title: Copy number expansion of the STX17 duplication in melanoma tissue from Grey horses.
abstract: BACKGROUND
  Greying with age in horses is an autosomal dominant trait, associated with loss of hair pigmentation, melanoma and vitiligo-like depigmentation. We recently identified a 4.6 kb duplication in STX17 to be associated with the phenotype. The aims of this study were to investigate if the duplication in Grey horses shows copy number variation and to exclude that any other polymorphism is uniquely associated with the Grey mutation.
  
  
  RESULTS
  We found little evidence for copy number expansion of the duplicated sequence in blood DNA from Grey horses. In contrast, clear evidence for copy number expansions was indicated in five out of eight tested melanoma tissues or melanoma cell lines. A tendency of a higher copy number in aggressive tumours was also found. Massively parallel resequencing of the ~350 kb Grey haplotype did not reveal any additional mutations perfectly associated with the phenotype, confirming the duplication as the true causative mutation. We identified three SNP alleles that were present in a subset of Grey haplotypes within the 350 kb region that shows complete linkage disequilibrium with the causative mutation. Thus, these three nucleotide substitutions must have occurred subsequent to the duplication, consistent with our interpretation that the Grey mutation arose more than 2,000 years before present.
  
  
  CONCLUSIONS
  These results suggest that the mutation acts as a melanoma-driving regulatory element. The elucidation of the mechanistic features of the duplication will be of considerable interest for the characterization of these horse melanomas as well as for the field of human melanoma research.
authors.affiliation: Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Sundström
authors.forename: Freyja
authors.initials: F
authors.lastname: Imsland
authors.forename: Sofia
authors.initials: S
authors.lastname: Mikko
authors.forename: Claire
authors.initials: C
authors.lastname: Wade
authors.forename: Snaevar
authors.initials: S
authors.lastname: Sigurdsson
authors.forename: Gerli Rosengren
authors.initials: GR
authors.lastname: Pielberg
authors.forename: Anna
authors.initials: A
authors.lastname: Golovko
authors.forename: Ino
authors.initials: I
authors.lastname: Curik
authors.forename: Monika H
authors.initials: MH
authors.lastname: Seltenhammer
authors.forename: Johann
authors.initials: J
authors.lastname: Sölkner
authors.forename: Kerstin
authors.initials: K
authors.lastname: Lindblad-Toh
authors.forename: Leif
authors.initials: L
authors.lastname: Andersson
mesh_terms: D000483:Alleles; D000818:Animals; D045744:Cell Line, Tumor; D004247:DNA / Q000097:blood / Q000378:metabolism; D056915:DNA Copy Number Variations / Q000235:genetics*; D020440:Gene Duplication; D016678:Genome; D005838:Genotype; D006239:Haplotypes; D006736:Horses / Q000235:genetics / Q000378:metabolism; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000662:veterinary; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D050765:Qa-SNARE Proteins / Q000235:genetics* / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000662:veterinary
chemical_list: D050765:Qa-SNARE Proteins; D004247:DNA