Population history and genomic signatures for high-altitude adaptation in Tibetan pigs

BMC Genomics

Jun Ren¹  Hao Chen¹  Xianhua Xie¹  Jing Li¹  Bin Yang¹  Huashui Ai¹ 

[1] Key Laboratory for Animal Biotechnology of Jiangxi Province and the Ministry of Agriculture of China, Jiangxi Agricultural University, Nanchang 330045, P. R China

关键词: Tibetan pigs;    Population history;    Genetic basis;    High-altitude adaptation;   

Others  :  1139346
DOI  :  10.1186/1471-2164-15-834

 received in 2014-01-25, accepted in 2014-09-25,  发布年份 2014

【 摘 要 】

Background

The Tibetan pig is one of domestic animals indigenous to the Qinghai-Tibet Plateau. Several geographically isolated pig populations are distributed throughout the Plateau. It remained an open question if these populations have experienced different demographic histories and have evolved independent adaptive loci for the harsh environment of the Plateau. To address these questions, we herein investigated ~ 40,000 genetic variants across the pig genome in a broad panel of 678 individuals from 5 Tibetan geographic populations and 34 lowland breeds.

Results

Using a series of population genetic analyses, we show that Tibetan pig populations have marked genetic differentiations. Tibetan pigs appear to be 3 independent populations corresponding to the Tibetan, Gansu and Sichuan & Yunnan locations. Each population is more genetically similar to its geographic neighbors than to any of the other Tibetan populations. By applying a locus-specific branch length test, we identified both population-specific and -shared candidate genes under selection in Tibetan pigs. These genes, such as PLA2G12A, RGCC, C9ORF3, GRIN2B, GRID1 and EPAS1, are involved in high-altitude physiology including angiogenesis, pulmonary hypertension, oxygen intake, defense response and erythropoiesis. A majority of these genes have not been implicated in previous studies of highlanders and high-altitude animals.

Conclusion

Tibetan pig populations have experienced substantial genetic differentiation. Historically, Tibetan pigs likely had admixture with neighboring lowland breeds. During the long history of colonization in the Plateau, Tibetan pigs have developed a complex biological adaptation mechanism that could be different from that of Tibetans and other animals. Different Tibetan pig populations appear to have both distinct and convergent adaptive loci for the harsh environment of the Plateau.

