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

Nature Genetics volume 40, pages 1004–1009 (2008)Cite this article

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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Author notes

  1. Anna Golovko and Elisabeth Sundström: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Biochemistry and Microbiology, Uppsala University, Box 597, Uppsala, SE-751 24, Sweden

    Gerli Rosengren Pielberg, Anna Golovko, Carolyn Fitzsimmons, Kerstin Lindblad-Toh & Leif Andersson

  2. Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, SE-751 24, Sweden

    Elisabeth Sundström, Gabriella Lindgren, Kaj Sandberg & Leif Andersson

  3. Animal Science Department, Faculty of Agriculture, University of Zagreb, Zagreb, HR-10000, Croatia

    Ino Curik

  4. Ludwig Institute of Cancer Research, Uppsala University, Box 595, Uppsala, SE-751 24, Sweden

    Johan Lennartsson & Carl-Henrik Heldin

  5. Department of Clinical Surgery and Ophthalmology, University of Veterinary Medicine, Vienna, A-1200, Austria

    Monika H Seltenhammer

  6. Department of Sustainable Agricultural Systems, University of Natural Resources and Applied Life Sciences, Vienna, Vienna, A-1180, Austria

    Thomas Druml, Roswitha Baumung & Johann Sölkner

  7. Royal Veterinary College, Royal College Street, London, NW1 0TU, UK

    Matthew Binns

  8. Department of Cell Biology and Ultrastructure Research, Centre for Anatomy and Cell Biology, Medical University of Vienna, Vienna, A-1080, Austria

    Monika Vetterlein

  9. Department of Genetics and Pathology, Rudbeck laboratory, Uppsala University, Uppsala, SE-751 85, Sweden

    Sara Strömberg & Fredrik Pontén

  10. Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, 02142, Massachusetts, USA

    Manfred Grabherr, Claire Wade & Kerstin Lindblad-Toh

  11. Center for Human Genetic Research, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA

    Claire Wade

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  1. Gerli Rosengren Pielberg
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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.

Corresponding author

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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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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