MKL1基因多态性与高原环境适应性的遗传关联研究
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摘要
高原环境适应性与遗传因素密切相关,已有多个基因被报道与高原环境适应性显著相关。巨核细胞白血病因子1(megakaryoblastic leukemia 1,MKL1)是一种转录调节因子,在平滑肌细胞的表型调变中发挥重要作用。为探讨MKL1基因是否与高原环境适应性相关,本研究进行了MKL1基因多态性与高原环境适应性的遗传关联分析。本研究招募了世居青藏高原的藏族人群(n=595)和世居平原地区的汉族人群(n=442),并采用MassARRAY阵列图谱技术对MKL1基因的多态性位点rs59098711进行基因分型,比较了其基因型及等位基因型在两组人群中的分布是否存在显著差异。结果发现,在藏、汉两组人群间rs59098711位点的基因型和等位基因型频率存在显著差异(P<0.05)。进一步通过与公共数据库比较发现,藏族人群中rs59098711的基因型及等位基因型的频率分布与其他人种存在显著差异(P<0.05)。生物信息学分析表明,rs59098711位点位于MKL1基因增强子区域,与MKL1基因表达的调控密切相关。同时,基于公共数据集进行的基因差异表达分析发现,MKL1基因在低压性缺氧环境中显著上调。以上研究结果表明,MKL1基因的多态性位点rs59098711与人类的高原适应能力存在相关性。
Genetic factors are closely related to the high-altitude adaptation. Several candidate genes have been reported to be significantly associated with high-altitude adaptation. Megakaryocytic leukemia 1(MKL1) is a transcriptional regulator, which plays crucial roles in the phenotypic modulation of smooth muscle cells. To explore whether MKL1 gene is involved in high-altitude adaptation, we performed genetic association study between MKL1 gene polymorphisms and high-altitude adaptation. We recruited 595 Tibetans from the Qinghai-Tibet plateau and 442 Hans living at low altitude. The SNP rs59098711 locus in the MKL1 gene was genotyped using the Mass ARRAY assays. We compared the genotypes and allele frequency distributions of rs59098711 between the Hans and Tibetans. The results showed that the genotypes of rs59098711 are significantly different between these two populations(P<0.05). We further compared the genotypes of rs59098711 between Tibetans and other ethnic groups using data from various public databases. We also observed that the genotypes of rs59098711 are significantly different between Tibetans and these other populations(P<0.05). Bioinformatics analyses suggested that rs59098711 could be located at the enhancer region and regulate the expression of the MKL1 gene.Additional study of gene expression data from available public datasets showed that MKL1 gene was up-regulated in a hypobaric hypoxic environment. Our results suggested that the genetic polymorphism rs59098711 locus of the MKL1 gene is associated with high-altitude adaption.
Genetic factors are closely related to the high-altitude adaptation. Several candidate genes have been reported to be significantly associated with high-altitude adaptation. Megakaryocytic leukemia 1(MKL1) is a transcriptional regulator, which plays crucial roles in the phenotypic modulation of smooth muscle cells. To explore whether MKL1 gene is involved in high-altitude adaptation, we performed genetic association study between MKL1 gene polymorphisms and high-altitude adaptation. We recruited 595 Tibetans from the Qinghai-Tibet plateau and 442 Hans living at low altitude. The SNP rs59098711 locus in the MKL1 gene was genotyped using the Mass ARRAY assays. We compared the genotypes and allele frequency distributions of rs59098711 between the Hans and Tibetans. The results showed that the genotypes of rs59098711 are significantly different between these two populations(P<0.05). We further compared the genotypes of rs59098711 between Tibetans and other ethnic groups using data from various public databases. We also observed that the genotypes of rs59098711 are significantly different between Tibetans and these other populations(P<0.05). Bioinformatics analyses suggested that rs59098711 could be located at the enhancer region and regulate the expression of the MKL1 gene.Additional study of gene expression data from available public datasets showed that MKL1 gene was up-regulated in a hypobaric hypoxic environment. Our results suggested that the genetic polymorphism rs59098711 locus of the MKL1 gene is associated with high-altitude adaption.
