California 94720, USA [4] Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Rasmus
authors.initials: R
authors.lastname: Nielsen
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics*; D000531:Altitude; D000818:Animals; D044466:Asian People / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D004247:DNA / Q000235:genetics*; D005787:Gene Frequency; D014644:Genetic Variation; D006239:Haplotypes; D015186:Hominidae / Q000235:genetics*; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D018609:Tibet; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004247:DNA; D000099162:Endothelial PAS Domain-Containing Protein 1