FREE SHIPPING over $40
OVER 9000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
Home / Equine Research Bank / J Hered / Evidence of positive selection for a glycogen synthase (GYS1...
The Journal of heredity2013; 105(2); 163-172; doi: 10.1093/jhered/est075

Evidence of positive selection for a glycogen synthase (GYS1) mutation in domestic horse populations.

Abstract: A dominantly inherited gain-of-function mutation in the glycogen synthase (GYS1) gene, resulting in excess skeletal muscle glycogen, has been identified in more than 30 horse breeds. This mutation is associated with the disease Equine Polysaccharide Storage Myopathy Type 1, yet persists at high frequency in some breeds. Under historical conditions of daily work and limited feed, excess muscle glycogen may have been advantageous, driving the increase in frequency of this allele. Fine-scale DNA sequencing in 80 horses and genotype assays in 279 horses revealed a paucity of haplotypes carrying the mutant allele when compared with the wild-type allele. Additionally, we found increased linkage disequilibrium, measured by relative extended haplotype homozygosity, in haplotypes carrying the mutation compared with haplotypes carrying the wild-type allele. Coalescent simulations of Belgian horse populations demonstrated that the high frequency and extended haplotype associated with the GYS1 mutation were unlikely to have arisen under neutrality or due to population demography. In contrast, in Quarter Horses, elevated relative extended haplotype homozygosity was associated with multiple haplotypes and may be the result of recent population expansion or a popular sire effect. These data suggest that the GYS1 mutation underwent historical selection in the Belgian, but not in the Quarter Horse.
Get Full Text
Publication Date: 2013-11-08 PubMed ID: 24215078PubMed Central: PMC3920812DOI: 10.1093/jhered/est075Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Journal Article
  • Research Support
  • N.I.H.
  • Extramural
  • Research Support
  • Non-U.S. Gov't

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.

This research investigates a mutation in the glycogen synthase gene in horses which results in overproduction of muscle glycogen and is linked to a disease, yet remains prevalent in some breeds. The study suggests the mutation was historically advantageous, increasing its frequency, while DNA sequencing and genotype tests indicate the mutation is not neutral or driven by population demographics. The results suggest selective breeding in some horse breeds, not others.

Understanding the GYS1 Mutation

  • The researchers analyzed a specific mutation in the glycogen synthase (GYS1) gene in domestic horses. This gene encodes an enzyme that regulates the conversion of glucose to glycogen, a type of sugar that is stored in muscles.
  • A mutation in this gene—known as a gain-of-function mutation—leads to overproduction of muscle glycogen. This excess glycogen is associated with a disease known as Equine Polysaccharide Storage Myopathy Type 1. Despite this, the mutation remains prevalent in several horse breeds, raising questions about its persistence.

Advantages of the GYS1 Mutation

  • The researchers hypothesize that under particular historical conditions—such as daily work and limited feed availability—the excessive muscle glycogen may have been advantageous to horses. This could explain the increased frequency of this mutation in certain breeds.

Methods for Studying the GYS1 Mutation

  • To further investigate, the researchers undertook fine-scale DNA sequencing in 80 horses and genotype assays in 279 horses.
  • They compared the number of haplotypes (groups of genes inherited together) carrying the mutant allele (a variant form of a gene) with those carrying the wild-type allele (the standard form of a gene).

Results from GYS1 Mutation Investigation

  • The results revealed an increased degree of linkage disequilibrium in haplotypes carrying the mutation. Linkage disequilibrium refers to a situation where the occurrence of some combinations of alleles or genetic markers in a genetic locus is higher or lower than expected.
  • Conversely, the researchers found fewer haplotypes carrying the mutant allele compared with the wild-type allele.

Interpretation of Results and Conclusion

  • The researchers conducted coalescent simulations (modeling of genealogical processes) on Belgian horse populations and found that the high frequency and associated haplotype of the GYS1 mutation were unlikely to have arisen under neutrality or due to population demographics.
  • However, in Quarter Horses, elevated relative extended haplotype homozygosity was associated with multiple haplotypes, likely due to recent population expansion or a popular sire effect.
  • This finding indicates that the occurrence and persistence of the GYS1 mutation in certain horse breeds may have been shaped by selective breeding. However, this selection process is not evident in all horse breeds, suggesting varied evolutionary processes across different breeds.

