A potential regulatory region near the EDN3 gene may control both harness racing performance and coat color variation in horses.
- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
The research investigates genetic factors influencing racing performance and coat color variation in horses, focusing specifically on the Endothelin3 gene (EDN3).
Understanding the Study
The principal objective of this research study was to pinpoint genetic variances that have been acquired through selective breeding for harness racing performance. In this context, the research studied three breeds of horses:
- The Swedish-Norwegian Coldblooded trotter – a breed selected for racing performance
- The North-Swedish draught horse – primarily used for agricultural/forestry work and considered close to the ancestral gene pool
- The Standardbreds – used for harness racing, like the Coldblooded trotters
The researchers scanned the genomes of these horse breeds to identify single-nucleotide polymorphisms (SNPs) – variations at a single position in a DNA sequence among individuals. They anticipated that genetic selection towards racing aptitude, coupled with unauthorized crossbreeding between Coldblooded trotters and Standardbreds, might have resulted in specific gene regions in which these two breeds are similar, differing from the North-Swedish draught horse.
Methods and Analysis
At the core of their approach was the fixation index (Fst) analysis. This method calculates the difference between genetic diversity within a species and genetic diversity across different species. The study generated ‘sliding window Delta Fst values’ to identify areas of the genome where variation was most significant across breeds. They eventually selected five windows, characterized by both low Fst values between Coldblooded trotters and Standardbreds (indicating shared genes likely due to racing selection or crossbreeding) and high Fst values between Coldblooded trotters and North-Swedish draught horses (indicating genetic difference).
Findings of the Study
A subsequent analysis linked one of the top-ranked SNPs with racing performance in a tested group of 400 raced Coldblooded trotters. The CC genotype of this SNP was found to have a negative association with racing performance. When this SNP was observed in a larger group of 1915 horses from 18 breeds, they found that high-performance breeds (used for racing and show jumping) typically had the TT genotype, while lower-performance breeds (ponies and draught horses) frequently had the CC genotype.
Interestingly, the gene proximate to this performance-related SNP was the EDN3, mainly involved in melanocyte (cells responsible for pigmentation) and enteric neuron (neurons governing gut function) development, suggesting it may influence both performance and coat color. However, the exact influence of the EDN3 gene on racing performance remains to be clarified through in-depth functional genetic and physiological studies.
Cite This Article
Publication
Researcher Affiliations
- Department of Animal Breeding & Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.
- Department of Animal Breeding & Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.
- Department of Animal Breeding & Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.
- Faculty of Science, University of Sydney, Sydney, Australia.
- Faculty of Science, University of Sydney, Sydney, Australia.
- Department of Animal Breeding & Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas.
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
- Department of Animal Breeding & Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.
MeSH Terms
- Animals
- Endothelin-3 / genetics
- Female
- Gene Frequency
- Haplotypes
- Horses / genetics
- Male
- Norway
- Polymorphism, Single Nucleotide
- Regulatory Sequences, Nucleic Acid
- Running
- Selective Breeding
- Sweden
References
- Andersson LS, Larhammar M, Memic F, Wootz H, Schwochow D, Rubin CJ, Patra K, Arnason T, Wellbring L, Hju00e4lm G, Imsland F, Petersen JL, McCue ME, Mickelson JR, Cothran G, Ahituv N, Roepstorff L, Mikko S, Vallstedt A, Lindgren G, Andersson L, Kullander K. Mutations in DMRT3 affect locomotion in horses and spinal circuit function in mice.. Nature 2012 Aug 30;488(7413):642-6.
- u00c1rnason, T . 1994. The importance of different traits in genetic improvement of trotters. Proceedings of World Congress on Genetics Applied to Livestock Production. University of Guelph, Guelph, Canada. August 7u201012, 17: 462u2010469.
- u00c1rnason, T. 2001. Trends and asymptotic limits for racing speed in Standardbred trotters. Livest. Prod. Sci. 72:135u2013145.
- u00c1rnason, T. , Bendroth M., Philipsson J., Henriksson K., and Darenius A.. 1989. Genetic evaluations of Swedish trotters. Pp. 106u2013129 in Langlois B., ed. State of breeding evaluation in trotters. Proceedings of the European Federation of Animal Science symposium of the Commission on horse production, 1 July 1989, Helsinki, Finland. European Federation of Animal Science publication no. 42. Pudoc, Wageningen, The Netherlands.
- Baynash AG, Hosoda K, Giaid A, Richardson JA, Emoto N, Hammer RE, Yanagisawa M. Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons.. Cell 1994 Dec 30;79(7):1277-85.
