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The causal mutation was initially reported as a duplication of a 4.6\u2009kb intronic sequence in <jats:italic>Syntaxin 17<\/jats:italic>. The speed of greying varies considerably among Grey horses. Here we demonstrate the presence of two different <jats:italic>Grey<\/jats:italic> alleles, <jats:italic>G2<\/jats:italic> carrying two tandem copies of the duplicated sequence and <jats:italic>G3<\/jats:italic> carrying three. The latter is by far the most common allele, probably due to strong selection for the striking white phenotype. Our results reveal a remarkable dosage effect where the <jats:italic>G3<\/jats:italic> allele is associated with fast greying and high incidence of melanoma whereas <jats:italic>G2<\/jats:italic> is associated with slow greying and low incidence of melanoma. The copy number expansion transforms a weak enhancer to a strong melanocyte-specific enhancer that underlies hair greying (<jats:italic>G2<\/jats:italic> and <jats:italic>G3<\/jats:italic>) and a drastically elevated risk of melanoma (<jats:italic>G3<\/jats:italic> only). Our direct pedigree-based observation of the origin of a <jats:italic>G2<\/jats:italic> allele from a <jats:italic>G3<\/jats:italic> allele by copy number contraction demonstrates the dynamic evolution of this locus and provides the ultimate evidence for causality of the copy number variation of the 4.6\u2009kb intronic sequence.<\/jats:p>","DOI":"10.1038\/s41467-024-51898-2","type":"journal-article","created":{"date-parts":[[2024,8,29]],"date-time":"2024-08-29T19:02:26Z","timestamp":1724958146000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["An intronic copy number variation in Syntaxin 17 determines speed of greying and melanoma incidence in Grey horses"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8238-5052","authenticated-orcid":false,"given":"Carl-Johan","family":"Rubin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"McKaela","family":"Hodge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rakan","family":"Naboulsi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeleine","family":"Beckman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8838-7227","authenticated-orcid":false,"given":"Rebecca R.","family":"Bellone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7993-6597","authenticated-orcid":false,"given":"Angelica","family":"Kallenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"J\u2019Usrey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajime","family":"Ohmura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Seki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4673-0845","authenticated-orcid":false,"given":"Risako","family":"Furukawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aoi","family":"Ohnuma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6121-135X","authenticated-orcid":false,"given":"Brian W.","family":"Davis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8797-6644","authenticated-orcid":false,"given":"Teruaki","family":"Tozaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6046-9669","authenticated-orcid":false,"given":"Gabriella","family":"Lindgren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4085-6968","authenticated-orcid":false,"given":"Leif","family":"Andersson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,8,29]]},"reference":[{"key":"51898_CR1","doi-asserted-by":"publisher","first-page":"1004","DOI":"10.1038\/ng.185","volume":"40","author":"G Rosengren Pielberg","year":"2008","unstructured":"Rosengren Pielberg, G. et al. 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Bellone, A. Kallenberg, and S. J'Usrey are affiliated with the UC Davis Veterinary Genetics Laboratory, which provides genetic diagnostic tests in horses and other species. The other authors declare no competing interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"7510"}}