BMC genomics2012; 13; 365; doi: 10.1186/1471-2164-13-365

Copy number expansion of the STX17 duplication in melanoma tissue from Grey horses.

Abstract: Greying with age in horses is an autosomal dominant trait, associated with loss of hair pigmentation, melanoma and vitiligo-like depigmentation. We recently identified a 4.6 kb duplication in STX17 to be associated with the phenotype. The aims of this study were to investigate if the duplication in Grey horses shows copy number variation and to exclude that any other polymorphism is uniquely associated with the Grey mutation. Results: We found little evidence for copy number expansion of the duplicated sequence in blood DNA from Grey horses. In contrast, clear evidence for copy number expansions was indicated in five out of eight tested melanoma tissues or melanoma cell lines. A tendency of a higher copy number in aggressive tumours was also found. Massively parallel resequencing of the ~350 kb Grey haplotype did not reveal any additional mutations perfectly associated with the phenotype, confirming the duplication as the true causative mutation. We identified three SNP alleles that were present in a subset of Grey haplotypes within the 350 kb region that shows complete linkage disequilibrium with the causative mutation. Thus, these three nucleotide substitutions must have occurred subsequent to the duplication, consistent with our interpretation that the Grey mutation arose more than 2,000 years before present. Conclusions: These results suggest that the mutation acts as a melanoma-driving regulatory element. The elucidation of the mechanistic features of the duplication will be of considerable interest for the characterization of these horse melanomas as well as for the field of human melanoma research.
Publication Date: 2012-08-02 PubMed ID: 22857264PubMed Central: PMC3443021DOI: 10.1186/1471-2164-13-365Google Scholar: Lookup
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  • 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.

The study investigates the presence of an expanded copy of a duplication specific to the STX17 gene in melanoma tissues from Grey horses. Grey horses specifically, exhibit aging-related greying, melanoma and vitiligo-like symptoms due to a 4.6 kb duplication in their STX17 gene. Blood DNA and melanoma tissues were used to show that this particular gene mutation drives the development of melanoma, and this finding can contribute to the field of human melanoma research.

Copy Number Variation in Grey Horses

  • The study aimed to find out if the duplication in STX17 in Grey horses shows copy number variation. Copy number variation refers to variations in the number of copies of a particular gene in the genome of an individual.
  • Another objective was to ensure that no other polymorphism was solely related to the Grey mutation. Polymorphism is the presence of genetic variation within a population, upon which natural selection can operate.
  • In blood DNA from Grey horses, there was little evidence for copy number expansion of the duplicated sequence.

Duplication Expansion in Melanoma Tissues

  • In contrast to the blood DNA, five out of the eight tested melanoma tissues or cell lines showed clear evidence of copy number expansions.
  • There was also an observed tendency of higher copy number in more aggressive tumours.

Resequencing of Grey Haplotype

  • The ~350 kb Grey haplotype was massively parallel re-sequenced, the process of sequencing DNA to detect mutations among other things.
  • It was confirmed that the Grey mutation is the true cause as no other mutations perfectly associated with the phenotype were found.
  • Three SNP alleles (variants of a gene) were present within the 350 kb region that shows complete linkage disequilibrium (non-random association) with the causative mutation.
  • These three nucleotide substitutions must have happened after the Grey mutation, further supporting the theory that the Grey mutation arose over 2000 years ago.

Conclusions and Further Research

  • The expansion of the duplication in the STX17 gene is suggested to act as a melanoma-driving regulatory element.
  • Understanding the mechanistic features of this duplication will be of considerable interest not only for characterizing these horse melanomas but also for human melanoma research.

Cite This Article

APA
Sundstru00f6m E, Imsland F, Mikko S, Wade C, Sigurdsson S, Pielberg GR, Golovko A, Curik I, Seltenhammer MH, Su00f6lkner J, Lindblad-Toh K, Andersson L. (2012). Copy number expansion of the STX17 duplication in melanoma tissue from Grey horses. BMC Genomics, 13, 365. https://doi.org/10.1186/1471-2164-13-365

Publication

ISSN: 1471-2164
NlmUniqueID: 100965258
Country: England
Language: English
Volume: 13
Pages: 365

Researcher Affiliations

Sundstru00f6m, Elisabeth
  • Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.
Imsland, Freyja
    Mikko, Sofia
      Wade, Claire
        Sigurdsson, Snaevar
          Pielberg, Gerli Rosengren
            Golovko, Anna
              Curik, Ino
                Seltenhammer, Monika H
                  Su00f6lkner, Johann
                    Lindblad-Toh, Kerstin
                      Andersson, Leif

