Asian-Australasian Journal of Animal Sciences

Asian Australasian Association of Animal Production Societies (아세아태평양축산학회)
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Multiple Genes Related to Muscle Identified through a Joint Analysis of a Two-stage Genome-wide Association Study for Racing Performance of 1,156 Thoroughbreds

  • Shin, Dong-Hyun (Department of Agricultural Biotechnology, Animal Biotechnology Major, and Research Institute for Agriculture and Life Sciences, Seoul National University) ;
  • Lee, Jin Woo (Horse Industry Research Center, Korea Racing Authority (KRA)) ;
  • Park, Jong-Eun (Department of Agricultural Biotechnology, Animal Biotechnology Major, and Research Institute for Agriculture and Life Sciences, Seoul National University) ;
  • Choi, Ik-Young (Genome Analysis Center, National Instrumentation and Environmental Management (NICEM), Seoul National University) ;
  • Oh, Hee-Seok (Department of Statistics, Seoul National University) ;
  • Kim, Hyeon Jeong (C&K Genomics) ;
  • Kim, Heebal (Department of Agricultural Biotechnology, Animal Biotechnology Major, and Research Institute for Agriculture and Life Sciences, Seoul National University)
  • Received : 2014.01.04
  • Accepted : 2014.08.14
  • Published : 2015.06.01
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Abstract

Thoroughbred, a relatively recent horse breed, is best known for its use in horse racing. Although myostatin (MSTN) variants have been reported to be highly associated with horse racing performance, the trait is more likely to be polygenic in nature. The purpose of this study was to identify genetic variants strongly associated with racing performance by using estimated breeding value (EBV) for race time as a phenotype. We conducted a two-stage genome-wide association study to search for genetic variants associated with the EBV. In the first stage of genome-wide association study, a relatively large number of markers (~54,000 single-nucleotide polymorphisms, SNPs) were evaluated in a small number of samples (240 horses). In the second stage, a relatively small number of markers identified to have large effects (170 SNPs) were evaluated in a much larger number of samples (1,156 horses). We also validated the SNPs related to MSTN known to have large effects on racing performance and found significant associations in the stage two analysis, but not in stage one. We identified 28 significant SNPs related to 17 genes. Among these, six genes have a function related to myogenesis and five genes are involved in muscle maintenance. To our knowledge, these genes are newly reported for the genetic association with racing performance of Thoroughbreds. It complements a recent horse genome-wide association studies of racing performance that identified other SNPs and genes as the most significant variants. These results will help to expand our knowledge of the polygenic nature of racing performance in Thoroughbreds.