【 授权许可】

   
2014 Ai et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Beall CM: Two routes to functional adaptation: Tibetan and Andean high-altitude natives. Proc Natl Acad Sci U S A 2007, 104(Suppl 1):8655-8660.
• [2]Beall CM, Brittenham GM, Strohl KP, Blangero J, Williams-Blangero S, Goldstein MC, Decker MJ, Vargas E, Villena M, Soria R, Alarcon AM, Gonzales C: Hemoglobin concentration of high-altitude Tibetans and Bolivian Aymara. Am J Phys Anthropol 1998, 106(3):385-400.
• [3]Wu T, Wang X, Wei C, Cheng H, Wang X, Li Y, Ge D, Zhao H, Young P, Li G, Wang Z: Hemoglobin levels in Qinghai-Tibet: different effects of gender for Tibetans vs. Han. J Appl Physiol 2005, 98(2):598-604.
• [4]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.
• [5]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.
• [6]Bigham A, Bauchet M, Pinto D, Mao X, Akey JM, Mei R, Scherer SW, Julian CG, Wilson MJ, Lopez Herraez D, Brutsaert T, Parra EJ, Moore LG, Shriver MD: Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data. PLoS Genet 2010, 6(9):e1001116.
• [7]Scheinfeldt LB, Soi S, Thompson S, Ranciaro A, Woldemeskel D, Beggs W, Lambert C, Jarvis JP, Abate D, Belay G, Tishkoff SA: Genetic adaptation to high altitude in the Ethiopian highlands. Genome Biol 2012, 13(1):R1. BioMed Central Full Text
• [8]Yi X, Liang Y, Huerta-Sanchez E, Jin X, Cuo ZX, Pool JE, Xu X, Jiang H, Vinckenbosch N, Korneliussen TS, Zheng H, Liu T, He W, Li K, Luo R, Nie X, Wu H, Zhao M, Cao H, Zou J, Shan Y, Li S, Yang Q, Asan , Ni P, Tian G, Xu J, Liu X, Jiang T, Wu R, et al.: Sequencing of 50 human exomes reveals adaptation to high altitude. Science 2010, 329(5987):75-78.
• [9]Beall CM, Cavalleri GL, Deng L, Elston RC, Gao Y, Knight J, Li C, Li JC, Liang Y, McCormack M, Montgomery HE, Pan H, Robbins PA, Shianna KV, Tam SC, Tsering N, Veeramah KR, Wang W, Wangdui P, Weale ME, Xu Y, Xu Z, Yang L, Zaman MJ, Zeng C, Zhang L, Zhang X, Zhaxi P, Zheng YT: Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders. Proc Natl Acad Sci U S A 2010, 107(25):11459-11464.
• [10]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.
• [11]Xiang K, Ouzhuluobu , Peng Y, Yang Z, Zhang X, Cui C, Zhang H, Li M, Zhang Y, Bianba G, Basang C, Wu T, Chen H, Shi H, Qi X, Su B: Identification of a Tibetan-specific mutation in the hypoxic gene EGLN1 and its contribution to high-altitude adaptation. Mol Biol Evol 2013, 30(8):1889-1898.
• [12]Simonson TS, McClain DA, Jorde LB, Prchal JT: Genetic determinants of Tibetan high-altitude adaptation. Hum Genet 2012, 131(4):527-533.
• [13]Huerta-Sanchez E, Degiorgio M, Pagani L, Tarekegn A, Ekong R, Antao T, Cardona A, Montgomery HE, Cavalleri GL, Robbins PA, Weale ME, Bradman N, Bekele E, Kivisild T, Tyler-Smith C, Nielsen R: Genetic signatures reveal high-altitude adaptation in a set of ethiopian populations. Mol Biol Evol 2013, 30(8):1877-1888.
• [14]Ge RL, Cai Q, Shen YY, San A, Ma L, Zhang Y, Yi X, Chen Y, Yang L, Huang Y, He R, Hui Y, Hao M, Li Y, Wang B, Ou X, Xu J, Zhang Y, Wu K, Geng C, Zhou W, Zhou T, Irwin DM, Yang Y, Ying L, Bao H, Kim J, Larkin DM, Ma J, Lewin HA, et al.: Draft genome sequence of the Tibetan antelope. Nat Commun 2013, 4:1858.
• [15]Qiu Q, Zhang G, Ma T, Qian W, Wang J, Ye Z, Cao C, Hu Q, Kim J, Larkin DM, Auvil L, Capitanu B, Ma J, Lewin HA, Qian X, Lang Y, Zhou R, Wang L, Wang K, Xia J, Liao S, Pan S, Lu X, Hou H, Wang Y, Zang X, Yin Y, Ma H, Zhang J, Wang Z, et al.: The yak genome and adaptation to life at high altitude. Nat Genet 2012, 44(8):946-949.
• [16]Wang L, Wang A, Wang L, Li K, Yang G, He R, Qian L, Xu N, Huang R, Peng Z, Zeng Y, Pang Y: Animal Genetic Resourses in China: Pigs. Beijing: China Agricultural Press; 2011:361-374. in Chinese
• [17]Chama Y, Zhang H, Baina Y, Liu J, Shang P, Danzeng W: Determination of blood physiological parameters in Tibet pig at high altitude. Southwest China J Agric Sci 2011, 24(6):2382-2384. (in Chinese)