引文
[1]Qi X,Cui C,Peng Y,Zhang X,Yang Z,Zhong H,Zhang H,Xiang K,Cao X,Wang Y,Ouzhuluobu,Basang,Ciwangsangbu,Bianba,Gonggalanzi,Wu T,Chen H,Shi H,Su B.Genetic evidence of paleolithic colonization and neolithic expansion of modern humans on the tibetan plateau.Mol Biol Evol,2013,30(8):1761-1778.
[2]Taylor AT.High-altitude illnesses:physiology,risk factors,prevention,and treatment.Rambam Maimonides Med J,2011,2(1):e0022.
[3]Beall CM.Two routes to functional adaptation:tibetan and Andean high-altitude natives.Proc Natl Acad Sci USA,2007,104(Suppl.1):8655-8660.
[4]Majmundar AJ,Wong WJ,Simon MC.Hypoxia-inducible factors and the response to hypoxic stress.Mol Cell,2010,40(2):294-309.
[5]Beall CM.Tibetan and andean patterns of adaptation to high-altitude hypoxia.Hum Biol,2000,72(1):201-228.
[6]Ren Y,Fu Z,Shen W,Jiang P,He Y,Peng S,Wu Z,Cui B.Incidence of high altitude illnesses among unacclimatized persons who acutely ascended to tibet.High Alt Med Biol,2010,11(1):39-42.
[7]Jiang C,Chen J,Liu F,Luo Y,Xu G,Shen HY,Gao Y,Gao W.Chronic mountain sickness in Chinese Han males who migrated to the Qinghai-Tibetan plateau:application and evaluation of diagnostic criteria for chronic mountain sickness.BMC Public Health,2014,14:701.
[8]Wu TY.Chronic mountain sickness on the QinghaiTibetan plateau.Chin Med J,2005,118(2):161-168.
[9]Wu TY,Ding SQ,Liu JL,Yu MT,Jia JH,Duan JQ,Chai ZC,Dai RC,Zhang SL,Liang BZ,Zhao JZ,Qi de T,Sun YF,Kayser B.Reduced incidence and severity of acute mountain sickness in Qinghai-Tibet railroad construction workers after repeated 7-month exposures despite 5-month low altitude periods.High Alt Med Biol,2009,10(3):221-232.
[10]Moore LG.Human genetic adaptation to high altitude.High Alt Med Biol,2001,2(2):257-279.
[11]Wu T,Kayser B.High altitude adaptation in tibetans.High Alt Med Biol,2006,7(3):193-208.
[12]Grocott M,Montgomery H.Genetophysiology:using genetic strategies to explore hypoxic adaptation.High Alt Med Biol,2008,9(2):123-129.
[13]Simonson TS,Yang Y,Huff CD,Yun H,Qin G,Witherspoon DJ,Bai Z,Lorenzo FR,Xing J,Jorde LB,Prchal JT,Ge R.Genetic evidence for high-altitude adaptation in tibet.Science,2010,329(5987):72-75.
[14]Xu S,Li S,Yang Y,Tan J,Lou H,Jin W,Yang L,Pan X,Wang J,Shen Y,Wu B,Wang H,Jin L.A genome-wide search for signals of high-altitude adaptation in tibetans.Mol Biol Evol,2011,28(2):1003-1011.
[15]Li Q,Liu SY,Lin KQ,Sun H,Yu L,Huang XQ,Chu JY,Yang ZQ.Association between six single nucleotide polymorphisms of EGLN1 gene and adaptation to highaltitude hypoxia.Hereditas(Beijing),2013,35(8):992-998.李骞,刘舒媛,林克勤,孙浩,于亮,黄小琴,褚嘉祐,杨昭庆.EGLN1基因6个单核苷酸多态性与高海拔低氧适应的相关性.遗传,2013,35(8):992-998.