- Benamou AE, Art T, Marlin DJ, Roberts CA, Lekeux P. Variations in systemic and pulmonary endothelin-1 in horses with recurrent airway obstruction (heaves).. Pulm Pharmacol Ther 1998 Apr-Jun;11(2-3):231-5.
- 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 Dec;41 Suppl 2:154-8.
- Bohlin, O. , and Ru00f6nningen K.. 1975. Inbreeding and relationship within the Northu2010Swedish horse. Acta Agric. Scand. 25:121u2013125.
- Brown AH. The estimation of Wright's fixation index from genotypic frequencies.. Genetica 1970;41(3):399-406.
- Edery P, Attiu00e9 T, Amiel J, Pelet A, Eng C, Hofstra RM, Martelli H, Bidaud C, Munnich A, Lyonnet S. Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome).. Nat Genet 1996 Apr;12(4):442-4.
- Evans DL. Physiology of equine performance and associated tests of function.. Equine Vet J 2007 Jul;39(4):373-83.
- Gu J, Orr N, Park SD, Katz LM, Sulimova G, MacHugh DE, Hill EW. A genome scan for positive selection in thoroughbred horses.. PLoS One 2009 Jun 2;4(6):e5767.
- Gu J, MacHugh DE, McGivney BA, Park SD, Katz LM, Hill EW. 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 Suppl 2010 Nov;(38):569-75.
- Hill EW, Gu J, Eivers SS, Fonseca RG, McGivney BA, Govindarajan P, Orr N, Katz LM, MacHugh DE. A sequence polymorphism in MSTN predicts sprinting ability and racing stamina in thoroughbred horses.. PLoS One 2010 Jan 20;5(1):e8645.
- 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 Dec;41 Suppl 2:56-63.
- Hofstra RM, Osinga J, Tan-Sindhunata G, Wu Y, Kamsteeg EJ, Stulp RP, van Ravenswaaij-Arts C, Majoor-Krakauer D, Angrist M, Chakravarti A, Meijers C, Buys CH. A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome).. Nat Genet 1996 Apr;12(4):445-7.
- Hosoda K, Hammer RE, Richardson JA, Baynash AG, Cheung JC, Giaid A, Yanagisawa M. Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice.. Cell 1994 Dec 30;79(7):1267-76.
- Inoue A, Yanagisawa M, Kimura S, Kasuya Y, Miyauchi T, Goto K, Masaki T. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes.. Proc Natl Acad Sci U S A 1989 Apr;86(8):2863-7.
- Ehret GB, Munroe PB, Rice KM, Bochud M, Johnson AD, Chasman DI, Smith AV, Tobin MD, Verwoert GC, Hwang SJ, Pihur V, Vollenweider P, O'Reilly PF, Amin N, Bragg-Gresham JL, Teumer A, Glazer NL, Launer L, Zhao JH, Aulchenko Y, Heath S, Su00f5ber S, Parsa A, Luan J, Arora P, Dehghan A, Zhang F, Lucas G, Hicks AA, Jackson AU, Peden JF, Tanaka T, Wild SH, Rudan I, Igl W, Milaneschi Y, Parker AN, Fava C, Chambers JC, Fox ER, Kumari M, Go MJ, van der Harst P, Kao WH, Sju00f6gren M, Vinay DG, Alexander M, Tabara Y, Shaw-Hawkins S, Whincup PH, Liu Y, Shi G, Kuusisto J, Tayo B, Seielstad M, Sim X, Nguyen KD, Lehtimu00e4ki T, Matullo G, Wu Y, Gaunt TR, Onland-Moret NC, Cooper MN, Platou CG, Org E, Hardy R, Dahgam S, Palmen J, Vitart V, Braund PS, Kuznetsova T, Uiterwaal CS, Adeyemo A, Palmas W, Campbell H, Ludwig B, Tomaszewski M, Tzoulaki I, Palmer ND, Aspelund T, Garcia M, Chang YP, O'Connell JR, Steinle NI, Grobbee DE, Arking DE, Kardia SL, Morrison AC, Hernandez