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A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse

Abstract

In horses, graying with age is an autosomal dominant trait associated with a high incidence of melanoma and vitiligo-like depigmentation. Here we show that the Gray phenotype is caused by a 4.6-kb duplication in intron 6 of STX17 (syntaxin-17) that constitutes a cis-acting regulatory mutation. Both STX17 and the neighboring NR4A3 gene are overexpressed in melanomas from Gray horses. Gray horses carrying a loss-of-function mutation in ASIP (agouti signaling protein) had a higher incidence of melanoma, implying that increased melanocortin-1 receptor signaling promotes melanoma development in Gray horses. The Gray horse provides a notable example of how humans have cherry-picked mutations with favorable phenotypic effects in domestic animals.

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Figure 1: Graying with age in horses.
Figure 2: Molecular characterization of the locus of the Gray-causing mutation in horses.
Figure 3: Analysis of phenotypic differences between heterozygous (G/g; black lines) and homozygous (G/G; red lines) Gray Lipizzaner horses.
Figure 4: Expression analysis of STX17 and NR4A3.

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Acknowledgements

We thank H. Andersson, E.-M. Eriksson, S. Mikko and the directors of Piber, Lipica, Djakovo, Szilvasvarad and Topolcianky Lippizaner studs for valuable assistance with sample collections; T. Gunn for valuable discussions on agouti expression; U. Gustafson for expert technical assistance; D.F. Antczak for genomic DNA from Twilight; and J. Hansson (Radiumhemmet, Karolinska University Hospital) for the human melanoma cell lines. This work was supported by grants from the Swedish Cancer Society; the Olle Engkvist Foundation; the Swedish Foundation for Strategic Research; the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning; and the Uppsala Centre for Comparative Genomics.

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Contributions

G.R.P. was responsible for marker development, positional cloning, characterization of the STX17 transcripts and real-time PCR analysis; A.G. was responsible for generation of antibodies to STX17, immunohistochemistry and northern blot analysis; E.S. was responsible for genotyping the Lipizzaner population material and analyzing allelic imbalance in melanoma tissue; I.C., M.H.S., T.D., R.B. and J.S. collected phenotypic data and blood samples from Lipizzaners; J.S. did the statistical analysis of genotype-phenotype relationships; J.L. and C.-H.H. took part in the functional characterization of STX17 and NR4A3; M.H.S. and M.V. established Gray melanoma cell lines and provided skin samples from Gray and non-Gray horses; M.B. provided samples from Gray tumors and helped isolate BAC clones; C.F. assisted with northern blot analysis; G.L. assisted with characterization of BAC clones; K.S. provided samples from Gray and non-Gray horses; S.S. and F.P. assisted with immunohistochemistry analysis; M.G., C.W. and K.L.-T. did the bioinformatics analysis of the horse genome assembly; L.A. planned the study and prepared the manuscript with input from the other authors.

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Correspondence to Leif Andersson.

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A patent application has been filed on the basis of the data presented in this paper.

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Supplementary Methods, Supplementary Note, Supplementary Tables 1–3, Supplementary Figures 1–3 (PDF 305 kb)

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Rosengren Pielberg, G., Golovko, A., Sundström, E. et al. A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse. Nat Genet 40, 1004–1009 (2008). https://doi.org/10.1038/ng.185

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