[16]Wang DZ,Li S,Hockemeyer D,Sutherland L,Wang Z,Schratt G,Richardson JA,Nordheim A,Olson EN.Potentiation of serum response factor activity by a family of myocardin-related transcription factors.Proc Natl Acad Sci USA,2002,99(23):14855-14860.
[17]Cen B,Selvaraj A,Burgess RC,Hitzler JK,Ma Z,Morris SW,Prywes R.Megakaryoblastic leukemia 1,a potent transcriptional coactivator for serum response factor(SRF),is required for serum induction of SRF target genes.Mol Cell Biol,2003,23(18):6597-6608.
[18]Kuwahara K,Kinoshita H,Kuwabara Y,Nakagawa Y,Usami S,Minami T,Yamada Y,Fujiwara M,Nakao K.Myocardin-related transcription factor A is a common mediator of mechanical stress-and neurohumoral stimulation-induced cardiac hypertrophic signaling leading to activation of brain natriuretic peptide gene expression.Mol Cell Biol,2010,30(17):4134-4148.
[19]Small EM,Thatcher JE,Sutherland LB,Kinoshita H,Gerard RD,Richardson JA,Dimaio JM,Sadek H,Kuwahara K,Olson EN.Myocardin-related transcription factor-a controls myofibroblast activation and fibrosis in response to myocardial infarction.Circ Res,2010,107(2):294-304.
[20]Yuan Z,Chen J,Chen D,Xu G,Xia M,Xu Y,Gao Y.Megakaryocytic leukemia 1(MKL1)regulates hypoxia induced pulmonary hypertension in rats.PLoS One,2014,9(3):e83895.
[21]Fang F,Yang Y,Yuan Z,Gao Y,Zhou J,Chen Q,Xu Y.Myocardin-related transcription factor A mediates OxLDL-induced endothelial injury.Circ Res,2011,108(7):797-807.
[22]Marsden PA,Heng HH,Scherer SW,Stewart RJ,Hall AV,Shi XM,Tsui LC,Schappert KT.Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene.J Biol Chem,1993,268(23):17478-17488.
[23]Droma Y,Hanaoka M,Ota M,Katsuyama Y,Koizumi T,Fujimoto K,Kobayashi T,Kubo K.Positive association of the endothelial nitric oxide synthase gene polymorphisms with high-altitude pulmonary edema.Circulation,2002,106(7):826-830.
[24]Sun YJ,Ming-wu F,Wen-quan N,Guang-ping L,Jing-liang L,Shou-quan D,Ying X,Guo-shu Y,Jian-qun D,Yun-jun P,Wei-ya D,Tian W,Jing-wen C,Xiao-bo L,Zhong-xiang W,Guang-Xue Y,Hui-cheng S,Zhong-hou J,Jun L,Xiao-ming W,Qin S,Qi-xia W,Wen-yu Z,Tong-chun Z,Chang-chun Q.Endothelial nitric oxide synthase gene polymorphisms associated with susceptibility to high altitude pulmonary edema in Chinese railway construction workers at Qinghai-Tibet over 4 500 meters above sea level.Chin Med Sci J,2010,25(4):215-221.
[25]Ahsan A,Norboo T,Baig MA,Qadar Pasha MA.Simultaneous selection of the wild-type genotypes of the G894T and 4B/4A polymorphisms of NOS3 associate with high-altitude adaptation.Ann Hum Genet,2005,69(Pt 3):260-267.
[26]Wang QQ,Yu L,Huang GR,Zhang L,Liu YQ,Wang TW,Lin H,Ren Q,Liu P,Huang L,Qin J,Wu GM,Li QN,Li YF,Xiong HY.Polymorphisms of angiotensin converting enzyme and nitric oxide synthase 3 genes as risk factors of high-altitude pulmonary edema:a case-control study and meta-analysis.Tohoku J Exp Med,2013,229(4):255-266.
