Complex Inheritance of Melanoma and Pigmentation of Coat and Skin in Grey Horses

Abstract

The dominant phenotype of greying with age in horses, caused by a 4.6-kb duplication in intron 6 of STX17, is associated with a high incidence of melanoma and vitiligo-like skin depigmentation. However, the progressive greying and the incidence of melanoma, vitiligo-like depigmentation, and amount of speckling in these horses do not follow a simple inheritance pattern. To understand their inheritance, we analysed the melanoma grade, grey level, vitiligo grade, and speckling grade of 1,119 Grey horses (7,146 measurements) measured in six countries over a 9-year period. We estimated narrow sense heritability (h²), and we decomposed this parameter into polygenic heritability (h²_POLY), heritability due to the Grey (STX17) mutation (h²_STX17), and heritability due to agouti (ASIP) locus (h²_ASIP). A high heritability was found for greying (h² = 0.79), vitiligo (h² = 0.63), and speckling (h² = 0.66), while a moderate heritability was estimated for melanoma (h² = 0.37). The additive component of ASIP was significantly different from zero only for melanoma (h²_ASIP = 0.02). STX17 controlled large proportions of phenotypic variance (h²_STX17 = 0.18–0.55) and overall heritability (h²_STX17/h² = 0.28–0.83) for all traits. Genetic correlations among traits were estimated as moderate to high, primarily due to the effects of the STX17 locus. Nevertheless, the correlation between progressive greying and vitiligo-like depigmentation remained large even after taking into account the effects of STX17. We presented a model where four traits with complex inheritance patterns are strongly influenced by a single mutation. This is in line with evidence of recent studies in domestic animals indicating that some complex traits are, in addition to the large number of genes with small additive effects, influenced by genes of moderate-to-large effect. Furthermore, we demonstrated that the STX17 mutation explains to a large extent the moderate to high genetic correlations among traits, providing an example of strong pleiotropic effects caused by a single gene.

Vyšlo v časopise: Complex Inheritance of Melanoma and Pigmentation of Coat and Skin in Grey Horses. PLoS Genet 9(2): e32767. doi:10.1371/journal.pgen.1003248
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003248

Souhrn

Abstract

Zdroje

1. FrazerKA, MurraySS, SchorkNJ, TopolEJ (2009) Human genetic variation and its contribution to complex traits. Nat Rev Genet 10 : 241–251.

2. MackayTFC, StoneEA, AyrolesJF (2009) The genetics of quantitative traits: challenges and prospects. Nat Rev Genet 10 : 565–577.

3. GoddardME, HayesBJ (2009) Mapping genes for complex traits in domestic animals and their use in breeding programs. Nat Rev Genet 10 : 381–391.

4. FlintJ, MackayT (2009) Genetic architecture of quantitative traits in mice, flies, and humans. Genome Res 19 : 723–733.

5. YangJ, BenyaminB, McEvoyBP, GordonS, HendersAK, et al. (2010) Common SNPs explain a large proportion of the heritability for human height. Nat Genet 42 : 565–569.

6. KemperKE, VisscherPM, GoddardME (2012) Genetic architecture of body size in mammals. Genome Biol 13 : 244.

7. KemperKE, GoddardME (2012) Understanding and predicting complex traits: knowledge from cattle. Hum Mol Genet 21: R45–R51.

8. PielbergRG, GolovkoA, SundströmE, CurikI, LennartssonJ, et al. (2008) A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse. Nat Genet 40 : 1004–1009.

9. SundströmE, KomisarczukAZ, JiangL, GolovkoA, NavratilovaP, et al. (2012) Identification of a melanocyte-specific, microphthalmia-associated transcription factor-dependent regulatory element in the intronic duplication causing hair greying and melanoma in horses. Pigm Cell Mel Res 25 : 28–36.

10. SundströmE, ImslandF, MikkoS, WadeC, SigurdssonS, et al. (2012) Copy number expansion of the STX17 duplication in melanoma tissue from Grey horses. BMC Genomics 13 : 365.

11. Sponenberg DP (2003) Equine Color Genetics. Ames and London: Iowa State University Press/Blackwell. 215 p.

12. Curik I, Seltenhammer M, Sölkner J (2002) Quantitative genetic analysis of melanoma and grey level in Lipizzan horses. Proceedings of the 7th World Congress on Genetics Applied to Livestock Production, CD-ROM: Communication No. 05-09, August 19–23, Monpellier, France.

13. TothZ, KapsM, SolknerJ, BodoI, CurikI (2006) Quantitative genetic aspects of coat color in horses. J Anim Sci 84 : 2623–2628.

14. FoleyGL, ValentineBA, KincaidAL (1991) Congenital and acquired melanocytomas (benign melanomas) in Eighteen Young Horses. Vet Pathol 28 : 363–369.

15. Pulley LT, Stannard AA (1990) Tumors of the skin and soft tissues. In: Moulton JE, editor. Tumors in domestic animals. Berkeley: University California Press. pp. 75–82.