Cite This Article

APA
McCoy AM, Schaefer R, Petersen JL, Morrell PL, Slamka MA, Mickelson JR, Valberg SJ, McCue ME. (2013). Evidence of positive selection for a glycogen synthase (GYS1) mutation in domestic horse populations. J Hered, 105(2), 163-172. https://doi.org/10.1093/jhered/est075

Publication

The Journal of heredity
ISSN: 1465-7333
NlmUniqueID: 0375373
Country: United States
Language: English
Volume: 105
Issue: 2
Pages: 163-172

Researcher Affiliations

McCoy, Annette M
  • the Veterinary Population Medicine Department, 225 Veterinary Medical Center, University of Minnesota, 1365 Gortner Avenue, St Paul, MN 55108.
Schaefer, Robert
    Petersen, Jessica L
      Morrell, Peter L
        Slamka, Megan A
          Mickelson, James R
            Valberg, Stephanie J
              McCue, Molly E

                MeSH Terms

                • Alleles
                • Animals
                • Breeding
                • Genetic Predisposition to Disease
                • Glycogen / chemistry
                • Glycogen Storage Disease / genetics
                • Glycogen Synthase / genetics
                • Haplotypes
                • Homozygote
                • Horse Diseases / genetics
                • Horses / genetics
                • Muscle, Skeletal / chemistry
                • Mutation
                • Selection, Genetic
                • Sequence Analysis, DNA

                Grant Funding

                • T32 AR007612 / NIAMS NIH HHS
                • K08 AR055713 / NIAMS NIH HHS
                • 1K08AR055713-01A2 / NIAMS NIH HHS
                • T32 OD010993 / NIH HHS
                • T32OD10993 / NIH HHS