D, Najjar S, McArdle WL, Hadley D, Brown MJ, Connell JM, Hingorani AD, Day IN, Lawlor DA, Beilby JP, Lawrence RW, Clarke R, Hopewell JC, Ongen H, Dreisbach AW, Li Y, Young JH, Bis JC, Ku00e4hu00f6nen M, Viikari J, Adair LS, Lee NR, Chen MH, Olden M, Pattaro C, Bolton JA, Ku00f6ttgen A, Bergmann S, Mooser V, Chaturvedi N, Frayling TM, Islam M, Jafar TH, Erdmann J, Kulkarni SR, Bornstein SR, Gru00e4ssler J, Groop L, Voight BF, Kettunen J, Howard P, Taylor A, Guarrera S, Ricceri F, Emilsson V, Plump A, Barroso I, Khaw KT, Weder AB, Hunt SC, Sun YV, Bergman RN, Collins FS, Bonnycastle LL, Scott LJ, Stringham HM, Peltonen L, Perola M, Vartiainen E, Brand SM, Staessen JA, Wang TJ, Burton PR, Soler Artigas M, Dong Y, Snieder H, Wang X, Zhu H, Lohman KK, Rudock ME, Heckbert SR, Smith NL, Wiggins KL, Doumatey A, Shriner D, Veldre G, Viigimaa M, Kinra S, Prabhakaran D, Tripathy V, Langefeld CD, Rosengren A, Thelle DS, Corsi AM, Singleton A, Forrester T, Hilton G, McKenzie CA, Salako T, Iwai N, Kita Y, Ogihara T, Ohkubo T, Okamura T, Ueshima H, Umemura S, Eyheramendy S, Meitinger T, Wichmann HE, Cho YS, Kim HL, Lee JY, Scott J, Sehmi JS, Zhang W, Hedblad B, Nilsson P, Smith GD, Wong A, Narisu N, Stanu010du00e1kovu00e1 A, Raffel LJ, Yao J, Kathiresan S, O'Donnell CJ, Schwartz SM, Ikram MA, Longstreth WT Jr, Mosley TH, Seshadri S, Shrine NR, Wain LV, Morken MA, Swift AJ, Laitinen J, Prokopenko I, Zitting P, Cooper JA, Humphries SE, Danesh J, Rasheed A, Goel A, Hamsten A, Watkins H, Bakker SJ, van Gilst WH, Janipalli CS, Mani KR, Yajnik CS, Hofman A, Mattace-Raso FU, Oostra BA, Demirkan A, Isaacs A, Rivadeneira F, Lakatta EG, Orru M, Scuteri A, Ala-Korpela M, Kangas AJ, Lyytiku00e4inen LP, Soininen P, Tukiainen T, Wu00fcrtz P, Ong RT, Du00f6rr M, Kroemer HK, Vu00f6lker U, Vu00f6lzke H, Galan P, Hercberg S, Lathrop M, Zelenika D, Deloukas P, Mangino M, Spector TD, Zhai G, Meschia JF, Nalls MA, Sharma P, Terzic J, Kumar MV, Denniff M, Zukowska-Szczechowska E, Wagenknecht LE, Fowkes FG, Charchar FJ, Schwarz PE, Hayward C, Guo X, Rotimi C, Bots ML, Brand E, Samani NJ, Polasek O, Talmud PJ, Nyberg F, Kuh D, Laan M, Hveem K, Palmer LJ, van der Schouw YT, Casas JP, Mohlke KL, Vineis P, Raitakari O, Ganesh SK, Wong TY, Tai ES, Cooper RS, Laakso M, Rao DC, Harris TB, Morris RW, Dominiczak AF, Kivimaki M, Marmot MG, Miki T, Saleheen D, Chandak GR, Coresh J, Navis G, Salomaa V, Han BG, Zhu X, Kooner JS, Melander O, Ridker PM, Bandinelli S, Gyllensten UB, Wright AF, Wilson JF, Ferrucci L, Farrall M, Tuomilehto J, Pramstaller PP, Elosua R, Soranzo N, Sijbrands EJ, Altshuler D, Loos RJ, Shuldiner AR, Gieger C, Meneton P, Uitterlinden AG, Wareham NJ, Gudnason V, Rotter JI, Rettig R, Uda M, Strachan DP, Witteman JC, Hartikainen AL, Beckmann JS, Boerwinkle E, Vasan RS, Boehnke M, Larson MG, Ju00e4rvelin MR, Psaty BM, Abecasis GR, Chakravarti A, Elliott P, van Duijn CM, Newton-Cheh C, Levy D, Caulfield MJ, Johnson T. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.. Nature 2011 Sep 11;478(7367):103-9.
