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Research article - Peer-reviewed, 2008

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

Pielberg, Gerli Rosengren; Golovko, Anna; Sundstrom, Elisabeth; Curik, Ino; Lennartsson, Johan; Seltenhammer, Monika H.; Druml, Thomas; Binns, Matthew; Fitzsimmons, Carolyn; Lindgren, Gabriella; Sandberg, Kaj; Baumung, Roswitha; Vetterlein, Monika; Stromberg, Sara; Grabherr, Manfred; Wade, Claire; Lindblad-Toh, Kerstin; Ponten, Fredrik; Heldin, Carl-Henrik; Soelkner, Johann; Andersson, Leif
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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.

Published in

Nature Genetics
2008, Volume: 40, number: 8, pages: 1004-1009