                References

                This article includes 45 references
                1. Aylor DL, Price EW, Carbone I. SNAP: Combine and Map modules for multilocus population genetic analysis.. Bioinformatics 2006 Jun 1;22(11):1399-401.
                  pubmed: 16601003doi: 10.1093/bioinformatics/btl136google scholar: lookup
                2. Baird JD, Valberg SJ, Anderson SM, McCue ME, Mickelson JR. Presence of the glycogen synthase 1 (GYS1) mutation causing type 1 polysaccharide storage myopathy in continental European draught horse breeds.. Vet Rec 2010 Nov 13;167(20):781-4.
                  pubmed: 21262610doi: 10.1136/vr.c3447google scholar: lookup
                3. Bedford HE, Valberg SJ, Firshman AM, Lucio M, Boyce MK, Trumble TN. Histopathologic findings in the sacrocaudalis dorsalis medialis muscle of horses with vitamin E-responsive muscle atrophy and weakness.. J Am Vet Med Assoc 2013 Apr 15;242(8):1127-37.
                  pubmed: 23547678doi: 10.2460/javma.242.8.1127google scholar: lookup
                4. Depaulis F, Veuille M. Neutrality tests based on the distribution of haplotypes under an infinite-site model.. Mol Biol Evol 1998 Dec;15(12):1788-90.
                  pubmed: 9917213doi: 10.1093/oxfordjournals.molbev.a025905google scholar: lookup
                5. Di Rienzo A. Population genetics models of common diseases.. Curr Opin Genet Dev 2006 Dec;16(6):630-6.
                  pubmed: 17055247doi: 10.1016/j.gde.2006.10.002google scholar: lookup
                6. Di Rienzo A, Hudson RR. An evolutionary framework for common diseases: the ancestral-susceptibility model.. Trends Genet 2005 Nov;21(11):596-601.
                  pubmed: 16153740doi: 10.1016/j.tig.2005.08.007google scholar: lookup
                7. Essén B, Lindholm A, Thornton J. Histochemical properties of muscle fibres types and enzyme activities in skeletal muscles of Standardbred trotters of different ages.. Equine Vet J 1980 Oct;12(4):175-80.
                  pubmed: 6449365doi: 10.1111/j.2042-3306.1980.tb03420.xgoogle scholar: lookup
                8. Firshman AM, Valberg SJ, Baird JD, Hunt L, DiMauro S. Insulin sensitivity in Belgian horses with polysaccharide storage myopathy.. Am J Vet Res 2008 Jun;69(6):818-23.
                  pubmed: 18518664doi: 10.2460/ajvr.69.6.818google scholar: lookup
                9. Firshman AM, Valberg SJ, Bender JB, Finno CJ. Epidemiologic characteristics and management of polysaccharide storage myopathy in Quarter Horses.. Am J Vet Res 2003 Oct;64(10):1319-27.
                  pubmed: 14596472doi: 10.2460/ajvr.2003.64.1319google scholar: lookup
                10. Flot JF. seqphase: a web tool for interconverting phase input/output files and fasta sequence alignments.. Mol Ecol Resour 2010 Jan;10(1):162-6.
                  pubmed: 21565002doi: 10.1111/j.1755-0998.2009.02732.xgoogle scholar: lookup
                11. Fu YX, Li WH. Statistical tests of neutrality of mutations.. Genetics 1993 Mar;133(3):693-709.
                  pmc: PMC1205353pubmed: 8454210doi: 10.1093/genetics/133.3.693google scholar: lookup
                12. Glick G, Shirak A, Uliel S, Zeron Y, Ezra E, Seroussi E, Ron M, Weller JI. Signatures of contemporary selection in the Israeli Holstein dairy cattle.. Anim Genet 2012 Jul;43 Suppl 1:45-55.
                  pubmed: 22742502doi: 10.1111/j.1365-2052.2012.02348.xgoogle scholar: lookup
                13. Hinchcliff KW, Geor RJ. The horse as an athlete: a physiological overview.. 2008; p. 2–11.
                14. Hudson RR. Two-locus sampling distributions and their application.. Genetics 2001 Dec;159(4):1805-17.
                  pmc: PMC1461925pubmed: 11779816doi: 10.1093/genetics/159.4.1805google scholar: lookup
                15. Hudson RR. Generating samples under a Wright-Fisher neutral model of genetic variation.. Bioinformatics 2002 Feb;18(2):337-8.
                  pubmed: 11847089doi: 10.1093/bioinformatics/18.2.337google scholar: lookup
                16. Hudson RR, Bailey K, Skarecky D, Kwiatowski J, Ayala FJ. Evidence for positive selection in the superoxide dismutase (Sod) region of Drosophila melanogaster.. Genetics 1994 Apr;136(4):1329-40.
                  pmc: PMC1205914pubmed: 8013910doi: 10.1093/genetics/136.4.1329google scholar: lookup
                17. Hudson RR, Kaplan NL. Statistical properties of the number of recombination events in the history of a sample of DNA sequences.. Genetics 1985 Sep;111(1):147-64.
                  pmc: PMC1202594pubmed: 4029609doi: 10.1093/genetics/111.1.147google scholar: lookup
                18. Innan H, Zhang K, Marjoram P, Tavaré S, Rosenberg NA. Statistical tests of the coalescent model based on the haplotype frequency distribution and the number of segregating sites.. Genetics 2005 Mar;169(3):1763-77.
                  pmc: PMC1449527pubmed: 15654103doi: 10.1534/genetics.104.032219google scholar: lookup
                19. Jose-Cunilleras E, Hinchcliff A. Carbohydrate metabolism in exercising horses.. Equine Comp Exerc Physiol 2004;1:23–32.
                20. Kelly JK. A test of neutrality based on interlocus associations.. Genetics 1997 Jul;146(3):1197-206.
                  pmc: PMC1208047pubmed: 9215920doi: 10.1093/genetics/146.3.1197google scholar: lookup
                21. Klopfstein S, Currat M, Excoffier L. The fate of mutations surfing on the wave of a range expansion.. Mol Biol Evol 2006 Mar;23(3):482-90.
                  pubmed: 16280540doi: 10.1093/molbev/msj057google scholar: lookup
                22. Lacombe VA, Hinchcliff KW, Geor RJ, Baskin CR. Muscle glycogen depletion and subsequent replenishment affect anaerobic capacity of horses.. J Appl Physiol (1985) 2001 Oct;91(4):1782-90.
                  pubmed: 11568163doi: 10.1152/jappl.2001.91.4.1782google scholar: lookup
                23. López-Rivero JL, Agüera E, Monterde JG, Vivo J, Rodríguez-Barbudo MV, Miró F. Comparative study of muscle fiber type composition in the middle gluteal muscle of Andalusian, Thoroughbred, and Arabian horses.. J Equine Vet Sci 1989;9:337–340.
                24. Maruyama T, Fuerst PA. Population bottlenecks and nonequilibrium models in population genetics. II. Number of alleles in a small population that was formed by a recent bottleneck.. Genetics 1985 Nov;111(3):675-89.
