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PLoS genetics2013; 9(1); e1003211; doi: 10.1371/journal.pgen.1003211

Genome-wide analysis reveals selection for important traits in domestic horse breeds.

Abstract: Intense selective pressures applied over short evolutionary time have resulted in homogeneity within, but substantial variation among, horse breeds. Utilizing this population structure, 744 individuals from 33 breeds, and a 54,000 SNP genotyping array, breed-specific targets of selection were identified using an F(ST)-based statistic calculated in 500-kb windows across the genome. A 5.5-Mb region of ECA18, in which the myostatin (MSTN) gene was centered, contained the highest signature of selection in both the Paint and Quarter Horse. Gene sequencing and histological analysis of gluteal muscle biopsies showed a promoter variant and intronic SNP of MSTN were each significantly associated with higher Type 2B and lower Type 1 muscle fiber proportions in the Quarter Horse, demonstrating a functional consequence of selection at this locus. Signatures of selection on ECA23 in all gaited breeds in the sample led to the identification of a shared, 186-kb haplotype including two doublesex related mab transcription factor genes (DMRT2 and 3). The recent identification of a DMRT3 mutation within this haplotype, which appears necessary for the ability to perform alternative gaits, provides further evidence for selection at this locus. Finally, putative loci for the determination of size were identified in the draft breeds and the Miniature horse on ECA11, as well as when signatures of selection surrounding candidate genes at other loci were examined. This work provides further evidence of the importance of MSTN in racing breeds, provides strong evidence for selection upon gait and size, and illustrates the potential for population-based techniques to find genomic regions driving important phenotypes in the modern horse.
Publication Date: 2013-01-17 PubMed ID: 23349635PubMed Central: PMC3547851DOI: 10.1371/journal.pgen.1003211Google Scholar: Lookup
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  • Journal Article
  • Research Support
  • N.I.H.
  • Extramural
  • Research Support
  • Non-U.S. Gov't
  • Research Support
  • U.S. Gov't
  • Non-P.H.S.

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The study delves into the genetics of various horse breeds, identifying specific patterns of selection for traits such as size, gait, and muscle fiber composition. Particularly, it looks into two genes–MSTN and DMRT3–which respectively influence muscle fiber and gait in horses. These genes have been selected for in different breeds leading to diverse physical attributes.

Genome-Wide Analysis and Selection Traits

  • The research utilized a pool of 744 individual horses from 33 different breeds and a 54,000 SNP genotyping array. Selection pressures applied over a short evolutionary time have caused homogeneity within breeds but considerable variation between them.
  • The study focused on identifying breed-specific selection targets by using an F(ST)-based statistic calculated across 500-kb windows of the genome. This approach identifies areas of the genome where there is a statistically significant amount of variation between the selected populations.

The Role of MSTN and DMRT3 Genes

  • The MSTN gene positioned on the ECA18 chromosome exhibited a significant signature of selection in both the Paint and Quarter Horse breeds.
  • Sequencing of this gene and histological analysis of muscle biopsies revealed that variations of MSTN were significantly associated with changes in muscle fiber composition. Specifically, certain variations were linked with higher Type 2B and lower Type 1 muscle fiber proportions in the Quarter Horse. This shows that selection at this locus had tangible effects on the muscle composition of certain horse breeds.
  • On chromosome ECA23, strong signatures of selection were spotted in all gaited breeds involved in the study and it led to the discovery of a shared, 186-kb haplotype including two genes related to the “doublesex” mab transcription factor genes (DMRT2 and DMRT3).
  • A mutation in the DMRT3 gene within this haplotype appears necessary for alternative gaits. The recent identification of this mutation adds further evidence of selection happening at this locus.

Identification of Loci influencing Size

  • The researchers also identified potential loci for the determination of size in draft breeds and the Miniature horse on chromosome ECA11.
  • Other loci that were potentially under selection surrounding candidate genes were also examined, providing more details on how selection has been shaping diverse horse phenotypes.

