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EPAS1 Gain-of-Function Mutation Contributes to High-Altitude Adaptation in Tibetan Horses

High altitude represents some of the most extreme environments worldwide. The genetic changes underlying adaptation to such environments have been recently identified in multiple animals but remain unknown in horses. Here, we sequence the complete genome of 138 domestic horses encompassing a whole a...

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Autores principales: Liu, Xuexue, Zhang, Yanli, Li, Yefang, Pan, Jianfei, Wang, Dandan, Chen, Weihuang, Zheng, Zhuqing, He, Xiaohong, Zhao, Qianjun, Pu, Yabin, Guan, Weijun, Han, Jianlin, Orlando, Ludovic, Ma, Yuehui, Jiang, Lin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805228/
https://www.ncbi.nlm.nih.gov/pubmed/31273382
http://dx.doi.org/10.1093/molbev/msz158
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author Liu, Xuexue
Zhang, Yanli
Li, Yefang
Pan, Jianfei
Wang, Dandan
Chen, Weihuang
Zheng, Zhuqing
He, Xiaohong
Zhao, Qianjun
Pu, Yabin
Guan, Weijun
Han, Jianlin
Orlando, Ludovic
Ma, Yuehui
Jiang, Lin
author_facet Liu, Xuexue
Zhang, Yanli
Li, Yefang
Pan, Jianfei
Wang, Dandan
Chen, Weihuang
Zheng, Zhuqing
He, Xiaohong
Zhao, Qianjun
Pu, Yabin
Guan, Weijun
Han, Jianlin
Orlando, Ludovic
Ma, Yuehui
Jiang, Lin
author_sort Liu, Xuexue
collection PubMed
description High altitude represents some of the most extreme environments worldwide. The genetic changes underlying adaptation to such environments have been recently identified in multiple animals but remain unknown in horses. Here, we sequence the complete genome of 138 domestic horses encompassing a whole altitudinal range across China to uncover the genetic basis for adaptation to high-altitude hypoxia. Our genome data set includes 65 lowland animals across ten Chinese native breeds, 61 horses living at least 3,300 m above sea level across seven locations along Qinghai-Tibetan Plateau, as well as 7 Thoroughbred and 5 Przewalski’s horses added for comparison. We find that Tibetan horses do not descend from Przewalski’s horses but were most likely introduced from a distinct horse lineage, following the emergence of pastoral nomadism in Northwestern China ∼3,700 years ago. We identify that the endothelial PAS domain protein 1 gene (EPAS1, also HIF2A) shows the strongest signature for positive selection in the Tibetan horse genome. Two missense mutations at this locus appear strongly associated with blood physiological parameters facilitating blood circulation as well as oxygen transportation and consumption in hypoxic conditions. Functional validation through protein mutagenesis shows that these mutations increase EPAS1 stability and its hetero dimerization affinity to ARNT (HIF1B). Our study demonstrates that missense mutations in the EPAS1 gene provided key evolutionary molecular adaptation to Tibetan horses living in high-altitude hypoxic environments. It reveals possible targets for genomic selection programs aimed at increasing hypoxia tolerance in livestock and provides a textbook example of evolutionary convergence across independent mammal lineages.
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spelling pubmed-68052282019-10-25 EPAS1 Gain-of-Function Mutation Contributes to High-Altitude Adaptation in Tibetan Horses Liu, Xuexue Zhang, Yanli Li, Yefang Pan, Jianfei Wang, Dandan Chen, Weihuang Zheng, Zhuqing He, Xiaohong Zhao, Qianjun Pu, Yabin Guan, Weijun Han, Jianlin Orlando, Ludovic Ma, Yuehui Jiang, Lin Mol Biol Evol Discoveries High altitude represents some of the most extreme environments worldwide. The genetic changes underlying adaptation to such environments have been recently identified in multiple animals but remain unknown in horses. Here, we sequence the complete genome of 138 domestic horses encompassing a whole altitudinal range across China to uncover the genetic basis for adaptation to high-altitude hypoxia. Our genome data set includes 65 lowland animals across ten Chinese native breeds, 61 horses living at least 3,300 m above sea level across seven locations along Qinghai-Tibetan Plateau, as well as 7 Thoroughbred and 5 Przewalski’s horses added for comparison. We find that Tibetan horses do not descend from Przewalski’s horses but were most likely introduced from a distinct horse lineage, following the emergence of pastoral nomadism in Northwestern China ∼3,700 years ago. We identify that the endothelial PAS domain protein 1 gene (EPAS1, also HIF2A) shows the strongest signature for positive selection in the Tibetan horse genome. Two missense mutations at this locus appear strongly associated with blood physiological parameters facilitating blood circulation as well as oxygen transportation and consumption in hypoxic conditions. Functional validation through protein mutagenesis shows that these mutations increase EPAS1 stability and its hetero dimerization affinity to ARNT (HIF1B). Our study demonstrates that missense mutations in the EPAS1 gene provided key evolutionary molecular adaptation to Tibetan horses living in high-altitude hypoxic environments. It reveals possible targets for genomic selection programs aimed at increasing hypoxia tolerance in livestock and provides a textbook example of evolutionary convergence across independent mammal lineages. Oxford University Press 2019-11 2019-07-04 /pmc/articles/PMC6805228/ /pubmed/31273382 http://dx.doi.org/10.1093/molbev/msz158 Text en © The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Discoveries
Liu, Xuexue
Zhang, Yanli
Li, Yefang
Pan, Jianfei
Wang, Dandan
Chen, Weihuang
Zheng, Zhuqing
He, Xiaohong
Zhao, Qianjun
Pu, Yabin
Guan, Weijun
Han, Jianlin
Orlando, Ludovic
Ma, Yuehui
Jiang, Lin
EPAS1 Gain-of-Function Mutation Contributes to High-Altitude Adaptation in Tibetan Horses
title EPAS1 Gain-of-Function Mutation Contributes to High-Altitude Adaptation in Tibetan Horses
title_full EPAS1 Gain-of-Function Mutation Contributes to High-Altitude Adaptation in Tibetan Horses
title_fullStr EPAS1 Gain-of-Function Mutation Contributes to High-Altitude Adaptation in Tibetan Horses
title_full_unstemmed EPAS1 Gain-of-Function Mutation Contributes to High-Altitude Adaptation in Tibetan Horses
title_short EPAS1 Gain-of-Function Mutation Contributes to High-Altitude Adaptation in Tibetan Horses
title_sort epas1 gain-of-function mutation contributes to high-altitude adaptation in tibetan horses
topic Discoveries
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805228/
https://www.ncbi.nlm.nih.gov/pubmed/31273382
http://dx.doi.org/10.1093/molbev/msz158
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