A 3.4-kb Copy-Number Deletion near EPAS1 Is Significantly Enriched in High-Altitude Tibetans but Absent from the Denisovan Sequence

doi:10.1016/j.ajhg.2015.05.005

	A 3.4-kb Copy-Number Deletion near EPAS1 Is Significantly Enriched in High-Altitude Tibetans but Absent from the Denisovan Sequence
	Lou, Haiyi 1; Lu, Yan 1; Lu, Dongsheng 1; Fu, Ruiqing 1; Wang, Xiaoji1,2 ; Feng, Qidi 1; Wu, Sijie 1; Yang, Yajun 3,4; Li, Shilin 3,4; Kang, Longli 5; Guan, Yaqun 6; Hoh, Boon-Peng 7; Chung, Yeun-Jun 8; Jin, Li 3,4; Su, Bing 9; Xu, Shuhua1,2,10
	2015-07-02
发表期刊	AMERICAN JOURNAL OF HUMAN GENETICS (IF:8.1[JCR-2023],9.7[5-Year])
ISSN	0002-9297
卷号	97 期号:1 页码:54-66
发表状态	已发表
DOI	10.1016/j.ajhg.2015.05.005
摘要	Tibetan high-altitude adaptation (HAA) has been studied extensively, and many candidate genes have been reported. Subsequent efforts targeting HAA functional variants, however, have not been that successful (e.g., no functional variant has been suggested for the top candidate HAA gene, EPAS1). With WinXPCNVer, a method developed in this study, we detected in microarray data a Tibetanen-riched deletion (TED) carried by 90% of Tibetans; 50% were homozygous for the deletion, whereas only 3% carried the TED and 0% carried the homozygous deletion in 2,792 worldwide samples (p < 10(-15)). We employed long PCR and Sanger sequencing technologies to determine the exact copy number and breakpoints of the TED in 70 additional Tibetan and 182 diverse samples. The TED had identical boundaries (chr2: 46,694,276-46,697,683; hg19) and was 80 kb downstream of EPAS1. Notably, the TED was in strong linkage disequilibrium (LD; r(2) = 0.8) with EPAS1 variants associated with reduced blood concentrations of hemoglobin. It was also in complete LD with the 5-SNP motif, which was suspected to be introgressed from Denisovans, but the deletion itself was absent from the Denisovan sequence. Correspondingly, we detected that footprints of positive selection for the TED occurred 12,803 (95% confidence interval = 12,075-14,725) years ago. We further whole-genome deep sequenced (>60x) seven Tibetans and verified the TED but failed to identify any other copy-number variations with comparable patterns, giving this TED top priority for further study. We speculate that the specific patterns of the TED resulted from its own functionality in HAA of Tibetans or LD with a functional variant of EPAS1.
收录类别	SCI
语种	英语
资助项目	Science and Technology Commission of Shanghai Municipality[14YE1406800]
WOS研究方向	Genetics & Heredity
WOS类目	Genetics & Heredity
WOS记录号	WOS:000358189500005
出版者	CELL PRESS
WOS关键词	STRUCTURAL VARIATION ; GENOME SEQUENCE ; ADAPTATION ; SELECTION ; VARIANTS ; IDENTIFICATION ; MECHANISMS ; INFERENCE ; SITES ; SIZE
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/2182
专题	生命科学与技术学院生命科学与技术学院_特聘教授组_徐书华组生命科学与技术学院_硕士生
通讯作者	Xu, Shuhua
作者单位	1.Chinese Acad Sci, Shanghai Inst Biol Sci, Max Planck Independent Res Grp Populat Genom, Key Lab Computat Biol,Partner Inst Computat Biol, Shanghai 200031, Peoples R China 2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China 3.Fudan Univ, State Key Lab Genet Engn, Shanghai 200433, Peoples R China 4.Fudan Univ, Collaborat Innovat Ctr Genet & Dev, Key Lab Contemporary Anthropol, Minist Educ,Sch Life Sci, Shanghai 200433, Peoples R China 5.Xizang Univ Nationalities, Sch Med, Xianyang 712082, Shaanxi, Peoples R China 6.Xinjiang Med Univ, Preclin Med Coll, Dept Biochem & Mol Biol, Urumqi 830011, Peoples R China 7.UCSI Univ, Fac Med & Hlth Sci, Kuala Lumpur 56000, Malaysia 8.Catholic Univ Korea, Sch Med, Dept Microbiol, Integrated Res Ctr Genome Polymorphism, Seoul 137701, South Korea 9.Chinese Acad Sci, Kunming Inst Zool, State Key Lab Genet Resources & Evolut, Kunming 650223, Peoples R China 10.Collaborat Innovat Ctr Genet & Dev, Shanghai 200438, Peoples R China
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Lou, Haiyi,Lu, Yan,Lu, Dongsheng,et al. A 3.4-kb Copy-Number Deletion near EPAS1 Is Significantly Enriched in High-Altitude Tibetans but Absent from the Denisovan Sequence[J]. AMERICAN JOURNAL OF HUMAN GENETICS,2015,97(1):54-66.
APA	Lou, Haiyi.,Lu, Yan.,Lu, Dongsheng.,Fu, Ruiqing.,Wang, Xiaoji.,...&Xu, Shuhua.(2015).A 3.4-kb Copy-Number Deletion near EPAS1 Is Significantly Enriched in High-Altitude Tibetans but Absent from the Denisovan Sequence.AMERICAN JOURNAL OF HUMAN GENETICS,97(1),54-66.
MLA	Lou, Haiyi,et al."A 3.4-kb Copy-Number Deletion near EPAS1 Is Significantly Enriched in High-Altitude Tibetans but Absent from the Denisovan Sequence".AMERICAN JOURNAL OF HUMAN GENETICS 97.1(2015):54-66.