In summary, this research underscores the importance of the MSTN gene in racing breeds, shows strong evidence for the selection of gait and size, and demonstrates the potential of population-based techniques to find genomic regions influencing crucial phenotypes in modern horses.

Cite This Article

APA
Petersen JL, Mickelson JR, Rendahl AK, Valberg SJ, Andersson LS, Axelsson J, Bailey E, Bannasch D, Binns MM, Borges AS, Brama P, da Câmara Machado A, Capomaccio S, Cappelli K, Cothran EG, Distl O, Fox-Clipsham L, Graves KT, Guérin G, Haase B, Hasegawa T, Hemmann K, Hill EW, Leeb T, Lindgren G, Lohi H, Lopes MS, McGivney BA, Mikko S, Orr N, Penedo MC, Piercy RJ, Raekallio M, Rieder S, Røed KH, Swinburne J, Tozaki T, Vaudin M, Wade CM, McCue ME. (2013). Genome-wide analysis reveals selection for important traits in domestic horse breeds. PLoS Genet, 9(1), e1003211. https://doi.org/10.1371/journal.pgen.1003211

Publication

ISSN: 1553-7404
NlmUniqueID: 101239074
Country: United States
Language: English
Volume: 9
Issue: 1
Pages: e1003211

Researcher Affiliations

Petersen, Jessica L
  • College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota, USA. jlpeters@umn.edu
Mickelson, James R
    Rendahl, Aaron K
      Valberg, Stephanie J
        Andersson, Lisa S
          Axelsson, Jeanette
            Bailey, Ernie
              Bannasch, Danika
                Binns, Matthew M
                  Borges, Alexandre S
                    Brama, Pieter
                      da Câmara Machado, Artur
                        Capomaccio, Stefano
                          Cappelli, Katia
                            Cothran, E Gus
                              Distl, Ottmar
                                Fox-Clipsham, Laura
                                  Graves, Kathryn T
                                    Guérin, Gérard
                                      Haase, Bianca
                                        Hasegawa, Telhisa
                                          Hemmann, Karin
                                            Hill, Emmeline W
                                              Leeb, Tosso
                                                Lindgren, Gabriella
                                                  Lohi, Hannes
                                                    Lopes, Maria Susana
                                                      McGivney, Beatrice A
                                                        Mikko, Sofia
                                                          Orr, Nicholas
                                                            Penedo, M Cecilia T
                                                              Piercy, Richard J
                                                                Raekallio, Marja
                                                                  Rieder, Stefan
                                                                    Røed, Knut H
                                                                      Swinburne, June
                                                                        Tozaki, Teruaki
                                                                          Vaudin, Mark
                                                                            Wade, Claire M
                                                                              McCue, Molly E

                                                                                MeSH Terms

                                                                                • Animals
                                                                                • Biological Evolution
                                                                                • Breeding
                                                                                • Genome-Wide Association Study
                                                                                • Genotype
                                                                                • Haplotypes
                                                                                • Horses / genetics
                                                                                • Myostatin / genetics
                                                                                • Phenotype
                                                                                • Polymorphism, Single Nucleotide
                                                                                • Selection, Genetic

                                                                                Grant Funding

                                                                                • K08 AR055713 / NIAMS NIH HHS
                                                                                • T32 AR007612 / NIAMS NIH HHS
                                                                                • 1K08AR055713-01A2 / NIAMS NIH HHS
                                                                                • 2T32AR007612 / NIAMS NIH HHS

                                                                                Conflict of Interest Statement

                                                                                Equinome Ltd. (EWH, Director) has been granted a license for commercial use of MSTN data as contained within patent applications: U.S. Provisional Serial Number 61/136553; Irish Patent Application Numbers 2008/0735 and 2010/0151; and Patent Cooperation Treaty number PCT/IE2009/000062. The PCT publication WO2010/029527A published 18 March 2010. Title: “A method for predicting athletics performance potential” and U.S. publication US2011/0262915 published 27 October 2011. Title: “Method for predicting the athletic performance potential of a subject.” EWH, NO, and BAM are named on the applications. MMB works for The Genetic Edge, previously published a paper on the association between SNPs in the MSTN region and best racing distance for elite Thoroughbred horses [46], and uses these markers in commercial tests. LSA and GL are co-applicants on a patent application concerning the commercial utilization of the DMRT3 mutation. These commercial ventures had no influence on the interpretation of the results relating to myostatin or gait presented in the paper.