[27]Ahsan A,Mohd G,Norboo T,Baig MA,Pasha MA.Heterozygotes of NOS3 polymorphisms contribute to reduced nitrogen oxides in high-altitude pulmonary edema.Chest,2006,130(5):1511-1519.
[28]Zhang H,Chamba Y,Zhao CJ,Bao HG,Ling Y,Wu CX.Function of inducible nitric oxide synthase on adaptability to hypoxia in Tibetan chicken.Hereditas(Beijing),2009,31(4):400-406.张浩,强巴央宗,赵春江,鲍海港,凌遥,吴常信.藏鸡诱导型一氧化氮合酶基因低氧适应功能分析.遗传,2009,31(4):400-406.
[29]Yang Y,Chen D,Yuan Z,Fang F,Cheng X,Xia J,Fang M,Xu Y,Gao Y.Megakaryocytic leukemia 1(MKL1)ties the epigenetic machinery to hypoxia-induced transactivation of endothelin-1.Nucleic Acids Res,2013,41(12):6005-6017.
[30]Goerre S,Wenk M,B?rtsch P,Lüscher TF,Niroomand F,Hohenhaus E,Oelz O,Reinhart WH.Endothelin-1 in pulmonary hypertension associated with high-altitude exposure.Circulation,1995,91(2):359-364.
[31]Jankowich MD,Wu WC,Choudhary G.Association of elevated plasma Endothelin-1 levels with pulmonary hypertension,mortality,and heart failure in africanamerican individuals:the jackson heart study.JAMA Cardiol,2016,1(4):461-469.
[32]Shao D,Park JE,Wort SJ.The role of endothelin-1 in the pathogenesis of pulmonary arterial hypertension.Pharmacol Res,2011,63(6):504-511.
[33]Modesti PA,Vanni S,Morabito M,Modesti A,Marchetta M,Gamberi T,Sofi F,Savia G,Mancia G,Gensini GF,Parati G.Role of endothelin-1 in exposure to high altitude:acute mountain sickness and Endothelin-1(ACME-1)study.Circulation,2006,114(13):1410-1416.
[34]Yang J,Jin ZB,Chen J,Huang XF,Li XM,Liang YB,Mao JY,Chen X,Zheng Z,Bakshi A,Zheng DD,Zheng MQ,Wray NR,Visscher PM,Lu F,Qu J.Genetic signatures of high-altitude adaptation in tibetans.Proc Natl Acad Sci USA,2017,114(16):4189-4194.
[35]Nicolae DL,Gamazon E,Zhang W,Duan S,Dolan ME,Cox NJ.Trait-associated SNPs are more likely to be eQTLs:annotation to enhance discovery from GWAS.PLoS Genet,2010,6(4):e1000888.
[36]Pugliese SC,Kumar S,Janssen WJ,Graham BB,Frid MG,Riddle SR,El Kasmi KC,Stenmark KR.A Time-and Compartment-Specific activation of lung macrophages in hypoxic pulmonary hypertension.J Immunol,2017,198(12):4802-4812.
[37]Subudhi AW,Bourdillon N,Bucher J,Davis C,Elliott JE,Eutermoster M,Evero O,Fan JL,Jameson-Van Houten S,Julian CG,Kark J,Kark S,Kayser B,Kern JP,Kim SE,Lathan C,Laurie SS,Lovering AT,Paterson R,Polaner DM,Ryan BJ,Spira JL,Tsao JW,Wachsmuth NB,Roach RC.AltitudeOmics:the integrative physiology of human acclimatization to hypobaric hypoxia and its retention upon reascent.PLoS One,2014,9(3):e92191.
[38]Balloux F,Lugon-Moulin N.The estimation of population differentiation with microsatellite markers.Mol Ecol,2002,11(2):155-165.
