Whole-genome sequencing of six dog breeds from continuous altitudes reveals adaptation to high-altitude hypoxia.
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.
College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China; College of Animal Science and Technology/State Key Laboratory for Agrobiotechnology, China Agricultural University, Beijing 100094, China;
Xiao
X
Gou
Key Laboratory of Systems Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Shanghai Center for Bioinformation Technology, Shanghai Industrial Technology Institute, Shanghai 201203, China;
Zhen
Z
Wang
College of Animal Science and Technology/State Key Laboratory for Agrobiotechnology, China Agricultural University, Beijing 100094, China;
Ning
N
Li
Shanghai Center for Bioinformation Technology, Shanghai Industrial Technology Institute, Shanghai 201203, China; EG Information Technology Enterprise (EGI), Encode Genomics Biotechnology Co., Ltd., Shanghai 200235, China;
Feng
F
Qiu
EG Information Technology Enterprise (EGI), Encode Genomics Biotechnology Co., Ltd., Shanghai 200235, China;
Ze
Z
Xu
College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China;
Dawei
D
Yan
College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China;
Shuli
S
Yang
Shanghai Center for Bioinformation Technology, Shanghai Industrial Technology Institute, Shanghai 201203, China;
Jia
J
Jia
College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China;
Xiaoyan
X
Kong
College of Animal Science and Technology, Northwest Agricultural and Forestry University, Yangling 712100, China;
Zehui
Z
Wei
College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China;
Shaoxiong
S
Lu
College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China;
Linsheng
L
Lian
College of Animal Science and Technology/State Key Laboratory for Agrobiotechnology, China Agricultural University, Beijing 100094, China;
Changxin
C
Wu
College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China;
Xueyan
X
Wang
College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China;
Guozhi
G
Li
College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China;
Teng
T
Ma
College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China;
Qiang
Q
Jiang
College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China;
Xue
X
Zhao
College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China;
Jiaqiang
J
Yang
EG Information Technology Enterprise (EGI), Encode Genomics Biotechnology Co., Ltd., Shanghai 200235, China;
Baohong
B
Liu
EG Information Technology Enterprise (EGI), Encode Genomics Biotechnology Co., Ltd., Shanghai 200235, China;
Dongkai
D
Wei
Key Laboratory of Systems Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Shanghai Center for Bioinformation Technology, Shanghai Industrial Technology Institute, Shanghai 201203, China;
Hong
H
Li
College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China;
Jianfa
J
Yang
College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China;
Yulin
Y
Yan
College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China;
Guiying
G
Zhao
College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China;
Xinxing
X
Dong
College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China;
Mingli
M
Li
College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China;
Weidong
W
Deng
College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China;
Jing
J
Leng
Shanghai Center for Bioinformation Technology, Shanghai Industrial Technology Institute, Shanghai 201203, China; School of Life Science and Technology, Shanghai Jiaotong University, Shanghai 200240, China;
Chaochun
C
Wei
National Center for Protein Science Shanghai, National Facility for Protein Science in Shanghai, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China;
Chuan
C
Wang
College of Animal Science and Technology, Yunnan Agricultural University, Kunming 650201, China;
Huaming
H
Mao
College of Animal Science and Technology/State Key Laboratory for Agrobiotechnology, China Agricultural University, Beijing 100094, China;
Hao
H
Zhang
Key Laboratory of Systems Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Shanghai Center for Bioinformation Technology, Shanghai Industrial Technology Institute, Shanghai 201203, China;
Guohui
G
Ding
Key Laboratory of Systems Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Shanghai Center for Bioinformation Technology, Shanghai Industrial Technology Institute, Shanghai 201203, China; School of Life Science and Technology, Shanghai Jiaotong University, Shanghai 200240, China; School of Life Science and Technology, Shanghai Tongji University, Shanghai 200092, China.
Yixue
Y
Li
D000222:Adaptation, Physiological / Q000235:genetics*; D000531:Altitude; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D015687:Cell Hypoxia; D004252:DNA Mutational Analysis; D004285:Dogs / Q000235:genetics*; D016678:Genome; D059014:High-Throughput Nucleotide Sequencing; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1