                                                                                References

                                                                                This article includes 89 references
                                                                                1. Lippold S, Matzke NJ, Reissmann M, Hofreiter M. Whole mitochondrial genome sequencing of domestic horses reveals incorporation of extensive wild horse diversity during domestication.. BMC Evol Biol 2011 11: 328.
                                                                                  pmc: PMC3247663pubmed: 22082251
                                                                                2. Ludwig A, Pruvost M, Reissmann M, Benecke N, Brockmann GA. Coat color variation at the beginning of horse domestication.. Science 2009 324: 485.
                                                                                  pmc: PMC5102060pubmed: 19390039
                                                                                3. Outram AK, Stear NA, Bendrey R, Olsen S, Kasparov A. The earliest horse harnessing and milking.. Science 2009 323: 1332–1335.
                                                                                  pubmed: 19265018
                                                                                4. Akey JM, Ruhe AL, Akey DT, Wong AK, Connelly CF. Tracking footprints of artificial selection in the dog genome.. PNAS 2010 107: 1160–1165.
                                                                                  pmc: PMC2824266pubmed: 20080661
                                                                                5. Olsson M, Meadows JR, Truve K, Rosengren Pielberg G, Puppo F. A novel unstable duplication upstream of HAS2 predisposes to a breed-defining skin phenotype and a periodic fever syndrome in Chinese Shar-Pei dogs.. PLoS Genet 2011 7: e1001332.
                                                                                6. Boyko AR, Quignon P, Li L, Schoenebeck JJ, Degenhardt JD. A simple genetic architecture underlies morphological variation in dogs.. PLoS Biol 2010 8: e1000451.
                                                                                7. Pollinger JP, Bustamante CD, Fledel-Alon A, Schmutz S, Gray MM. Selective sweep mapping of genes with large phenotypic effects.. Genome Res 2005 15: 1809–1819.
                                                                                  pmc: PMC1356119pubmed: 16339379
                                                                                8. Quilez J, Short AD, Martinez V, Kennedy LJ, Ollier W. A selective sweep of >8 Mb on chromosome 26 in the Boxer genome.. BMC Genomics 2011 12.
                                                                                  pmc: PMC3152542pubmed: 21722374
                                                                                9. Vaysse A, Ratnakumar A, Derrien T, Axelsson E, Rosengren Pielberg G. Identification of Genomic Regions Associated with Phenotypic Variation between Dog Breeds using Selection Mapping.. PLoS Genet 2011 7: e1002316.
                                                                                10. Barendse W, Harrison BE, Bunch RJ, Thomas MB, Turner LB. Genome wide signatures of positive selection: the comparison of independent samples and the identification of regions associated to traits.. BMC Genomics 2009 10: 178.
                                                                                  pmc: PMC2681478pubmed: 19393047
                                                                                11. Consortium TBH, Gibbs RA, Taylor JF, Van Tassell CP, Barendse W. Genome-wide survey of SNP variation uncovers the genetic structure of cattle breeds.. Science 2009 324: 528–532.
                                                                                  pmc: PMC2735092pubmed: 19390050
                                                                                12. Qanbari S, Gianola D, Hayes B, Schenkel F, Miller S. Application of site and haplotype-frequency based approaches for detecting selection signatures in cattle.. BMC Genomics 2011 12: 318.
                                                                                  pmc: PMC3146955pubmed: 21679429
                                                                                13. Qanbari S, Pimentel EC, Tetens J, Thaller G, Lichtner P. A genome-wide scan for signatures of recent selection in Holstein cattle.. Anim Genet 2010 41: 377–389.
                                                                                  pubmed: 20096028
                                                                                14. Kijas JW, Lenstra JA, Hayes B, Boitard S, Porto Neto LR. Genome-wide analysis of the world's sheep breeds reveals high levels of historic mixture and strong recent selection.. PLoS Biol 2012 10: e1001258.