- Ju00e4derkvist Fegraeus K, Lawrence C, Petu00e4jistu00f6 K, Johansson MK, Wiklund M, Olsson C, Andersson L, Andersson LS, Ru00f8ed KH, Ihler CF, Strand E, Lindgren G, Velie BD. Lack of significant associations with early career performance suggest no link between the DMRT3 "Gait Keeper" mutation and precocity in Coldblooded trotters.. PLoS One 2017;12(5):e0177351.
- Ju00e4derkvist K, Andersson LS, Johansson AM, u00c1rnason T, Mikko S, Eriksson S, Andersson L, Lindgren G. The DMRT3 'Gait keeper' mutation affects performance of Nordic and Standardbred trotters.. J Anim Sci 2014 Oct;92(10):4279-86.
- Kusafuka T, Wang Y, Puri P. Mutation analysis of the RET, the endothelin-B receptor, and the endothelin-3 genes in sporadic cases of Hirschsprung's disease.. J Pediatr Surg 1997 Mar;32(3):501-4.
- Lee HO, Levorse JM, Shin MK. The endothelin receptor-B is required for the migration of neural crest-derived melanocyte and enteric neuron precursors.. Dev Biol 2003 Jul 1;259(1):162-75.
- Levy D, Ehret GB, Rice K, Verwoert GC, Launer LJ, Dehghan A, Glazer NL, Morrison AC, Johnson AD, Aspelund T, Aulchenko Y, Lumley T, Ku00f6ttgen A, Vasan RS, Rivadeneira F, Eiriksdottir G, Guo X, Arking DE, Mitchell GF, Mattace-Raso FU, Smith AV, Taylor K, Scharpf RB, Hwang SJ, Sijbrands EJ, Bis J, Harris TB, Ganesh SK, O'Donnell CJ, Hofman A, Rotter JI, Coresh J, Benjamin EJ, Uitterlinden AG, Heiss G, Fox CS, Witteman JC, Boerwinkle E, Wang TJ, Gudnason V, Larson MG, Chakravarti A, Psaty BM, van Duijn CM. Genome-wide association study of blood pressure and hypertension.. Nat Genet 2009 Jun;41(6):677-87.
- McKeever KH, Antas LA, Kearns CF. Endothelin response during and after exercise in horses.. Vet J 2002 Jul;164(1):38-46.
- Metallinos DL, Bowling AT, Rine J. A missense mutation in the endothelin-B receptor gene is associated with Lethal White Foal Syndrome: an equine version of Hirschsprung disease.. Mamm Genome 1998 Jun;9(6):426-31.
- Puffenberger EG, Hosoda K, Washington SS, Nakao K, deWit D, Yanagisawa M, Chakravart A. A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung's disease.. Cell 1994 Dec 30;79(7):1257-66.
- 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 Sep;81(3):559-75.
- nR Development Core Teamn. 2016. nR: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria: Available at http://www.r-project.org/(accessed 01 February 2018).
- Santschi EM, Purdy AK, Valberg SJ, Vrotsos PD, Kaese H, Mickelson JR. Endothelin receptor B polymorphism associated with lethal white foal syndrome in horses.. Mamm Genome 1998 Apr;9(4):306-9.
- Schru00f6der W, Klostermann A, Distl O. Candidate genes for physical performance in the horse.. Vet J 2011 Oct;190(1):39-48.
- nnSinnwell, J. P.n, and Schaid D. J.. 2016. nHaplo. stats: statistical analysis of haplotypes with traits and covariates when linkage phase is ambiguous. R package version 1.7.7. Available at http://www.mayo.edu/research/labs/statistical-genetics-genetic-epidemiology/software (accessed 01 February 2018)
- Sponenberg, D. P . 2009. Mealy: definition and classification Pp. 32u201335 in Sponenberg D. P., ed. Equine color genetics. 3rd ed. Wileyu2010Blackwell, Hobeken, NJ.
- Stanchina L, Baral V, Robert F, Pingault V, Lemort N, Pachnis V, Goossens M, Bondurand N. Interactions between Sox10, Edn3 and Ednrb during enteric nervous system and melanocyte development.. Dev Biol 2006 Jul 1;295(1):232-49.
- Thiruvenkadan, A. K. , Kandasamy N., and Panneerselvam S.. 2009. Inheritance of racing performance of trotter horses: an overview. Livest Sci. 124:163u2013181.
- Thomas KC, Hamilton NA, North KN, Houweling PJ. Sequence analysis of the equine ACTN3 gene in Australian horse breeds.. Gene 2014 Mar 15;538(1):88-93.