                        MeSH Terms

                        • Alleles
                        • Animals
                        • Cell Line, Tumor
                        • DNA / blood
                        • DNA / metabolism
                        • DNA Copy Number Variations / genetics
                        • Gene Duplication
                        • Genome
                        • Genotype
                        • Haplotypes
                        • Horses / genetics
                        • Horses / metabolism
                        • Melanoma / genetics
                        • Melanoma / metabolism
                        • Melanoma / veterinary
                        • Phenotype
                        • Polymorphism, Single Nucleotide
                        • Qa-SNARE Proteins / genetics
                        • Qa-SNARE Proteins / metabolism
                        • Skin Neoplasms / genetics
                        • Skin Neoplasms / metabolism
                        • Skin Neoplasms / veterinary

                        References

                        This article includes 25 references
                        1. Lerner AB, Cage GW. Melanomas in horses.. Yale J Biol Med 1973 Dec;46(5):646-9.
                          pmc: PMC2592037pubmed: 4779136
                        2. Rosengren Pielberg G, Golovko A, Sundstru00f6m E, Curik I, Lennartsson J, Seltenhammer MH, Druml T, Binns M, Fitzsimmons C, Lindgren G, Sandberg K, Baumung R, Vetterlein M, Stru00f6mberg S, Grabherr M, Wade C, Lindblad-Toh K, Pontu00e9n F, Heldin CH, Su00f6lkner J, Andersson L. A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse.. Nat Genet 2008 Aug;40(8):1004-9.
                          doi: 10.1038/ng.185pubmed: 18641652google scholar: lookup
                        3. Sutton RH, Coleman GT. RIRDC Research Paper Series. Barton, Australia; 1997. Melanoma and the Graying Horse; pp. 1u201334.
                        4. Fleury C, Bu00e9rard F, Leblond A, Faure C, Ganem N, Thomas L. The study of cutaneous melanomas in Camargue-type gray-skinned horses (2): epidemiological survey.. Pigment Cell Res 2000 Feb;13(1):47-51.
                        5. Pielberg G, Mikko S, Sandberg K, Andersson L. Comparative linkage mapping of the Grey coat colour gene in horses.. Anim Genet 2005 Oct;36(5):390-5.
                        6. Feuk L, Carson AR, Scherer SW. Structural variation in the human genome.. Nat Rev Genet 2006 Feb;7(2):85-97.
                          pubmed: 16418744doi: 10.1038/nrg1767google scholar: lookup
                        7. Wright D, Boije H, Meadows JR, Bed'hom B, Gourichon D, Vieaud A, Tixier-Boichard M, Rubin CJ, Imsland F, Hallbu00f6u00f6k F, Andersson L. Copy number variation in intron 1 of SOX5 causes the Pea-comb phenotype in chickens.. PLoS Genet 2009 Jun;5(6):e1000512.
                        8. Johansson Moller M, Chaudhary R, Hellmu00e9n E, Hu00f6yheim B, Chowdhary B, Andersson L. Pigs with the dominant white coat color phenotype carry a duplication of the KIT gene encoding the mast/stem cell growth factor receptor.. Mamm Genome 1996 Nov;7(11):822-30.
                          doi: 10.1007/s003359900244pubmed: 8875890google scholar: lookup
                        9. Giuffra E, Tu00f6rnsten A, Marklund S, Bongcam-Rudloff E, Chardon P, Kijas JM, Anderson SI, Archibald AL, Andersson L. A large duplication associated with dominant white color in pigs originated by homologous recombination between LINE elements flanking KIT.. Mamm Genome 2002 Oct;13(10):569-77.
                          doi: 10.1007/s00335-002-2184-5pubmed: 12420135google scholar: lookup
                        10. Pielberg G, Olsson C, Syvu00e4nen AC, Andersson L. Unexpectedly high allelic diversity at the KIT locus causing dominant white color in the domestic pig.. Genetics 2002 Jan;160(1):305-11.
                          pmc: PMC1461930pubmed: 11805065doi: 10.1093/genetics/160.1.305google scholar: lookup
                        11. Gault J, Hopkins J, Berger R, Drebing C, Logel J, Walton C, Short M, Vianzon R, Olincy A, Ross RG, Adler LE, Freedman R, Leonard S. Comparison of polymorphisms in the alpha7 nicotinic receptor gene and its partial duplication in schizophrenic and control subjects.. Am J Med Genet B Neuropsychiatr Genet 2003 Nov 15;123B(1):39-49.
                          doi: 10.1002/ajmg.b.20061pubmed: 14582144google scholar: lookup
                        12. Traherne JA. Human MHC architecture and evolution: implications for disease association studies.. Int J Immunogenet 2008 Jun;35(3):179-92.
                        13. Shlien A, Malkin D. Copy number variations and cancer susceptibility.. Curr Opin Oncol 2010 Jan;22(1):55-63.
                          doi: 10.1097/CCO.0b013e328333dca4pubmed: 19952747google scholar: lookup