• [18]Pei SX, Chen XJ, Si Ren BZ, Liu YH, Cheng XS, Harris EM, Anand IS, Harris PC: Chronic mountain sickness in Tibet. Q J Med 1989, 71(266):555-574.
• [19]Ai H, Huang L, Ren J: Genetic diversity, linkage disequilibrium and selection signatures in Chinese and Western pigs revealed by genome-wide SNP markers. PLoS One 2013, 8(2):e56001.
• [20]Li M, Tian S, Jin L, Zhou G, Li Y, Zhang Y, Wang T, Yeung CK, Chen L, Ma J, Zhang J, Jiang A, Li J, Zhou C, Zhang J, Liu Y, Sun X, Zhao H, Niu Z, Lou P, Xian L, Shen X, Liu S, Zhang S, Zhang M, Zhu L, Shuai S, Bai L, Tang G, Liu H, et al.: Genomic analyses identify distinct patterns of selection in domesticated pigs and Tibetan wild boars. Nat Genet 2013, 45(12):1431-1438.
• [21]Pickrell JK, Pritchard JK: Inference of population splits and mixtures from genome-wide allele frequency data. PLoS Genet 2012, 8(11):e1002967.
• [22]Zhang Z, Li B, Chen X: Pig Breeds in China. Shanghai: Shanghai Scientific and Technical Publisher; 1986.
• [23]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.
• [24]Wang Z: History of Nationalities in China. Beijing: China Social Science Press; 1994. in Chinese
• [25]Yang S, Zhang H, Mao H, Yan D, Lu S, Lian L, Zhao G, Yan Y, Deng W, Shi X, Han S, Li S, Wang X, Gou X: The local origin of the Tibetan pig and additional insights into the origin of Asian pigs. PLoS One 2011, 6(12):e28215.
• [26]Aldenderfer M: Peopling the Tibetan plateau: insights from archaeology. High Alt Med Biol 2011, 12(2):141-147.
• [27]Zhao M, Kong QP, Wang HW, Peng MS, Xie XD, Wang WZ, Jiayang , Duan JG, Cai MC, Zhao SN, Cidanpingcuo , Tu YQ, Wu SF, Yao YG, Bandelt HJ, Zhang YP: Mitochondrial genome evidence reveals successful Late Paleolithic settlement on the Tibetan Plateau. Proc Natl Acad Sci U S A 2009, 106(50):21230-21235.
• [28]Diaz-Perales A, Quesada V, Sanchez LM, Ugalde AP, Suarez MF, Fueyo A, Lopez-Otin C: Identification of human aminopeptidase O, a novel metalloprotease with structural similarity to aminopeptidase B and leukotriene A4 hydrolase. J Biol Chem 2005, 280(14):14310-14317.
• [29]Li XC, Campbell DJ, Ohishi M, Yuan S, Zhuo JL: AT1 receptor-activated signaling mediates angiotensin IV-induced renal cortical vasoconstriction in rats. Am J Physiol Renal Physiol 2006, 290(5):F1024-F1033.
• [30]Lochard N, Thibault G, Silversides DW, Touyz RM, Reudelhuber TL: Chronic production of angiotensin IV in the brain leads to hypertension that is reversible with an angiotensin II AT1 receptor antagonist. Circ Res 2004, 94(11):1451-1457.
• [31]Le MT, Vanderheyden PM, Szaszak M, Hunyady L, Vauquelin G: Angiotensin IV is a potent agonist for constitutive active human AT1 receptors. Distinct roles of the N-and C-terminal residues of angiotensin II during AT1 receptor activation. J Biol Chem 2002, 277(26):23107-23110.
• [32]Parikh H, Nilsson E, Ling C, Poulsen P, Almgren P, Nittby H, Eriksson KF, Vaag A, Groop LC: Molecular correlates for maximal oxygen uptake and type 1 fibers. Am J Physiol Endocrinol Metab 2008, 294(6):E1152-E1159.
• [33]Rappaport N, Nativ N, Stelzer G, Twik M, Guan-Golan Y, Stein TI, Bahir I, Belinky F, Morrey CP, Safran M, Lancet D: MalaCards: an integrated compendium for diseases and their annotation. Database (Oxford) 2013, 2013:bat018.
• [34]Endele S, Rosenberger G, Geider K, Popp B, Tamer C, Stefanova I, Milh M, Kortum F, Fritsch A, Pientka FK, Hellenbroich Y, Kalscheuer VM, Kohlhase J, Moog U, Rappold G, Rauch A, Ropers HH, von Spiczak S, Tonnies H, Villeneuve N, Villard L, Zabel B, Zenker M, Laube B, Reis A, Wieczorek D, Van Maldergem L, Kutsche K: Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet 2010, 42(11):1021-1026.
• [35]Yamazaki M, Araki K, Shibata A, Mishina M: Molecular cloning of a cDNA encoding a novel member of the mouse glutamate receptor channel family. Biochem Biophys Res Commun 1992, 183(2):886-892.
• [36]Nenadic I, Maitra R, Scherpiet S, Gaser C, Schultz CC, Schachtzabel C, Smesny S, Reichenbach JR, Treutlein J, Muhleisen TW, Deufel T, Cichon S, Rietschel M, Nothen MM, Sauer H, Schlosser RG: Glutamate receptor delta 1 (GRID1) genetic variation and brain structure in schizophrenia. J Psychiatr Res 2012, 46(12):1531-1539.