- nValutan. 9999. Available at https://www.valuta.se (accessed 04 June 2016).
- Velie BD, Shrestha M, Franu04abois L, Schurink A, Tesfayonas YG, Stinckens A, Blott S, Ducro BJ, Mikko S, Thomas R, Swinburne JE, Sundqvist M, Eriksson S, Buys N, Lindgren G. Using an Inbred Horse Breed in a High Density Genome-Wide Scan for Genetic Risk Factors of Insect Bite Hypersensitivity (IBH).. PLoS One 2016;11(4):e0152966.
- Wade CM, Giulotto E, Sigurdsson S, Zoli M, Gnerre S, Imsland F, Lear TL, Adelson DL, Bailey E, Bellone RR, Blu00f6cker H, Distl O, Edgar RC, Garber M, Leeb T, Mauceli E, MacLeod JN, Penedo MC, Raison JM, Sharpe T, Vogel J, Andersson L, Antczak DF, Biagi T, Binns MM, Chowdhary BP, Coleman SJ, Della Valle G, Fryc S, Guu00e9rin G, Hasegawa T, Hill EW, Jurka J, Kiialainen A, Lindgren G, Liu J, Magnani E, Mickelson JR, Murray J, Nergadze SG, Onofrio R, Pedroni S, Piras MF, Raudsepp T, Rocchi M, Ru00f8ed KH, Ryder OA, Searle S, Skow L, Swinburne JE, Syvu00e4nen AC, Tozaki T, Valberg SJ, Vaudin M, White JR, Zody MC, Lander ES, Lindblad-Toh K. Genome sequence, comparative analysis, and population genetics of the domestic horse.. Science 2009 Nov 6;326(5954):865-7.
- Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells.. Nature 1988 Mar 31;332(6163):411-5.
- Yang GC, Croaker D, Zhang AL, Manglick P, Cartmill T, Cass D. A dinucleotide mutation in the endothelin-B receptor gene is associated with lethal white foal syndrome (LWFS); a horse variant of Hirschsprung disease.. Hum Mol Genet 1998 Jun;7(6):1047-52.
Citations
This article has been cited 8 times.- Perdomo-Gonzu00e1lez DI, Garcu00eda de Paredes RLA, Valera M, Bartolomu00e9 E, Gu00f3mez MD. Morpho-Functional Traits in Pura Raza Menorquina Horses: Genetic Parameters and Relationship with Coat Color Variables.. Animals (Basel) 2022 Sep 7;12(18).
- Ricard A, Duluard A. Genomic analysis of gaits and racing performance of the French trotter.. J Anim Breed Genet 2021 Mar;138(2):204-222.
- Silva ILS, Junqueira GSB, Oliveira CAA, Costa RB, DE Camargo GMF. Inconsistencies in horse coat color registration: A case study.. J Equine Sci 2020 Oct;31(3):57-60.
- Li D, Sun G, Zhang M, Cao Y, Zhang C, Fu Y, Li F, Li G, Jiang R, Han R, Li Z, Wang Y, Tian Y, Liu X, Li W, Kang X. Breeding history and candidate genes responsible for black skin of Xichuan black-bone chicken.. BMC Genomics 2020 Jul 23;21(1):511.
- Pu Y, Zhang Y, Zhang T, Han J, Ma Y, Liu X. Identification of Novel lncRNAs Differentially Expressed in Placentas of Chinese Ningqiang Pony and Yili Horse Breeds.. Animals (Basel) 2020 Jan 11;10(1).
- Grilz-Seger G, Neuditschko M, Ricard A, Velie B, Lindgren G, Mesariu010d M, Cotman M, Horna M, Dobretsberger M, Brem G, Druml T. Genome-Wide Homozygosity Patterns and Evidence for Selection in a Set of European and Near Eastern Horse Breeds.. Genes (Basel) 2019 Jun 28;10(7).
- Velie BD, Solu00e9 M, Fegraeus KJ, Rosengren MK, Ru00f8ed KH, Ihler CF, Strand E, Lindgren G. Genomic measures of inbreeding in the Norwegian-Swedish Coldblooded Trotter and their associations with known QTL for reproduction and health traits.. Genet Sel Evol 2019 May 27;51(1):22.
- Velie BD, Lillie M, Fegraeus KJ, Rosengren MK, Solu00e9 M, Wiklund M, Ihler CF, Strand E, Lindgren G. Exploring the genetics of trotting racing ability in horses using a unique Nordic horse model.. BMC Genomics 2019 Feb 4;20(1):104.