                                                                                15. Gu J, Orr N, Park SD, Katz LM, Sulimova G. A genome scan for positive selection in thoroughbred horses.. PLoS ONE 2009 4: e5767.
                                                                                16. Marklund L, Moller MJ, Sandberg K, Andersson L. A missense mutation in the gene for melanocyte-stimulating hormone receptor (MC1R) is associated with the chestnut coat color in horses.. Mamm Genome 1996 7: 895–899.
                                                                                  pubmed: 8995760
                                                                                17. McCue ME, Bannasch DL, Petersen JL, Gurr J, Bailey E. A high density SNP array for the domestic horse and extant perissodactyla: utility for association mapping, genetic diversity, and phylogeny studies.. PLoS Genet 2012 8: e1002451.
                                                                                18. Bricker SJ, Penedo MCT, Millon LV, Murray JD. Linkage of the dun coat color locus to microsatellites on horse chomoromse 8. 2003; San Diego, CA.
                                                                                  pubmed: 12354140
                                                                                19. Hill EW, McGivney BA, Gu JJ, Whiston R, MacHugh DE. 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 2010 11.
                                                                                  pmc: PMC3091701pubmed: 20932346
                                                                                20. Hill EW, Gu J, Eivers SS, Fonseca RG, McGivney BA. A sequence polymorphism in MSTN predicts sprinting ability and racing stamina in thoroughbred horses.. PLoS ONE 2010 5: e8645.
                                                                                21. Dall'Olio S, Fontanesi L, Nanni Costa L, Tassinari M, Minieri L. Analysis of horse myostatin gene and identification of single nucleotide polymorphisms in breeds of different morphological types.. J Biomed Biotechnol ID542945.
                                                                                  pmc: PMC2913906pubmed: 20706663
                                                                                22. Clop A, Marcq F, Takeda H, Pirottin D, Tordoir X. A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep.. Nat Genet 2006 38: 813–818.
                                                                                  pubmed: 16751773
                                                                                23. Grobet L, Martin LJ, Poncelet D, Pirottin D, Brouwers B. A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle.. Nat Genet 1997 17: 71–74.
                                                                                  pubmed: 9288100
                                                                                24. McPherron AC, Lee SJ. Double muscling in cattle due to mutations in the myostatin gene.. PNAS 1997 94: 12457–12461.
                                                                                  pmc: PMC24998pubmed: 9356471
                                                                                25. Mosher DS, Quignon P, Bustamante CD, Sutter NB, Mellersh CS. A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote dogs.. PLoS Genet 2007 3: e79.
                                                                                26. Schuelke M, Wagner KR, Stolz LE, Hubner C, Riebel T. Myostatin mutation associated with gross muscle hypertrophy in a child.. N Engl J Med 2004 350: 2682–2688.
                                                                                  pubmed: 15215484
                                                                                27. Lindholm A, Piehl K. Fibre composition, enzyme activity and concentrations of metabolites and electrolytes in muscles of standardbred horses.. Acta Veterinaria Scandinavica 1974 15: 287–309.
                                                                                  pmc: PMC8407315pubmed: 4137664
                                                                                28. Galisteo AM, Aguera E, Monterde JG, Miro F. Gluteus-Medius Muscle-Fiber Type Composition in Young Andalusian and Arabian Horses.. J Equine Vet Sci 1992 12: 254–258.
                                                                                29. Lehnhard RA, McKeever KH, Kearns CF, Beekley MD. Myosin heavy chain profiles and body composition are different in old versus young Standardbred mares.. Vet J 2004 167: 59–66.
                                                                                  pubmed: 14623152
                                                                                30. Roneus M. Muscle characteristics in standardbreds of different ages and sexes.. Equine Vet J 1993 25: 143–146.
                                                                                  pubmed: 8467774