                        14. Weir BA, Woo MS, Getz G, Perner S, Ding L, Beroukhim R, Lin WM, Province MA, Kraja A, Johnson LA, Shah K, Sato M, Thomas RK, Barletta JA, Borecki IB, Broderick S, Chang AC, Chiang DY, Chirieac LR, Cho J, Fujii Y, Gazdar AF, Giordano T, Greulich H, Hanna M, Johnson BE, Kris MG, Lash A, Lin L, Lindeman N, Mardis ER, McPherson JD, Minna JD, Morgan MB, Nadel M, Orringer MB, Osborne JR, Ozenberger B, Ramos AH, Robinson J, Roth JA, Rusch V, Sasaki H, Shepherd F, Sougnez C, Spitz MR, Tsao MS, Twomey D, Verhaak RG, Weinstock GM, Wheeler DA, Winckler W, Yoshizawa A, Yu S, Zakowski MF, Zhang Q, Beer DG, Wistuba II, Watson MA, Garraway LA, Ladanyi M, Travis WD, Pao W, Rubin MA, Gabriel SB, Gibbs RA, Varmus HE, Wilson RK, Lander ES, Meyerson M. Characterizing the cancer genome in lung adenocarcinoma.. Nature 2007 Dec 6;450(7171):893-8.
                          doi: 10.1038/nature06358pmc: PMC2538683pubmed: 17982442google scholar: lookup
                        15. Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD, Girtman K, Mathew S, Ma J, Pounds SB, Su X, Pui CH, Relling MV, Evans WE, Shurtleff SA, Downing JR. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia.. Nature 2007 Apr 12;446(7137):758-64.
                          doi: 10.1038/nature05690pubmed: 17344859google scholar: lookup
                        16. Bastian BC, Olshen AB, LeBoit PE, Pinkel D. Classifying melanocytic tumors based on DNA copy number changes.. Am J Pathol 2003 Nov;163(5):1765-70.
                        17. 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.
                          doi: 10.1126/science.1178158pmc: PMC3785132pubmed: 19892987google scholar: lookup
                        18. Bailey JA, Gu Z, Clark RA, Reinert K, Samonte RV, Schwartz S, Adams MD, Myers EW, Li PW, Eichler EE. Recent segmental duplications in the human genome.. Science 2002 Aug 9;297(5583):1003-7.
                          doi: 10.1126/science.1072047pubmed: 12169732google scholar: lookup
                        19. Chapman SW, Metzger N, Grest P, Feige K, von Rechenberg B, Auer JA, Hottiger MO. Isolation, establishment, and characterization of ex vivo equine melanoma cell cultures.. In Vitro Cell Dev Biol Anim 2009 Mar-Apr;45(3-4):152-62.
                          pubmed: 19057970doi: 10.1007/s11626-008-9156-3google scholar: lookup
                        20. Ben-Izhak O, Bar-Chana M, Sussman L, Dobiner V, Sandbank J, Cagnano M, Cohen H, Sabo E. Ki67 antigen and PCNA proliferation markers predict survival in anorectal malignant melanoma.. Histopathology 2002 Dec;41(6):519-25.
                        21. Sundstru00f6m E, Komisarczuk AZ, Jiang L, Golovko A, Navratilova P, Rinkwitz S, Becker TS, Andersson L. Identification of a melanocyte-specific, microphthalmia-associated transcription factor-dependent regulatory element in the intronic duplication causing hair greying and melanoma in horses.. Pigment Cell Melanoma Res 2012 Jan;25(1):28-36.
                        22. Wong GK, Liu B, Wang J, Zhang Y, Yang X, Zhang Z, Meng Q, Zhou J, Li D, Zhang J, Ni P, Li S, Ran L, Li H, Zhang J, Li R, Li S, Zheng H, Lin W, Li G, Wang X, Zhao W, Li J, Ye C, Dai M, Ruan J, Zhou Y, Li Y, He X, Zhang Y, Wang J, Huang X, Tong W, Chen J, Ye J, Chen C, Wei N, Li G, Dong L, Lan F, Sun Y, Zhang Z, Yang Z, Yu Y, Huang Y, He D, Xi Y, Wei D, Qi Q, Li W, Shi J, Wang M, Xie F, Wang J, Zhang X, Wang P, Zhao Y, Li N, Yang N, Dong W, Hu S, Zeng C, Zheng W, Hao B, Hillier LW, Yang SP, Warren WC, Wilson RK, Brandstru00f6m M, Ellegren H, Crooijmans RP, van der Poel JJ, Bovenhuis H, Groenen MA, Ovcharenko I, Gordon L, Stubbs L, Lucas S, Glavina T, Aerts A, Kaiser P, Rothwell L, Young JR, Rogers S, Walker BA, van Hateren A, Kaufman J, Bumstead N, Lamont SJ, Zhou H, Hocking PM, Morrice D, de Koning DJ, Law A, Bartley N, Burt DW, Hunt H, Cheng HH, Gunnarsson U, Wahlberg P, Andersson L, Kindlund E, Tammi MT, Andersson B, Webber C, Ponting CP, Overton IM, Boardman PE, Tang H, Hubbard SJ, Wilson SA, Yu J, Wang J, Yang H. A genetic variation map for chicken with 2.8 million single-nucleotide polymorphisms.. Nature 2004 Dec 9;432(7018):717-22.
                          doi: 10.1038/nature03156pmc: PMC2263125pubmed: 15592405google scholar: lookup
                        23. Cao Y, Bryan TM, Reddel RR. Increased copy number of the TERT and TERC telomerase subunit genes in cancer cells.. Cancer Sci 2008 Jun;99(6):1092-9.
                        24. Li H, Ruan J, Durbin R. Mapping short DNA sequencing reads and calling variants using mapping quality scores.. Genome Res 2008 Nov;18(11):1851-8.
                          doi: 10.1101/gr.078212.108pmc: PMC2577856pubmed: 18714091google scholar: lookup
                        25. Mariat D, Taourit S, Guu00e9rin G. A mutation in the MATP gene causes the cream coat colour in the horse.. Genet Sel Evol 2003 Jan-Feb;35(1):119-33.
                          doi: 10.1186/1297-9686-35-1-119pmc: PMC2732686pubmed: 12605854google scholar: lookup

