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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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.

Author information

Author notes

    • Anna Golovko
    •  & Elisabeth Sundström

    These authors contributed equally to this work.

Affiliations

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

    • Elisabeth Sundström
    • , Gabriella Lindgren
    • , Kaj Sandberg
    •  & Leif Andersson
  3. Animal Science Department, Faculty of Agriculture, University of Zagreb, HR-10000 Zagreb, Croatia.

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

    • Johan Lennartsson
    •  & Carl-Henrik Heldin
  5. Department of Clinical Surgery and Ophthalmology, University of Veterinary Medicine, A-1200 Vienna, Austria.

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

    • Thomas Druml
    • , Roswitha Baumung
    •  & Johann Sölkner
  7. Royal Veterinary College, Royal College Street, London, NW1 0TU, UK.

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

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

    • Sara Strömberg
    •  & Fredrik Pontén
  10. Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.

    • Manfred Grabherr
    • , Claire Wade
    •  & Kerstin Lindblad-Toh
  11. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Claire Wade

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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.

Competing interests

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

Corresponding author

Correspondence to Leif Andersson.

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    Supplementary Methods, Supplementary Note, Supplementary Tables 1–3, Supplementary Figures 1–3

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DOI

https://doi.org/10.1038/ng.185

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