                                                                                31. Roneus M, Lindholm A, Asheim A. Muscle characteristics in Thoroughbreds of different ages and sexes.. Equine Vet J 1991 23: 207–210.
                                                                                  pubmed: 1884703
                                                                                32. Sabeti PC, Reich DE, Higgins JM, Levine HZ, Richter DJ. Detecting recent positive selection in the human genome from haplotype structure.. Nature 2002 419: 832–837.
                                                                                  pubmed: 12397357
                                                                                33. Brunberg E, Andersson L, Cothran G, Sandberg K, Mikko S. A missense mutation in PMEL17 is associated with the Silver coat color in the horse.. BMC Genet 2006 7: 46.
                                                                                  pmc: PMC1617113pubmed: 17029645
                                                                                34. Cook D, Brooks S, Bellone R, Bailey E. Missense mutation in exon 2 of SLC36A1 responsible for champagne dilution in horses.. PLoS Genet 2008 4: e1000195.
                                                                                35. Mariat D, Taourit S, Guerin G. A mutation in the MATP gene causes the cream coat colour in the horse.. Genet Sel Evol 2003 35: 119–133.
                                                                                  pmc: PMC2732686pubmed: 12605854
                                                                                36. Reissmann M, Bierwolf J, Brockmann GA. Two SNPs in the SILV gene are associated with silver coat colour in ponies.. Anim Genet 2007 38: 1–6.
                                                                                  pubmed: 17257181
                                                                                37. Rieder S, Taourit S, Mariat D, Langlois B, Guerin G. Mutations in the agouti (ASIP), the extension (MC1R), and the brown (TYRP1) loci and their association to coat color phenotypes in horses (Equus caballus).. Mamm Genome 2001 12: 450–455.
                                                                                  pubmed: 11353392
                                                                                38. Rosengren Pielberg G, Golovko A, Sundstrom E, Curik I, Lennartsson J. A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse.. Nat Genet 2008 40: 1004–1009.
                                                                                  pubmed: 18641652
                                                                                39. Terry RB, Archer S, Brooks S, Bernoco D, Bailey E. Assignment of the appaloosa coat colour gene (LP) to equine chromosome 1.. Anim Genet 2004 35: 134–137.
                                                                                  pubmed: 15025575
                                                                                40. Hendricks BL. International Encyclopedia of Horse Breeds.. 2007 Norman: University of Oklahoma Pres. 486 p.
                                                                                41. Weatherley L. Great Horses of Britain.. 1978 Hindhead: Spur Publications. viii, 269 p.
                                                                                42. Lee SJ. Regulation of muscle mass by myostatin.. Annu Rev Cell Dev Biol 2004 20: 61–86.
                                                                                  pubmed: 15473835
                                                                                43. Girgenrath S, Song K, Whittemore LA. Loss of myostatin expression alters fiber-type distribution and expression of myosin heavy chain isoforms in slow- and fast-type skeletal muscle.. Muscle Nerve 2005 31: 34–40.
                                                                                  pubmed: 15468312
                                                                                44. Hennebry A, Berry C, Siriett V, O'Callaghan P, Chau L. Myostatin regulates fiber-type composition of skeletal muscle by regulating MEF2 and MyoD gene expression.. Am J Physiol Cell Physiol 2009 296: C525–534.
                                                                                  pubmed: 19129464
                                                                                45. Wegner J, Albrecht E, Fiedler I, Teuscher F, Papstein HJ. Growth- and breed-related changes of muscle fiber characteristics in cattle.. J Anim Sci 2000 78: 1485–1496.
                                                                                  pubmed: 10875630
                                                                                46. Binns MM, Boehler DA, Lambert DH. Identification of the myostatin locus (MSTN) as having a major effect on optimum racing distance in the Thoroughbred horse in the USA.. Anim Genet 2010 41 Suppl 2: 154–158.
                                                                                  pubmed: 21070290
