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Expression variation of the porcine ADRB2 has a complex genetic background


Porcine adrenergic receptor beta 2 (ADRB2) gene exhibits differential allelic expression in skeletal muscle, and its genetic variation has been associated with muscle pH. Exploring the molecular–genetic background of expression variation for porcine ADRB2 will provide insight into the mechanisms driving its regulatory divergence and may also contribute to unraveling the genetic basis of muscle-related traits in pigs. In the present study, we therefore examined haplotype effects on the expression of porcine ADRB2 in four tissues: longissimus dorsi muscle, liver, subcutaneous fat, and spleen. The diversity and structure of haplotypes of the proximal gene region segregating in German commercial breeds were characterized. Seven haplotypes falling into three clades were identified. Two clades including five haplotypes most likely originated from introgression of Asian genetics during formation of modern breeds. Expression analyses revealed that the Asian-derived haplotypes increase expression of the porcine ADRB2 compared to the major, wild-type haplotype independently of tissue type. In addition, several tissue-specific differences in the expression of the Asian-derived haplotypes were found. Inspection of haplotype sequences showed that differentially expressed haplotypes exhibit polymorphisms in a polyguanine tract located in the core promoter region. These findings demonstrate that expression variation of the porcine ADRB2 has a complex genetic basis and suggest that the promoter polyguanine tract is causally involved. This study highlights the challenges of finding causal genetic variants underlying complex traits.

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  1. Andersson L (2012) How selective sweeps in domestic animals provide new insight into biological mechanisms. J Intern Med 271:1–14

  2. Babbitt CC, Silverman JS, Haygood R, Reininga JM, Rockman MV, Wray GA (2010) Multiple functional variants in cis modulate PDYN expression. Mol Biol Evol 27:465–479

  3. Barnes PJ (1995) Beta-adrenergic receptors and their regulation. Am J Respir Crit Care Med 152:838–860

  4. Brodde OE, Leineweber K (2005) Beta2-adrenoceptor gene polymorphisms. Pharmacogenet Genomics 15:267–275

  5. Cagliani R, Fumagalli M, Pozzoli U, Riva S, Comi GP, Torri F, Macciardi F, Bresolin N, Sironi M (2009) Diverse evolutionary histories for beta-adrenoreceptor genes in humans. Am J Hum Genet 85:64–75

  6. Chikuni K, Horiuchi A, Ide H, Shibata M, Hayashi T, Nakajima I, Oe M, Muroya S (2008) Nucleotide sequence polymorphisms of beta1-, beta2-, and beta3-adrenergic receptor genes on Jinhua, Meishan, Duroc and Landrace pigs. Anim Sci J 79:665–672

  7. Clement M, Posada D, Crandall KA (2000) TCS: a computer program to estimate gene genealogies. Mol Ecol 9:1657–1659

  8. Cornett LE, Hiller FC, Jacobi SE, Cao W, McGraw DW (1998) Identification of a glucocorticoid response element in the rat beta2-adrenergic receptor gene. Mol Pharmacol 54:1016–1023

  9. Cowles CR, Hirschhorn JN, Altshuler D, Lander ES (2002) Detection of regulatory variation in mouse genes. Nat Genet 32:432–437

  10. Dimas AS, Deutsch S, Stranger BE, Montgomery SB, Borel C, Attar-Cohen H, Ingle C, Beazley C, Gutierrez AM, Sekowska M, Gagnebin M, Nisbett J, Deloukas P, Dermitzakis ET, Antonarakis SE (2009) Common regulatory variation impacts gene expression in a cell type-dependent manner. Science 325:1246–1250

  11. Excoffier L, Slatkin M (1995) Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 12:921–927

  12. Flicek P, Ahmed I, Amode MR, Barrell D, Beal K et al (2013) Ensembl 2013. Nucleic Acids Res 41:D48–D55

  13. Forton JT, Udalova IA, Campino S, Rockett KA, Hull J, Kwiatkowski DP (2007) Localization of a long-range cis-regulatory element of IL13 by allelic transcript ratio mapping. Genome Res 17:82–87

  14. Gaffney DJ, Veyrieras JB, Degner JF, Pique-Regi R, Pai AA, Crawford GE, Stephens M, Gilad Y, Pritchard JK (2012) Dissecting the regulatory architecture of gene expression QTLs. Genome Biol 13:R7

  15. Ge B, Gurd S, Gaudin T, Dore C, Lepage P, Harmsen E, Hudson TJ, Pastinen T (2005) Survey of allelic expression using EST mining. Genome Res 15:1584–1591

  16. Gemayel R, Vinces MD, Legendre M, Verstrepen KJ (2010) Variable tandem repeats accelerate evolution of coding and regulatory sequences. Annu Rev Genet 44:445–477

  17. Groenen MA, Archibald AL, Uenishi H, Tuggle CK, Takeuchi Y et al (2012) Analyses of pig genomes provide insight into porcine demography and evolution. Nature 491:393–398

  18. Hayes B, Goddard ME (2001) The distribution of the effects of genes affecting quantitative traits in livestock. Genet Sel Evol 33:209–229

  19. Jiang L, Gao B, Kunos G (1996) DNA elements and protein factors involved in the transcription of the beta 2-adrenergic receptor gene in rat liver. The negative regulatory role of C/EBP alpha. Biochemistry 35:13136–13146

  20. Johnatty SE, Abdellatif M, Shimmin L, Clark RB, Boerwinkle E (2002) Beta 2 adrenergic receptor 5′ haplotypes influence promoter activity. Br J Pharmacol 137:1213–1216