16. GorhamS, RoblM (1986) Melanoma in the grey horse: The darker side of equine aging. Vet Med 81 : 446–448.

17. DesserH, NiebauerGW, GebhartW (1980) Polyamin -⁠ und Hisatmingehalt im Blut von pigmentierten, depigmentierten und melanomtragenden Lipizzanerpferden. Zbl Vet Med, Reihe A 27 : 45–53.

18. FleuryC, BérardF, LeblondA, FaureC, GanemN, et al. (2000) The study of cutaneous melanomas in Camargue-type gray-skinned horses (2): Epidemiological survey. Pigment Cell Res 13 : 47–51.

19. ValentineBA (1995) Equine melanotic tumors: A retrospective study of 53 Horses (1988–1991). J Vet Int Med 9 : 291–297.

20. RiederS, StrickerCH, JoergH, DummerR, StranzingerG (2000) A comparative genetic approach for the investigation of aging grey horse melanoma. J Anim Breed Genet 117 : 73–82.

21. SeltenhammerMH, SimhoferH, ScherzerS, ZechnerP, CurikI, et al. (2003) Equine melanoma in a population of 296 grey Lipizzan horses. Equine Vet J 35 : 153–157.

22. Hann SK, Nordlund JJ (2000) Vitiligo. Oxford: Blackwell Science. 320 p.

23. PasseronT, OrtonneJP (2005) Physiopathology and genetics of vitiligo. J Autoimm 25 : 63–68.

24. ZhangXJ, ChenJJ, LiuJB (2005) The concept of vitiligo. J Dermatol Sci 39 : 137–146.

25. JinY, RiccardiSL, GowanK, FainPR, SpritzRA (2010) Fine-mapping of vitiligo susceptibility loci on chromosome 7 and 9 and interactions with NLRP1 (NALP1). J Invest Dermatol 130 : 774–783.

26. PirisiA (2010) Vitiligo and melanoma-two sides of the same coin? Lancet Oncol 11 : 517.

27. JeonJ-T, CarlborgÖ, TörnstenA, GiuffraE, AmargerV, et al. (1999) A paternally expressed QTL affecting skeletal and cardiac muscle mass in pigs maps to the IGF2 locus. Nat Genet 21 : 157–158.

28. Van LaereAS, NguyenM, BraunschweigM, NezerC, ColletteC, et al. (2003) A regulatory mutation in IGF2 causes a major QTL effect on muscle growth in the pig. Nature 425 : 832–836.

29. GrisartB, CoppietersW, FarnirF, KarimL, FordC, et al. (2002) Positional candidate cloning of a QTL in dairy cattle: identification of a missense mutation in the bovine DGAT1 gene with major effect on milk yield and composition. Genome Res 12 : 222–231.

30. LittlejohnM, GralaT, SandersK, WalkerC, WaghornG, et al. (2012) Genetic variation in PLAG1 associates with early life body weight and peripubertal weight and growth in Bos taurus. Anim Genet 43 : 591–594.

31. WienerP, WooliamsJA, Frank-LawaleA, RyanM, RichardsonRI, et al. (2009) The effects of a mutation in the myostatin gene on meat and carcass quality. Meat Sci 83 : 127–134.

32. HayesBJ, PryceJ, ChamberlainAJ, Bowman PJ, GoddardME (2010) Genetic architecture of complex traits and accuracy of genomic prediction: coat colour, milk-fat percentage, and type in Holstein cattle as contrasting model traits. PLoS Genet 6: e1001139 doi:10.1371/journal.pgen.1001139.

33. LiuF, WollsteinA, HysiPG, Ankra-BaduGA, SpectorTD, et al. (2010) Digital Quantification of Human Eye Color Highlights Genetic Association of Three New Loci. PLoS Genet 6: e1000934 doi:10.1371/journal.pgen.1000934.

34. ProtasME, PatelNH (2008) Evolution of coloration patterns. Annu Rev Cell Dev Biol 24 : 425–46.

35. FangM, LarsonG, Soares RibeiroH, LiN, AnderssonL (2009) Contrasting mode of evolution at a coat color locus in wild and domestic pigs. PLoS Genet 5: e1000341 doi:10.1371/journal.pgen.1000341.

36. RiederS, TaouritS, MariatD, LangloisB, Guerin (2001) Mutations in the agouti (ASIP), the extension (MC1R), and the brown (TYRP1) loci and their association to coat color phenotypes in horses (Equus caballus). Mammal Genome 12 : 450–455.

37. Gilmour AR, Gogel BJ, Cullis BR, Thompson R (2009) ASReml User Guide Release 3.0, Hemel Hempstead, UK: VSN International Ltd.

38. Mrode RA (2005) Linear Models for the Prediction of Animal Breeding Values. Cambridge: CABI Publishing. 344 p.

39. Falconer DS, Mackay TFC (1996) Introduction to quantitative genetics. Harlow, Essex, UK: Longman Group. 464 p.