                                                                                47. Hill EW, Fonseca RG, McGivney BA, Gu J, MacHugh DE. MSTN genotype (g.66493737C/T) association with speed indices in Thoroughbred racehorses.. J Appl Phys 2012 112: 86–90.
                                                                                  pubmed: 22016373
                                                                                48. Tozaki T, Hill EW, Hirota K, Kakoi H, Gawahara H. A cohort study of racing performance in Japanese Thoroughbred racehorses using genome information on ECA18.. Anim Genet 2012 43: 42–52.
                                                                                  pubmed: 22221024
                                                                                49. Tozaki T, Sato F, Hill EW, Miyake T, Endo Y. Sequence Variants at the myostatin Gene Locus Influence the Body Composition of Thoroughbred Horses.. J Vet Med Sci 2011 73: 1617–1624.
                                                                                  pubmed: 21836385
                                                                                50. Elashry MI, Otto A, Matsakas A, El-Morsy SE, Patel K. Morphology and myofiber composition of skeletal musculature of the forelimb in young and aged wild type and myostatin null mice.. Rejuv Res 2009 12: 269–281.
                                                                                  pubmed: 19725775
                                                                                51. McGivney BA, Browne JA, Fonseca RG, Katz LM, MacHugh DE. MSTN genotypes in Thoroughbred horses influence skeletal muscle gene expression and racetrack performance.. Anim Genet 2012 43: 810–812.
                                                                                  pubmed: 22497477
                                                                                52. Allen DL, Unterman TG. Regulation of myostatin expression and myoblast differentiation by FoxO and SMAD transcription factors.. Am J Physiol Cell Physiol 2007 292: C188–199.
                                                                                  pubmed: 16885393
                                                                                53. Guimaraes SEF, Stahl CH, Lonergan SM, Geiger B, Rothschild MF. Myostatin promoter analysis and expression pattern in pigs.. Livestock Sci 2007 112: 143–150.
                                                                                54. Salerno MS, Thomas M, Forbes D, Watson T, Kambadur R. Molecular analysis of fiber type-specific expression of murine myostatin promoter.. Am J Physiol Cell Physiol 2004 287: C1031–1040.
                                                                                  pubmed: 15189813
                                                                                55. Spiller MP, Kambadur R, Jeanplong F, Thomas M, Martyn JK. The myostatin gene is a downstream target gene of basic helix-loop-helix transcription factor MyoD.. Mol Cell Biol 2002 22: 7066–7082.
                                                                                  pmc: PMC139803pubmed: 12242286
                                                                                56. Raymond CS, Shamu CE, Shen MM, Seifert KJ, Hirsch B. Evidence for evolutionary conservation of sex-determining genes.. Nature 1998 391: 691–695.
                                                                                  pubmed: 9490411
                                                                                57. Yi W, Zarkower D. Similarity of DNA binding and transcriptional regulation by Caenorhabditis elegans MAB-3 and Drosophila melanogaster DSX suggests conservation of sex determining mechanisms.. Development 1999 126: 873–881.
                                                                                  pubmed: 9927589
                                                                                58. Hong CS, Park BY, Saint-Jeannet JP. The function of Dmrt genes in vertebrate development: it is not just about sex.. Dev Biol 2007 310: 1–9.
                                                                                  pubmed: 17720152
                                                                                59. Andersson LS, Larhammar M, Memic F, Wootz H, Schwochow D. Mutations in DMRT3 alter locomotion in horses and spinal circuit function in mice.. Nature 2012 488: 642–646.
                                                                                  pmc: PMC3523687pubmed: 22932389
                                                                                60. Thiruvenkadan AK, Kandasamy N, Panneerselvam S. Inheritance of racing performance of trotter horses: An overview.. Livestock Sci 2009 124: 163–181.
                                                                                61. Gu J, MacHugh DE, McGivney BA, Park SD, Katz LM. 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 2010 42 Suppl 38: 569–575.