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References

  1. Bach, A.-S., S. Enjalbert, F. Comunale, S. Bodin, N. Vitale, S. Charrasse, and C. Gauthier-Rouviere. 2010. ADP-ribosylation factor 6 regulates mammalian myoblast fusion through phospholipase D1 and phosphatidylinositol 4,5-bisphosphate signaling pathways. Mol. Biol. Cell 21:2412-2424. https://doi.org/10.1091/mbc.E09-12-1063
  2. Binns, M., D. A. Boehler, and D. H. Lambert. 2010. Identification of the myostatin locus (MSTN) as having a major effect on optimum racing distance in the Thoroughbred horse in the USA. Anim. Genet. 41:154-158. https://doi.org/10.1111/j.1365-2052.2010.02126.x
  3. Bosio, Y., G. Berto, P. Camera, F. Bianchi, C. Ambrogio, P. Claus, and F. Di Cunto. 2012. PPP4R2 regulates neuronal cell differentiation and survival, functionally cooperating with SMN. Eur. J. Cell Biol. 91:662-674. https://doi.org/10.1016/j.ejcb.2012.03.002
  4. Bray, M. S., J. M. Hagberg, L. Perusse, T. Rankinen, S. M. Roth, B. Wolfarth, and C. Bouchard. 2009. The human gene map for performance and health-related fitness phenotypes: the 2006-2007 update. Med. Sci. Sports Exerc. 41:34-72.
  5. Gaffney, B. and E. P. Cunningham. 1988. Estimation of genetic trend in racing performance of thoroughbred horses. Nature 332:722-724. https://doi.org/10.1038/332722a0
  6. Goldstein, J. L. and M. S. Brown. 1990. Regulation of the mevalonate pathway. Nature 343:425-430. https://doi.org/10.1038/343425a0
  7. Grozdanov, P. N., S. Roy, N. Kittur, and U. T. Meier. 2009. SHQ1 is required prior to NAF1 for assembly of H/ACA small nucleolar and telomerase RNPs. RNA 15:1188-1197. https://doi.org/10.1261/rna.1532109
  8. Gu, J., D. MacHugh, B. McGivney, S. Park, L. Katz, and E. Hill. 2010. Association of sequence variants in CKM (creatine kinase, muscle) and COX4I2 (cytochrome c oxidase, subunit 4, isoform 2) genes with racing performance in Thoroughbred horses. Equine Vet. J. 42:569-575. https://doi.org/10.1111/j.2042-3306.2010.00181.x
  9. Gu, J., N. Orr, S. D. Park, L. M. Katz, G. Sulimova, D. E. MacHugh, and E. W. Hill. 2009. A genome scan for positive selection in thoroughbred horses. PloS one 4(6):e5767. https://doi.org/10.1371/journal.pone.0005767
  10. Hill, E. W., D. G. Bradley, M. Al-Barody, O. Ertugrul, R. K. Splan, I. Zakharov, and E. P. Cunningham. 2002. History and integrity of thoroughbred dam lines revealed in equine mtDNA variation. Anim. Genet. 33:287-294. https://doi.org/10.1046/j.1365-2052.2002.00870.x
  11. Hill, E. W., S. S. Eivers, B. A. McGivney, R. G. Fonseca, J. Gu, N. A. Smith, J. A. Browne, D. E. MacHugh, and L. M. Katz. 2010a. Moderate and high intensity sprint exercise induce differential responses in COX4I2 and PDK4 gene expression in Thoroughbred horse skeletal muscle. Equine Vet. J. 42:576-581.
  12. Hill, E. W., J. Gu, B. A. McGivney, and D. E. MacHugh. 2010b. Targets of selection in the Thoroughbred genome contain exercise-relevant gene SNPs associated with elite racecourse performance. Anim. Genet. 41:56-63. https://doi.org/10.1111/j.1365-2052.2010.02104.x
  13. Hill, E. W., J. Gu, S. S. Eivers, R. G. Fonseca, B. A. McGivney, P. Govindarajan, N. Orr, L. M. Katz, and D. MacHugh. 2010c. A sequence polymorphism in MSTN predicts sprinting ability and racing stamina in thoroughbred horses. PLoS One 5:(1) e8645. https://doi.org/10.1371/journal.pone.0008645
  14. Hill, E. W., B. A. McGivney, J. Gu, R. Whiston, and D. E. MacHugh. 2010d. A genome-wide SNP-association study confirms a sequence variant (g. 66493737C> T) in the equine myostatin (MSTN) gene as the most powerful predictor of optimum racing distance for Thoroughbred racehorses. BMC Genomics 11:552. https://doi.org/10.1186/1471-2164-11-552
  15. Jelinsky, S. A., J. Archambault, L. Li, and H. Seeherman. 2010. Tendon-selective genes identified from rat and human musculoskeletal tissues. J. Orthop. Res. 28:289-297.
  16. Jorgensen, T. J., I. Ruczinski, B. Kessing, M. W. Smith, Y. Y. Shugart, and A. J. Alberg. 2009. Hypothesis-driven candidate gene association studies: practical design and analytical considerations. Am. J. Epidemiol. 170:986-993. https://doi.org/10.1093/aje/kwp242
  17. Kim, J., T. Lowe, and T. Hoppe. 2008. Protein quality control gets muscle into shape. Trends Cell Biol. 18:264-272. https://doi.org/10.1016/j.tcb.2008.03.007
  18. Kimball, S. R., T. C. Vary, and L. S. Jefferson. 1994. Regulation of protein synthesis by insulin. Ann. Rev. Physiol. 56:321-348. https://doi.org/10.1146/annurev.ph.56.030194.001541