[39]Peng Y,Yang Z,Zhang H,Cui C,Qi X,Luo X,Tao X,Wu T,Ouzhuluobu,Basang,Ciwangsangbu,Danzengduojie,Chen H,Shi H,Su B.Genetic variations in Tibetan populations and high-altitude adaptation at the himalayas.Mol Biol Evol,2011,28(2):1075-1081.
[2]Taylor AT.High-altitude illnesses:physiology,risk factors,prevention,and treatment.Rambam Maimonides Med J,2011,2(1):e0022.
[3]Beall CM.Two routes to functional adaptation:tibetan and Andean high-altitude natives.Proc Natl Acad Sci USA,2007,104(Suppl.1):8655-8660.
[4]Majmundar AJ,Wong WJ,Simon MC.Hypoxia-inducible factors and the response to hypoxic stress.Mol Cell,2010,40(2):294-309.
[5]Beall CM.Tibetan and andean patterns of adaptation to high-altitude hypoxia.Hum Biol,2000,72(1):201-228.
[6]Ren Y,Fu Z,Shen W,Jiang P,He Y,Peng S,Wu Z,Cui B.Incidence of high altitude illnesses among unacclimatized persons who acutely ascended to tibet.High Alt Med Biol,2010,11(1):39-42.
[7]Jiang C,Chen J,Liu F,Luo Y,Xu G,Shen HY,Gao Y,Gao W.Chronic mountain sickness in Chinese Han males who migrated to the Qinghai-Tibetan plateau:application and evaluation of diagnostic criteria for chronic mountain sickness.BMC Public Health,2014,14:701.
[8]Wu TY.Chronic mountain sickness on the QinghaiTibetan plateau.Chin Med J,2005,118(2):161-168.
[9]Wu TY,Ding SQ,Liu JL,Yu MT,Jia JH,Duan JQ,Chai ZC,Dai RC,Zhang SL,Liang BZ,Zhao JZ,Qi de T,Sun YF,Kayser B.Reduced incidence and severity of acute mountain sickness in Qinghai-Tibet railroad construction workers after repeated 7-month exposures despite 5-month low altitude periods.High Alt Med Biol,2009,10(3):221-232.
[10]Moore LG.Human genetic adaptation to high altitude.High Alt Med Biol,2001,2(2):257-279.
[11]Wu T,Kayser B.High altitude adaptation in tibetans.High Alt Med Biol,2006,7(3):193-208.
[12]Grocott M,Montgomery H.Genetophysiology:using genetic strategies to explore hypoxic adaptation.High Alt Med Biol,2008,9(2):123-129.
[13]Simonson TS,Yang Y,Huff CD,Yun H,Qin G,Witherspoon DJ,Bai Z,Lorenzo FR,Xing J,Jorde LB,Prchal JT,Ge R.Genetic evidence for high-altitude adaptation in tibet.Science,2010,329(5987):72-75.
[14]Xu S,Li S,Yang Y,Tan J,Lou H,Jin W,Yang L,Pan X,Wang J,Shen Y,Wu B,Wang H,Jin L.A genome-wide search for signals of high-altitude adaptation in tibetans.Mol Biol Evol,2011,28(2):1003-1011.
[15]Li Q,Liu SY,Lin KQ,Sun H,Yu L,Huang XQ,Chu JY,Yang ZQ.Association between six single nucleotide polymorphisms of EGLN1 gene and adaptation to highaltitude hypoxia.Hereditas(Beijing),2013,35(8):992-998.李骞,刘舒媛,林克勤,孙浩,于亮,黄小琴,褚嘉祐,杨昭庆.EGLN1基因6个单核苷酸多态性与高海拔低氧适应的相关性.遗传,2013,35(8):992-998.
[16]Wang DZ,Li S,Hockemeyer D,Sutherland L,Wang Z,Schratt G,Richardson JA,Nordheim A,Olson EN.Potentiation of serum response factor activity by a family of myocardin-related transcription factors.Proc Natl Acad Sci USA,2002,99(23):14855-14860.
