Whole-genome sequencing of six dog breeds from continuous altitudes reveals adaptation to high-altitude hypoxia

Author:

Gou Xiao,Wang Zhen,Li Ning,Qiu Feng,Xu Ze,Yan Dawei,Yang Shuli,Jia Jia,Kong Xiaoyan,Wei Zehui,Lu Shaoxiong,Lian Linsheng,Wu Changxin,Wang Xueyan,Li Guozhi,Ma Teng,Jiang Qiang,Zhao Xue,Yang Jiaqiang,Liu Baohong,Wei Dongkai,Li Hong,Yang Jianfa,Yan Yulin,Zhao Guiying,Dong Xinxing,Li Mingli,Deng Weidong,Leng Jing,Wei Chaochun,Wang Chuan,Mao Huaming,Zhang Hao,Ding Guohui,Li Yixue

Abstract

The hypoxic environment imposes severe selective pressure on species living at high altitude. To understand the genetic bases of adaptation to high altitude in dogs, we performed whole-genome sequencing of 60 dogs including five breeds living at continuous altitudes along the Tibetan Plateau from 800 to 5100 m as well as one European breed. More than 150× sequencing coverage for each breed provides us with a comprehensive assessment of the genetic polymorphisms of the dogs, including Tibetan Mastiffs. Comparison of the breeds from different altitudes reveals strong signals of population differentiation at the locus of hypoxia-related genes including endothelial Per-Arnt-Sim (PAS) domain protein 1 (EPAS1) and beta hemoglobin cluster. Notably, four novel nonsynonymous mutations specific to high-altitude dogs are identified at EPAS1, one of which occurred at a quite conserved site in the PAS domain. The association testing between EPAS1 genotypes and blood-related phenotypes on additional high-altitude dogs reveals that the homozygous mutation is associated with decreased blood flow resistance, which may help to improve hemorheologic fitness. Interestingly, EPAS1 was also identified as a selective target in Tibetan highlanders, though no amino acid changes were found. Thus, our results not only indicate parallel evolution of humans and dogs in adaptation to high-altitude hypoxia, but also provide a new opportunity to study the role of EPAS1 in the adaptive processes.

Funder

State Key Basic Research Program

CAS

National Natural Science Foundation of China

Chinese Ministry for Science and Technology

Chinese High-Tech R&D Program

China Postdoctoral Science Foundation

Shanghai Postdoctoral Scientific Program

Publisher

Cold Spring Harbor Laboratory

Subject

Genetics (clinical),Genetics

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