• [37]Treutlein J, Muhleisen TW, Frank J, Mattheisen M, Herms S, Ludwig KU, Treutlein T, Schmael C, Strohmaier J, Bosshenz KV, Breuer R, Paul T, Witt SH, Schulze TG, Schlosser RG, Nenadic I, Sauer H, Becker T, Maier W, Cichon S, Nothen MM, Rietschel M: Dissection of phenotype reveals possible association between schizophrenia and Glutamate Receptor Delta 1 (GRID1) gene promoter. Schizophr Res 2009, 111(1–3):123-130.
• [38]Fike CD, Kaplowitz MR, Pfister SL: Arachidonic acid metabolites and an early stage of pulmonary hypertension in chronically hypoxic newborn pigs. Am J Physiol Lung Cell Mol Physiol 2003, 284(2):L316-L323.
• [39]An X, Jin Y, Guo H, Foo SY, Cully BL, Wu J, Zeng H, Rosenzweig A, Li J: Response gene to complement 32, a novel hypoxia-regulated angiogenic inhibitor. Circulation 2009, 120(7):617-627.
• [40]Breen E, Tang K, Olfert M, Knapp A, Wagner P: Skeletal muscle capillarity during hypoxia: VEGF and its activation. High Alt Med Biol 2008, 9(2):158-166.
• [41]van Patot MC, Gassmann M: Hypoxia: adapting to high altitude by mutating EPAS-1, the gene encoding HIF-2alpha. High Alt Med Biol 2011, 12(2):157-167.
• [42]Pérez-Enciso M, Burgos-Paz W, Souza CA, Megens HJ, Ramayo-Caldas Y, Melo M, Lemús-Flores C, Caal E, Soto HW, Martínez R, Alvarez LA, Aguirre L, Iñiguez V, Revidatti MA, Martínez-López OR, Llambi S, Esteve-Codina A, Rodríguez MC, Crooijmans R, Paiva SR, Schook LB, Groenen MAM: Data from: porcine colonization of the Americas: a 60k SNP story. Dryad Data Repository 2012.
• [43]Ramos AM, Crooijmans RP, Affara NA, Amaral AJ, Archibald AL, Beever JE, Bendixen C, Churcher C, Clark R, Dehais P, Hansen MS, Hedegaard J, Hu ZL, Kerstens HH, Law AS, Megens HJ, Milan D, Nonneman DJ, Rohrer GA, Rothschild MF, Smith TP, Schnabel RD, Van Tassell CP, Taylor JF, Wiedmann RT, Schook LB, Groenen MA: Design of a high density SNP genotyping assay in the pig using SNPs identified and characterized by next generation sequencing technology. PLoS One 2009, 4(8):e6524.
• [44]Szpiech ZA, Jakobsson M, Rosenberg NA: ADZE: a rarefaction approach for counting alleles private to combinations of populations. Bioinformatics 2008, 24(21):2498-2504.
• [45]Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC: PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007, 81(3):559-575.
• [46]Felsenstein J: PHYLIP-phylogeny inference package (version 3.2). Cladistics 1989, 5:164-166.
• [47]Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D: Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 2006, 38(8):904-909.
• [48]Reich D, Thangaraj K, Patterson N, Price AL, Singh L: Reconstructing Indian population history. Nature 2009, 461(7263):489-494.
• [49]Wright S: The Genetical structure of populations. Ann Eugen 1951, 15:323-354.
• [50]Alexander DH, Novembre J, Lange K: Fast model-based estimation of ancestry in unrelated individuals. Genome Res 2009, 19(9):1655-1664.
• [51]Shriver MD, Kennedy GC, Parra EJ, Lawson HA, Sonpar V, Huang J, Akey JM, Jones KW: The genomic distribution of population substructure in four populations using 8,525 autosomal SNPs. Hum Genomics 2004, 1(4):274-286. BioMed Central Full Text
• [52]Groenen MA, Archibald AL, Uenishi H, Tuggle CK, Takeuchi Y, Rothschild MF, Rogel-Gaillard C, Park C, Milan D, Megens HJ, Li S, Larkin DM, Kim H, Frantz LA, Caccamo M, Ahn H, Aken BL, Anselmo A, Anthon C, Auvil L, Badaoui B, Beattie CW, Bendixen C, Berman D, Blecha F, Blomberg J, Bolund L, Bosse M, Botti S, Bujie Z, et al.: Analyses of pig genomes provide insight into porcine demography and evolution. Nature 2012, 491(7424):393-398.
• [53]Kent WJ: BLAT–the BLAST-like alignment tool. Genome Res 2002, 12(4):656-664.
• [54]Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A, Fridman WH, Pages F, Trajanoski Z, Galon J: ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics 2009, 25(8):1091-1093.