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.185. Epub 2008 Jul 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Gene Duplication
  • Genetic Predisposition to Disease*
  • Hair Color / genetics*
  • Horses
  • Humans
  • Melanoma / genetics*
  • Melanoma / metabolism
  • Mice
  • Molecular Sequence Data
  • Qa-SNARE Proteins / genetics*
  • Qa-SNARE Proteins / metabolism
  • Receptor, Melanocortin, Type 1 / metabolism
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Selection, Genetic


  • Qa-SNARE Proteins
  • Receptor, Melanocortin, Type 1
  • Receptors, Cytoplasmic and Nuclear