                        Citations

                        This article has been cited 18 times.
                        1. Pimenta J, Pires I, Prada J, Cotovio M. E-Cadherin Immunostaining in Equine Melanocytic Tumors.. Animals (Basel) 2023 Jul 6;13(13).
                          doi: 10.3390/ani13132216pubmed: 37444014google scholar: lookup
                        2. Bartolomu00e9 E, Perdomo-Gonzu00e1lez DI, Ripollu00e9s-Lobo M, Valera M. Basal Reactivity Evaluated by Infrared Thermography in the "Caballo de Deporte Espau00f1ol" Horse Breed According to Its Coat Color.. Animals (Basel) 2022 Sep 21;12(19).
                          doi: 10.3390/ani12192515pubmed: 36230256google scholar: lookup
                        3. Senczuk G, Landi V, Mastrangelo S, Persichilli C, Pilla F, Ciani E. Seven Shades of Grey: A Follow-Up Study on the Molecular Basis of Coat Colour in Indicine Grey Cattle Using Genome-Wide SNP Data.. Genes (Basel) 2022 Sep 7;13(9).
                          doi: 10.3390/genes13091601pubmed: 36140768google scholar: lookup
                        4. Weber LA, Delarocque J, Feige K, Kietzmann M, Kalbitz J, Meiu00dfner J, Paschke R, Cavalleri JV. Effects of Topically Applied Betulinic Acid and NVX-207 on Melanocytic Tumors in 18 Horses.. Animals (Basel) 2021 Nov 13;11(11).
                          doi: 10.3390/ani11113250pubmed: 34827981google scholar: lookup
                        5. Senczuk G, Guerra L, Mastrangelo S, Campobasso C, Zoubeyda K, Imane M, Marletta D, Kusza S, Karsli T, Gaouar SBS, Pilla F, Ciani E, The Bovita Consortium. Fifteen Shades of Grey: Combined Analysis of Genome-Wide SNP Data in Steppe and Mediterranean Grey Cattle Sheds New Light on the Molecular Basis of Coat Color.. Genes (Basel) 2020 Aug 13;11(8).
                          doi: 10.3390/genes11080932pubmed: 32823527google scholar: lookup
                        6. Guan D, Martu00ednez A, Castellu00f3 A, Landi V, Luigi-Sierra MG, Fernu00e1ndez-u00c1lvarez J, Cabrera B, Delgado JV, Such X, Jordana J, Amills M. A genome-wide analysis of copy number variation in Murciano-Granadina goats.. Genet Sel Evol 2020 Aug 8;52(1):44.
                          doi: 10.1186/s12711-020-00564-4pubmed: 32770942google scholar: lookup
                        7. 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).
                          doi: 10.3390/ani10010119pubmed: 31940795google scholar: lookup
                        8. Sun T, Hanif Q, Chen H, Lei C, Dang R. Copy Number Variations of Four Y-Linked Genes in Swamp Buffaloes.. Animals (Basel) 2019 Dec 22;10(1).
                          doi: 10.3390/ani10010031pubmed: 31877875google scholar: lookup
                        9. Ge F, Jia C, Chu M, Liang C, Yan P. Copy Number Variation of the CADM2 Gene and Its Association with Growth Traits in Yak.. Animals (Basel) 2019 Nov 21;9(12).
                          doi: 10.3390/ani9121008pubmed: 31766342google scholar: lookup
                        10. Prouteau A, Andru00e9 C. Canine Melanomas as Models for Human Melanomas: Clinical, Histological, and Genetic Comparison.. Genes (Basel) 2019 Jun 30;10(7).