                  pmc: PMC1202664pubmed: 4054612doi: 10.1093/genetics/111.3.675google scholar: lookup
                25. Smith JM, Haigh J. The hitch-hiking effect of a favourable gene.. Genet Res 1974 Feb;23(1):23-35.
                  pubmed: 4407212
                26. McCue ME, Anderson SM, Valberg SJ, Piercy RJ, Barakzai SZ, Binns MM, Distl O, Penedo MC, Wagner ML, Mickelson JR. Estimated prevalence of the Type 1 Polysaccharide Storage Myopathy mutation in selected North American and European breeds.. Anim Genet 2010 Dec;41 Suppl 2:145-9.
                  pubmed: 21070288doi: 10.1111/j.1365-2052.2010.02124.xgoogle scholar: lookup
                27. McCue ME, Valberg SJ, Miller MB, Wade C, DiMauro S, Akman HO, Mickelson JR. Glycogen synthase (GYS1) mutation causes a novel skeletal muscle glycogenosis.. Genomics 2008 May;91(5):458-66.
                  pmc: PMC2430182pubmed: 18358695doi: 10.1016/j.ygeno.2008.01.011google scholar: lookup
                28. Minetti AE, ArdigO LP, Reinach E, Saibene F. The relationship between mechanical work and energy expenditure of locomotion in horses.. J Exp Biol 1999 Sep;202(Pt 17):2329-38.
                  pubmed: 10441084doi: 10.1242/jeb.202.17.2329google scholar: lookup
                29. NEEL JV. Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"?. Am J Hum Genet 1962 Dec;14(4):353-62.
                  pmc: PMC1932342pubmed: 13937884
                30. Petersen JL, Mickelson JR, Cothran EG, Andersson LS, Axelsson J, Bailey E, Bannasch D, Binns MM, Borges AS, Brama P, da Câmara Machado A, Distl O, Felicetti M, 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, Silvestrelli M, Swinburne J, Tozaki T, Vaudin M, M Wade C, McCue ME. Genetic diversity in the modern horse illustrated from genome-wide SNP data.. PLoS One 2013;8(1):e54997.
                  pmc: PMC3559798pubmed: 23383025doi: 10.1371/journal.pone.0054997google scholar: lookup
                31. Rubin CJ, Megens HJ, Martinez Barrio A, Maqbool K, Sayyab S, Schwochow D, Wang C, Carlborg Ö, Jern P, Jørgensen CB, Archibald AL, Fredholm M, Groenen MA, Andersson L. Strong signatures of selection in the domestic pig genome.. Proc Natl Acad Sci U S A 2012 Nov 27;109(48):19529-36.
                  pmc: PMC3511700pubmed: 23151514doi: 10.1073/pnas.1217149109google scholar: lookup
                32. Sabeti PC, Reich DE, Higgins JM, Levine HZ, Richter DJ, Schaffner SF, Gabriel SB, Platko JV, Patterson NJ, McDonald GJ, Ackerman HC, Campbell SJ, Altshuler D, Cooper R, Kwiatkowski D, Ward R, Lander ES. Detecting recent positive selection in the human genome from haplotype structure.. Nature 2002 Oct 24;419(6909):832-7.
                  pubmed: 12397357doi: 10.1038/nature01140google scholar: lookup
                33. Sabeti PC, Schaffner SF, Fry B, Lohmueller J, Varilly P, Shamovsky O, Palma A, Mikkelsen TS, Altshuler D, Lander ES. Positive natural selection in the human lineage.. Science 2006 Jun 16;312(5780):1614-20.
                  pubmed: 16778047doi: 10.1126/science.1124309google scholar: lookup
                34. 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 Apr;78(4):629-44.
                  pmc: PMC1424677pubmed: 16532393doi: 10.1086/502802google scholar: lookup
                35. Stanley RL, McCue ME, Valberg SJ, Mickelson JR, Mayhew IG, McGowan C, Hahn CN, Patterson-Kane JC, Piercy RJ. A glycogen synthase 1 mutation associated with equine polysaccharide storage myopathy and exertional rhabdomyolysis occurs in a variety of UK breeds.. Equine Vet J 2009 Jul;41(6):597-601.
                  pubmed: 19803057doi: 10.2746/042516409x407611google scholar: lookup
                36. Stephens M, Scheet P. Accounting for decay of linkage disequilibrium in haplotype inference and missing-data imputation.. Am J Hum Genet 2005 Mar;76(3):449-62.
                  pmc: PMC1196397pubmed: 15700229doi: 10.1086/428594google scholar: lookup
                37. Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data.. Am J Hum Genet 2001 Apr;68(4):978-89.
                  pmc: PMC1275651pubmed: 11254454doi: 10.1086/319501google scholar: lookup
                38. Tajima F. Evolutionary relationship of DNA sequences in finite populations.. Genetics 1983 Oct;105(2):437-60.
                  pmc: PMC1202167pubmed: 6628982doi: 10.1093/genetics/105.2.437google scholar: lookup
                39. Tajima F. Statistical method for testing the neutral mutation hypothesis by DNA polymorphism.. Genetics 1989 Nov;123(3):585-95.
                  pmc: PMC1203831pubmed: 2513255doi: 10.1093/genetics/123.3.585google scholar: lookup
                40. Thornton K. Libsequence: a C++ class library for evolutionary genetic analysis.. Bioinformatics 2003 Nov 22;19(17):2325-7.
                  pubmed: 14630667doi: 10.1093/bioinformatics/btg316google scholar: lookup
                41. Topliff DR, Potter GD, Dutson TR, Kreider JL, Jessup GT. Diet manipulation and muscle glycogen in the equine.. 1983; p. 119–124.
                42. Valberg SJ, Macleay JM, Billstrom JA, Hower-Moritz MA, Mickelson JR. Skeletal muscle metabolic response to exercise in horses with 'tying-up' due to polysaccharide storage myopathy.. Equine Vet J 1999 Jan;31(1):43-7.
                  pubmed: 9952328doi: 10.1111/j.2042-3306.1999.tb03789.xgoogle scholar: lookup
                43. Wade CM, Giulotto E, Sigurdsson S, Zoli M, Gnerre S, Imsland F, Lear TL, Adelson DL, Bailey E, Bellone RR, Blöcker 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, Guérin 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, Røed KH, Ryder OA, Searle S, Skow L, Swinburne JE, Syvänen 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.
                  pmc: PMC3785132pubmed: 19892987doi: 10.1126/science.1178158google scholar: lookup
                44. Warmuth V, Eriksson A, Bower MA, Barker G, Barrett E, Hanks BK, Li S, Lomitashvili D, Ochir-Goryaeva M, Sizonov GV, Soyonov V, Manica A. Reconstructing the origin and spread of horse domestication in the Eurasian steppe.. Proc Natl Acad Sci U S A 2012 May 22;109(21):8202-6.
                  pmc: PMC3361400pubmed: 22566639doi: 10.1073/pnas.1111122109google scholar: lookup
                45. Watterson GA. On the number of segregating sites in genetical models without recombination.. Theor Popul Biol 1975 Apr;7(2):256-76.
                  pubmed: 1145509doi: 10.1016/0040-5809(75)90020-9google scholar: lookup