                                                                                  pubmed: 21059062
                                                                                62. Hill EW, Gu J, McGivney BA, MacHugh DE. Targets of selection in the Thoroughbred genome contain exercise-relevant gene SNPs associated with elite racecourse performance.. Anim Genet 2010 41 Suppl 2: 56–63.
                                                                                  pubmed: 21070277
                                                                                63. Chase K, Jones P, Martin A, Ostrander EA, Lark KG. Genetic mapping of fixed phenotypes: disease frequency as a breed characteristic.. J Hered 2009 100 Suppl 1: S37–41.
                                                                                  pmc: PMC3139361pubmed: 19321632
                                                                                64. Jones P, Chase K, Martin A, Davern P, Ostrander EA. Single-nucleotide-polymorphism-based association mapping of dog stereotypes.. Genetics 2008 179: 1033–1044.
                                                                                  pmc: PMC2429857pubmed: 18505865
                                                                                65. Sutter NB, Bustamante CD, Chase K, Gray MM, Zhao K. A single IGF1 allele is a major determinant of small size in dogs.. Science 2007 316: 112–115.
                                                                                  pmc: PMC2789551pubmed: 17412960
                                                                                66. Eberlein A, Takasuga A, Setoguchi K, Pfuhl R, Flisikowski K. Dissection of genetic factors modulating fetal growth in cattle indicates a substantial role of the non-SMC condensin I complex, subunit G (NCAPG) gene.. Genetics 2009 183: 951–964.
                                                                                  pmc: PMC2778990pubmed: 19720859
                                                                                67. Setoguchi K, Furuta M, Hirano T, Nagao T, Watanabe T. Cross-breed comparisons identified a critical 591-kb region for bovine carcass weight QTL (CW-2) on chromosome 6 and the Ile-442-Met substitution in NCAPG as a positional candidate.. BMC Genet 2009 10: 43.
                                                                                  pmc: PMC2736976pubmed: 19653884
                                                                                68. Setoguchi K, Watanabe T, Weikard R, Albrecht E, Kuhn C. The SNP c.1326T>G in the non-SMC condensin I complex, subunit G (NCAPG) gene encoding a p.Ile442Met variant is associated with an increase in body frame size at puberty in cattle.. Anim Genet 2011 42: 650–655.
                                                                                  pubmed: 22035007
                                                                                69. Gudbjartsson DF, Walters GB, Thorleifsson G, Stefansson H, Halldorsson BV. Many sequence variants affecting diversity of adult human height.. Nat Genet 2008 40: 609–615.
                                                                                  pubmed: 18391951
                                                                                70. Soranzo N, Rivadeneira F, Chinappen-Horsley U, Malkina I, Richards JB. Meta-analysis of genome-wide scans for human adult stature identifies novel loci and associations with measures of skeletal frame size.. PLoS Genet 2009 5: e1000445.
                                                                                71. Weedon MN, Lango H, Lindgren CM, Wallace C, Evans DM. Genome-wide association analysis identifies 20 loci that influence adult height.. Nat Genet 2008 40: 575–583.
                                                                                  pmc: PMC2681221pubmed: 18391952
                                                                                72. Brooks SA, Makvandi-Nejad S, Chu E, Allen JJ, Streeter C. Morphological variation in the horse: defining complex traits of body size and shape.. Anim Genet 2010 41 Suppl 2: 159–165.
                                                                                  pubmed: 21070291
                                                                                73. Makvandi-Nejad S, Hoffman GE, Allen JJ, Chu E, Gu E. Four Loci explain 83% of size variation in the horse.. PLoS ONE 2012 7: e39929.
                                                                                74. Signer-Hasler H, Flury C, Haase B, Burger D, Simianer H. A genome-wide association study reveals loci influencing height and other conformation traits in horses.. PLoS ONE 2012 7: e37282.
                                                                                75. Baker J, Liu JP, Robertson EJ, Efstratiadis A. Role of insulin-like growth factors in embryonic and postnatal growth.. Cell 1993 75: 73–82.