                          doi: 10.3390/genes10070501pubmed: 31262050google scholar: lookup
                        11. Grilz-Seger G, Druml T, Neuditschko M, Dobretsberger M, Horna M, Brem G. High-resolution population structure and runs of homozygosity reveal the genetic architecture of complex traits in the Lipizzan horse.. BMC Genomics 2019 Mar 5;20(1):174.
                          doi: 10.1186/s12864-019-5564-xpubmed: 30836959google scholar: lookup
                        12. Imsland F, McGowan K, Rubin CJ, Henegar C, Sundstru00f6m E, Berglund J, Schwochow D, Gustafson U, Imsland P, Lindblad-Toh K, Lindgren G, Mikko S, Millon L, Wade C, Schubert M, Orlando L, Penedo MC, Barsh GS, Andersson L. Regulatory mutations in TBX3 disrupt asymmetric hair pigmentation that underlies Dun camouflage color in horses.. Nat Genet 2016 Feb;48(2):152-8.
                          doi: 10.1038/ng.3475pubmed: 26691985google scholar: lookup
                        13. Wang H, Wang C, Yang K, Liu J, Zhang Y, Wang Y, Xu X, Michal JJ, Jiang Z, Liu B. Genome Wide Distributions and Functional Characterization of Copy Number Variations between Chinese and Western Pigs.. PLoS One 2015;10(7):e0131522.
                          doi: 10.1371/journal.pone.0131522pubmed: 26154170google scholar: lookup
                        14. Harris ML, Levy DJ, Watkins-Chow DE, Pavan WJ. Ectopic differentiation of melanocyte stem cells is influenced by genetic background.. Pigment Cell Melanoma Res 2015 Mar;28(2):223-8.
                          doi: 10.1111/pcmr.12344pubmed: 25495036google scholar: lookup
                        15. Jiang L, Campagne C, Sundstru00f6m E, Sousa P, Imran S, Seltenhammer M, Pielberg G, Olsson MJ, Egidy G, Andersson L, Golovko A. Constitutive activation of the ERK pathway in melanoma and skin melanocytes in Grey horses.. BMC Cancer 2014 Nov 21;14:857.
                          doi: 10.1186/1471-2407-14-857pubmed: 25413220google scholar: lookup
                        16. Wang Y, Tang Z, Sun Y, Wang H, Wang C, Yu S, Liu J, Zhang Y, Fan B, Li K, Liu B. Analysis of genome-wide copy number variations in Chinese indigenous and western pig breeds by 60 K SNP genotyping arrays.. PLoS One 2014;9(9):e106780.
                          doi: 10.1371/journal.pone.0106780pubmed: 25198154google scholar: lookup
                        17. Seltenhammer MH, Sundstru00f6m E, Meisslitzer-Ruppitsch C, Cejka P, Kosiuk J, Neumu00fcller J, Almeder M, Majdic O, Steinberger P, Losert UM, Stu00f6ckl J, Andersson L, Su00f6lkner J, Vetterlein M, Golovko A. Establishment and characterization of a primary and a metastatic melanoma cell line from Grey horses.. In Vitro Cell Dev Biol Anim 2014 Jan;50(1):56-65.
                          doi: 10.1007/s11626-013-9678-1pubmed: 23982913google scholar: lookup
                        18. Curik I, Druml T, Seltenhammer M, Sundstru00f6m E, Pielberg GR, Andersson L, Su00f6lkner J. Complex inheritance of melanoma and pigmentation of coat and skin in Grey horses.. PLoS Genet 2013;9(2):e1003248.
                          doi: 10.1371/journal.pgen.1003248pubmed: 23408897google scholar: lookup