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

Pielberg, G R and Golovko, A and Sundstrom, E and Curik, I and Lennartsson, J and Seltenhammer, M H and Druml, T and Binns, M and Fitzsimmons, C and Lindgren, G and Sandberg, K and Baumung, R and Vetterlein, M and Stromberg, S and Grabherr, M and Wade, C and Lindblad-Toh, K and Ponten, F and Heldin, C H and Solkner, J and Andersson, L (2008) A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse. Nature Genetics, 40 (8). pp. 1004-1009.

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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.