                                                                                  pubmed: 8402902
                                                                                76. Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r).. Cell 1993 75: 59–72.
                                                                                  pubmed: 8402901
                                                                                77. Okada Y, Kamatani Y, Takahashi A, Matsuda K, Hosono N. A genome-wide association study in 19 633 Japanese subjects identified LHX3-QSOX2 and IGF1 as adult height loci.. Hum Mol Genet 2010 19: 2303–2312.
                                                                                  pubmed: 20189936
                                                                                78. Woods KA, Camacho-Hubner C, Barter D, Clark AJ, Savage MO. Insulin-like growth factor I gene deletion causing intrauterine growth retardation and severe short stature.. Acta Paediatr Suppl 1997 423: 39–45.
                                                                                  pubmed: 9401537
                                                                                79. Pryce JE, Hayes BJ, Bolormaa S, Goddard ME. Polymorphic regions affecting human height also control stature in cattle.. Genetics 2011 187: 981–984.
                                                                                  pmc: PMC3048786pubmed: 21212230
                                                                                80. Visscher PM. Sizing up human height variation.. Nat Genet 2008 40: 489–490.
                                                                                  pubmed: 18443579
                                                                                81. Weedon MN, Lettre G, Freathy RM, Lindgren CM, Voight BF. A common variant of HMGA2 is associated with adult and childhood height in the general population.. Nat Genet 2007 39: 1245–1250.
                                                                                  pmc: PMC3086278pubmed: 17767157
                                                                                82. Monzen K, Ito Y, Naito AT, Kasai H, Hiroi Y. A crucial role of a high mobility group protein HMGA2 in cardiogenesis.. Nat Cell Biol 2008 10: 567–574.
                                                                                  pubmed: 18425117
                                                                                83. Maurano MT, Humber R, Rynes E, Thurman RE, Haugen E. Systematic localization of common disease-associated variation in regulatory DNA.. Science 2012 337: 1190–1195.
                                                                                  pmc: PMC3771521pubmed: 22955828
                                                                                84. Bernstein BE, Birney E, Dunham I, Green ED, Gunter C. An integrated encyclopedia of DNA elements in the human genome.. Nature 2012 489: 57–74.
                                                                                  pmc: PMC3439153pubmed: 22955616
                                                                                85. Vernot B, Stergachis AB, Maurano MT, Vierstr J, Neph S. Personal and population genomics of human regulatory variation.. Genome Res 2012 22: 1689–1697.
                                                                                  pmc: PMC3431486pubmed: 22955981
                                                                                86. Purcell S, Neale B, Tood-Brown K, Thomas L, Ferreira MAR. PLINK: a toolset for whole-genome association and population-based linkage analysis.. Amer J Hum Genet 2007 81: 559–575.
                                                                                  pmc: PMC1950838pubmed: 17701901
                                                                                87. Lettre G, Jackson AU, Gieger C, Schumacher FR, Berndt SI. Identification of ten loci associated with height highlights new biological pahtways in human growth.. Nat Genet 2008 40: 584–591.
                                                                                  pmc: PMC2687076pubmed: 18391950
                                                                                88. Scheet P, Stephens M. A fast and flexible statistical model for large-scale population genotype data: applications to inferring missing genotypes and haplotypic phase.. Am J Hum Genet 2006 78: 629–644.
                                                                                  pmc: PMC1424677pubmed: 16532393
                                                                                89. Rozen S, Skaletsky H. Primer3 on the WWW for general users and for biologist programmers.. 2000 In: Krawetz S, Misener S, editors. Bioinformatics Methods and Protocols: Methods in Molecular Biology. Humana Press, Totowa, NJ, pp 365–386.
                                                                                  pubmed: 10547847