  19. Ko, J.-A., Y. Kimura, K. Matsuura, H. Yamamoto, T. Gondo, and M. Inui. 2006. PDZRN3 (LNX3, SEMCAP3) is required for the differentiation of C2C12 myoblasts into myotubes. J. Cell Sci. 119:5106-5113. https://doi.org/10.1242/jcs.03290
  20. Liscurn, L. 2002. Cholesterol biosynthesis. New Comprehensive Biochemistry 36:409-431. https://doi.org/10.1016/S0167-7306(02)36017-4
  21. Moritsu, Y., H. Funakoshi, and S. Ichikawa. 1994. Genetic evaluation of sires and environmental factors influencing best racing times of Thoroughbred horses in Japan. J. Equine Sci. 5:53-58. https://doi.org/10.1294/jes.5.53
  22. Moschella, M. C., J. Watras, T. Jayaraman, and A. R. Marks. 1995. Inositol 1, 4, 5-trisphosphate receptor in skeletal muscle: differential expression in myofibres. J. Muscle Res. Cell Motil. 16:390-400. https://doi.org/10.1007/BF00114504
  23. Mota, M. D. S., A. R. Abrahao, and H. N. Oliveira. 2005. Genetic and environmental parameters for racing time at different distances in Brazilian Thoroughbreds. J. Anim. Breed. Genet. 122:393-399. https://doi.org/10.1111/j.1439-0388.2005.00551.x
  24. Myers, A. J., J. R. Gibbs, J. A. Webster, K. Rohrer, A. Zhao, L. Marlowe, M. Kaleem, D. Leung, L. Bryden, P. Nath et al. 2007. A survey of genetic human cortical gene expression. Nat. Genet. 39:1494-1499. https://doi.org/10.1038/ng.2007.16
  25. O'Connor, M. S., M. E. Carlson, and I. M. Conboy. 2009. Differentiation rather than aging of muscle stem cells abolishes their telomerase activity. Biotechnol. Prog. 25:1130-1137. https://doi.org/10.1002/btpr.223
  26. Oki, H., Y. Sasaki, and R. L. Willham. 1994. Genetics of racing performance in the Japanese Thoroughbred horse. J. Anim. Breed, Genet. 111:128-137. https://doi.org/10.1111/j.1439-0388.1994.tb00446.x
  27. Ooms, L., K. Horan, P. Rahman, G. Seaton, R. Gurung, D. Kethesparan, and C. Mitchell. 2009. The role of the inositol polyphosphate 5-phosphatases in cellular function and human disease. Biochem. J. 419:29-49. https://doi.org/10.1042/BJ20081673
  28. Park, J.-E., J.-R. Lee, S. Oh, J. W. Lee, H.-S. Oh, and H. Kim. 2011. Principal components analysis applied to genetic evaluation of racing performance of Thoroughbred race horses in Korea. Livest. Sci. 135:293-299. https://doi.org/10.1016/j.livsci.2010.07.014
  29. Purcell, S., B. Neale, K. Todd-Brown, L. Thomas, M. A. R. Ferreira, D. Bender, J. Maller, P. Sklar, P. I. W. De Bakker, M. J. Daly, and P. C. Sham. 2007. PLINK: a tool set for wholegenome association and population-based linkage analyses. Am. J. Hum. Genet. 81:559-575. https://doi.org/10.1086/519795
  30. Richards, J. B., D. Waterworth, S. O'Rahilly, M.-F. Hivert, R. J. F. Loos, J. R. B. Perry, T. Tanaka, N. J. Timpson, R. K. Semple, N. Soranzo et al. 2009. A genome-wide association study reveals variants in ARL15 that influence adiponectin levels. PLoS Genet. 5(12):e1000768. https://doi.org/10.1371/journal.pgen.1000768
  31. Skol, A. D., L. J. Scott, G. R. Abecasis, and M. Boehnke. 2006. Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat. Genet. 38:209-213. https://doi.org/10.1038/ng1706
  32. Skol, A. D., L. J. Scott, G. R. Abecasis, and M. Boehnke. 2007. Optimal designs for two-stage genome-wide association studies. Genet. Epidemiol. 31:776-788. https://doi.org/10.1002/gepi.20240
  33. Szustakowski, J. D., J.-H. Lee, C. A. Marrese, P. A. Kosinski, N. Nirmala, and D. M. Kemp. 2006. Identification of novel pathway regulation during myogenic differentiation. Genomics 87:129-138. https://doi.org/10.1016/j.ygeno.2005.08.009
  34. Thomas, D., R. Xie, and M. Gebregziabher. 2004. Two-Stage sampling designs for gene association studies. Genet. Epidemiol. 27:401-414. https://doi.org/10.1002/gepi.20047
  35. Tozaki, T., E. W. Hill, K. Hirota, H. Kakoi, H. Gawahara, T. Miyake, S. Sugita, T. Hasegawa, N. Ishida, Y. Nakano, and M. Kurosawa. 2012. A cohort study of racing performance in Japanese Thoroughbred racehorses using genome information on ECA18. Anim. Genet. 43:42-52. https://doi.org/10.1111/j.1365-2052.2011.02201.x
  36. Tozaki, T., T. Miyake, H. Kakoi, H. Gawahara, S. Sugita, T. Hasegawa, N. Ishida, K. Hirota, and Y. Nakano. 2010. A genome-wide association study for racing performances in Thoroughbreds clarifies a candidate region near the MSTN gene. Anim. Genet. 41:28-35. https://doi.org/10.1111/j.1365-2052.2010.02095.x
  37. Velleman, S. G., J. Shin, X. Li, and Y. Song. 2012. Review: The skeletal muscle extracellular matrix: Possible roles in the regulation of muscle development and growth. Can. J. Anim. Sci. 92:1-10. https://doi.org/10.4141/cjas2011-098

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