  21. Keane TM, Goodstadt L, Danecek P, White MA, Wong K, Yalcin B, Heger A, Agam A, Slater G, Goodson M, Furlotte NA, Eskin E, Nellaker C, Whitley H, Cleak J, Janowitz D, Hernandez-Pliego P, Edwards A, Belgard TG, Oliver PL, McIntyre RE, Bhomra A, Nicod J, Gan X, Yuan W, van der Weyden L, Steward CA, Bala S, Stalker J, Mott R, Durbin R, Jackson IJ, Czechanski A, Guerra-Assuncao JA, Donahue LR, Reinholdt LG, Payseur BA, Ponting CP, Birney E, Flint J, Adams DJ (2011) Mouse genomic variation and its effect on phenotypes and gene regulation. Nature 477:289–294

  22. Maurano MT, Humbert R, Rynes E, Thurman RE, Haugen E, Wang H, Reynolds AP, Sandstrom R, Qu H, Brody J, Shafer A, Neri F, Lee K, Kutyavin T, Stehling-Sun S, Johnson AK, Canfield TK, Giste E, Diegel M, Bates D, Hansen RS, Neph S, Sabo PJ, Heimfeld S, Raubitschek A, Ziegler S, Cotsapas C, Sotoodehnia N, Glass I, Sunyaev SR, Kaul R, Stamatoyannopoulos JA (2012) Systematic localization of common disease-associated variation in regulatory DNA. Science 337:1190–1195

  23. McDonald MJ, Wang WC, Huang HD, Leu JY (2011) Clusters of nucleotide substitutions and insertion/deletion mutations are associated with repeat sequences. PLoS Biol 9:e1000622

  24. Murani E, Ponsuksili S, Srikanchai T, Maak S, Wimmers K (2009) Expression of the porcine adrenergic receptor beta 2 gene in longissimus dorsi muscle is affected by cis-regulatory DNA variation. Anim Genet 40:80–89

  25. Murani E, Reyer H, Ponsuksili S, Fritschka S, Wimmers K (2012) A substitution in the ligand binding domain of the porcine glucocorticoid receptor affects activity of the adrenal gland. PLoS One 7:e45518

  26. Nicolae DL, Gamazon E, Zhang W, Duan S, Dolan ME, Cox NJ (2010) Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS. PLoS Genet 6:e1000888

  27. Nonogaki K (2000) New insights into sympathetic regulation of glucose and fat metabolism. Diabetologia 43:533–549

  28. Panebra A, Schwarb MR, Glinka CB, Liggett SB (2007) Allele-specific binding of airway nuclear extracts to polymorphic beta2-adrenergic receptor 5′ sequence. Am J Respir Cell Mol Biol 36:654–660

  29. Panebra A, Wang WC, Malone MM, Pitter DR, Weiss ST, Hawkins GA, Liggett SB (2010) Common ADRB2 haplotypes derived from 26 polymorphic sites direct beta2-adrenergic receptor expression and regulation phenotypes. PLoS One 5:e11819

  30. Ponsuksili S, Du Y, Murani E, Schwerin M, Wimmers K (2012) Elucidating molecular networks that either affect or respond to plasma cortisol concentration in target tissues of liver and muscle. Genetics 192:1109–1122

  31. Scott MG, Swan C, Wheatley AP, Hall IP (1999) Identification of novel polymorphisms within the promoter region of the human beta2 adrenergic receptor gene. Br J Pharmacol 126:841–844

  32. Tao H, Cox DR, Frazer KA (2006) Allele-specific KRT1 expression is a complex trait. PLoS Genet 2:e93

  33. Templeton AR, Crandall KA, Sing CF (1992) A cladistic analysis of phenotypic associations with haplotypes inferred from restriction endonuclease mapping and DNA sequence data. III. Cladogram estimation. Genetics 132:619–633

  34. The ENCODE Project Consortium (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489:57–74

  35. Veyrieras JB, Kudaravalli S, Kim SY, Dermitzakis ET, Gilad Y, Stephens M, Pritchard JK (2008) High-resolution mapping of expression-QTLs yields insight into human gene regulation. PLoS Genet 4:e1000214

  36. Vinces MD, Legendre M, Caldara M, Hagihara M, Verstrepen KJ (2009) Unstable tandem repeats in promoters confer transcriptional evolvability. Science 324:1213–1216

  37. Wittkopp PJ, Kalay G (2011) Cis-regulatory elements: molecular mechanisms and evolutionary processes underlying divergence. Nat Rev Genet 13:59–69

  38. Wray GA (2007) The evolutionary significance of cis-regulatory mutations. Nat Rev Genet 8:206–216

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The authors thank Angela Garve, Hannelore Tychsen, and Marlies Fuchs for excellent technical help. The authors are also grateful to Aline Foury and Pierre Morméde (INRA, France) and Do Van Khoa for providing Meishan and Muong Khuong tissue samples, respectively. This research was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, Grant MU2965/2-1) and by matched funding from the FBN.

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Correspondence to Eduard Murani.

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Communicated by M. Fredholm.

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Murani, E., Ponsuksili, S., Reyer, H. et al. Expression variation of the porcine ADRB2 has a complex genetic background. Mol Genet Genomics 288, 615–625 (2013).

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  • ADRB2
  • Pig
  • Haplotype structure
  • Differential allelic expression
  • Regulatory variation