                Citations

                This article has been cited 6 times.
                1. Wobbe M, Reinhardt F, Reents R, Tetens J, Stock KF. Quantifying the effect of Warmblood Fragile Foal Syndrome on foaling rates in the German riding horse population.. PLoS One 2022;17(7):e0267975.
                  doi: 10.1371/journal.pone.0267975pubmed: 35901076google scholar: lookup
                2. Zsoldos RR, Khayatzadeh N, Soelkner J, Schroeder U, Hahn C, Licka TF. Comparison of gluteus medius muscle activity in Haflinger and Noriker horses with polysaccharide storage myopathy.. J Anim Physiol Anim Nutr (Berl) 2021 May;105(3):549-557.
                  doi: 10.1111/jpn.13504pubmed: 33609063google scholar: lookup
                3. Beeson SK, Mickelson JR, McCue ME. Exploration of fine-scale recombination rate variation in the domestic horse.. Genome Res 2019 Oct;29(10):1744-1752.
                  doi: 10.1101/gr.243311.118pubmed: 31434677google scholar: lookup
                4. Avila F, Mickelson JR, Schaefer RJ, McCue ME. Genome-Wide Signatures of Selection Reveal Genes Associated With Performance in American Quarter Horse Subpopulations.. Front Genet 2018;9:249.
                  doi: 10.3389/fgene.2018.00249pubmed: 30105047google scholar: lookup
                5. Librado P, Fages A, Gaunitz C, Leonardi M, Wagner S, Khan N, Hanghøj K, Alquraishi SA, Alfarhan AH, Al-Rasheid KA, Der Sarkissian C, Schubert M, Orlando L. The Evolutionary Origin and Genetic Makeup of Domestic Horses.. Genetics 2016 Oct;204(2):423-434.
                  doi: 10.1534/genetics.116.194860pubmed: 27729493google scholar: lookup
                6. Maile CA, Hingst JR, Mahalingan KK, O'Reilly AO, Cleasby ME, Mickelson JR, McCue ME, Anderson SM, Hurley TD, Wojtaszewski JFP, Piercy RJ. A highly prevalent equine glycogen storage disease is explained by constitutive activation of a mutant glycogen synthase.. Biochim Biophys Acta Gen Subj 2017 Jan;1861(1 Pt A):3388-3398.
                  doi: 10.1016/j.bbagen.2016.08.021pubmed: 27592162google scholar: lookup
                Subscribe to our newsletter
                Join 99,357 horse owners like you who receive our email updates on horse health and nutrition.