[17]Cen B,Selvaraj A,Burgess RC,Hitzler JK,Ma Z,Morris SW,Prywes R.Megakaryoblastic leukemia 1,a potent transcriptional coactivator for serum response factor(SRF),is required for serum induction of SRF target genes.Mol Cell Biol,2003,23(18):6597-6608.
[18]Kuwahara K,Kinoshita H,Kuwabara Y,Nakagawa Y,Usami S,Minami T,Yamada Y,Fujiwara M,Nakao K.Myocardin-related transcription factor A is a common mediator of mechanical stress-and neurohumoral stimulation-induced cardiac hypertrophic signaling leading to activation of brain natriuretic peptide gene expression.Mol Cell Biol,2010,30(17):4134-4148.
[19]Small EM,Thatcher JE,Sutherland LB,Kinoshita H,Gerard RD,Richardson JA,Dimaio JM,Sadek H,Kuwahara K,Olson EN.Myocardin-related transcription factor-a controls myofibroblast activation and fibrosis in response to myocardial infarction.Circ Res,2010,107(2):294-304.
[20]Yuan Z,Chen J,Chen D,Xu G,Xia M,Xu Y,Gao Y.Megakaryocytic leukemia 1(MKL1)regulates hypoxia induced pulmonary hypertension in rats.PLoS One,2014,9(3):e83895.
[21]Fang F,Yang Y,Yuan Z,Gao Y,Zhou J,Chen Q,Xu Y.Myocardin-related transcription factor A mediates OxLDL-induced endothelial injury.Circ Res,2011,108(7):797-807.
[22]Marsden PA,Heng HH,Scherer SW,Stewart RJ,Hall AV,Shi XM,Tsui LC,Schappert KT.Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene.J Biol Chem,1993,268(23):17478-17488.
[23]Droma Y,Hanaoka M,Ota M,Katsuyama Y,Koizumi T,Fujimoto K,Kobayashi T,Kubo K.Positive association of the endothelial nitric oxide synthase gene polymorphisms with high-altitude pulmonary edema.Circulation,2002,106(7):826-830.
[24]Sun YJ,Ming-wu F,Wen-quan N,Guang-ping L,Jing-liang L,Shou-quan D,Ying X,Guo-shu Y,Jian-qun D,Yun-jun P,Wei-ya D,Tian W,Jing-wen C,Xiao-bo L,Zhong-xiang W,Guang-Xue Y,Hui-cheng S,Zhong-hou J,Jun L,Xiao-ming W,Qin S,Qi-xia W,Wen-yu Z,Tong-chun Z,Chang-chun Q.Endothelial nitric oxide synthase gene polymorphisms associated with susceptibility to high altitude pulmonary edema in Chinese railway construction workers at Qinghai-Tibet over 4 500 meters above sea level.Chin Med Sci J,2010,25(4):215-221.
[25]Ahsan A,Norboo T,Baig MA,Qadar Pasha MA.Simultaneous selection of the wild-type genotypes of the G894T and 4B/4A polymorphisms of NOS3 associate with high-altitude adaptation.Ann Hum Genet,2005,69(Pt 3):260-267.
[26]Wang QQ,Yu L,Huang GR,Zhang L,Liu YQ,Wang TW,Lin H,Ren Q,Liu P,Huang L,Qin J,Wu GM,Li QN,Li YF,Xiong HY.Polymorphisms of angiotensin converting enzyme and nitric oxide synthase 3 genes as risk factors of high-altitude pulmonary edema:a case-control study and meta-analysis.Tohoku J Exp Med,2013,229(4):255-266.
[27]Ahsan A,Mohd G,Norboo T,Baig MA,Pasha MA.Heterozygotes of NOS3 polymorphisms contribute to reduced nitrogen oxides in high-altitude pulmonary edema.Chest,2006,130(5):1511-1519.
[28]Zhang H,Chamba Y,Zhao CJ,Bao HG,Ling Y,Wu CX.Function of inducible nitric oxide synthase on adaptability to hypoxia in Tibetan chicken.Hereditas(Beijing),2009,31(4):400-406.张浩,强巴央宗,赵春江,鲍海港,凌遥,吴常信.藏鸡诱导型一氧化氮合酶基因低氧适应功能分析.遗传,2009,31(4):400-406.
[29]Yang Y,Chen D,Yuan Z,Fang F,Cheng X,Xia J,Fang M,Xu Y,Gao Y.Megakaryocytic leukemia 1(MKL1)ties the epigenetic machinery to hypoxia-induced transactivation of endothelin-1.Nucleic Acids Res,2013,41(12):6005-6017.
[30]Goerre S,Wenk M,B?rtsch P,Lüscher TF,Niroomand F,Hohenhaus E,Oelz O,Reinhart WH.Endothelin-1 in pulmonary hypertension associated with high-altitude exposure.Circulation,1995,91(2):359-364.
[31]Jankowich MD,Wu WC,Choudhary G.Association of elevated plasma Endothelin-1 levels with pulmonary hypertension,mortality,and heart failure in africanamerican individuals:the jackson heart study.JAMA Cardiol,2016,1(4):461-469.
[32]Shao D,Park JE,Wort SJ.The role of endothelin-1 in the pathogenesis of pulmonary arterial hypertension.Pharmacol Res,2011,63(6):504-511.
[33]Modesti PA,Vanni S,Morabito M,Modesti A,Marchetta M,Gamberi T,Sofi F,Savia G,Mancia G,Gensini GF,Parati G.Role of endothelin-1 in exposure to high altitude:acute mountain sickness and Endothelin-1(ACME-1)study.Circulation,2006,114(13):1410-1416.
[34]Yang J,Jin ZB,Chen J,Huang XF,Li XM,Liang YB,Mao JY,Chen X,Zheng Z,Bakshi A,Zheng DD,Zheng MQ,Wray NR,Visscher PM,Lu F,Qu J.Genetic signatures of high-altitude adaptation in tibetans.Proc Natl Acad Sci USA,2017,114(16):4189-4194.
[35]Nicolae DL,Gamazon E,Zhang W,Duan S,Dolan ME,Cox NJ.Trait-associated SNPs are more likely to be eQTLs:annotation to enhance discovery from GWAS.PLoS Genet,2010,6(4):e1000888.
[36]Pugliese SC,Kumar S,Janssen WJ,Graham BB,Frid MG,Riddle SR,El Kasmi KC,Stenmark KR.A Time-and Compartment-Specific activation of lung macrophages in hypoxic pulmonary hypertension.J Immunol,2017,198(12):4802-4812.
[37]Subudhi AW,Bourdillon N,Bucher J,Davis C,Elliott JE,Eutermoster M,Evero O,Fan JL,Jameson-Van Houten S,Julian CG,Kark J,Kark S,Kayser B,Kern JP,Kim SE,Lathan C,Laurie SS,Lovering AT,Paterson R,Polaner DM,Ryan BJ,Spira JL,Tsao JW,Wachsmuth NB,Roach RC.AltitudeOmics:the integrative physiology of human acclimatization to hypobaric hypoxia and its retention upon reascent.PLoS One,2014,9(3):e92191.
[38]Balloux F,Lugon-Moulin N.The estimation of population differentiation with microsatellite markers.Mol Ecol,2002,11(2):155-165.
[39]Peng Y,Yang Z,Zhang H,Cui C,Qi X,Luo X,Tao X,Wu T,Ouzhuluobu,Basang,Ciwangsangbu,Danzengduojie,Chen H,Shi H,Su B.Genetic variations in Tibetan populations and high-altitude adaptation at the himalayas.Mol Biol Evol,2011,28(2):1075-1081.