A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse.
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.
Rosengren Pielberg
Gerli
G
Department of Medical Biochemistry and Microbiology, Uppsala University, Box 597, SE-751 24 Uppsala, Sweden.
Golovko
Anna
A
Sundström
Elisabeth
E
Curik
Ino
I
Lennartsson
Johan
J
Seltenhammer
Monika H
MH
Druml
Thomas
T
Binns
Matthew
M
Fitzsimmons
Carolyn
C
Lindgren
Gabriella
G
Sandberg
Kaj
K
Baumung
Roswitha
R
Vetterlein
Monika
M
Strömberg
Sara
S
Grabherr
Manfred
M
Wade
Claire
C
Lindblad-Toh
Kerstin
K
Pontén
Fredrik
F
Heldin
Carl-Henrik
CH
Sölkner
Johann
J
Andersson
Leif
L
D000818:Animals; D045744:Cell Line, Tumor; D020440:Gene Duplication; D020022:Genetic Predisposition to Disease; D006200:Hair Color / Q000235:genetics*; D006736:Horses; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D050765:Qa-SNARE Proteins / Q000235:genetics* / Q000378:metabolism; D044102:Receptor, Melanocortin, Type 1 / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D012641:Selection, Genetic
D050765:Qa-SNARE Proteins; D044102:Receptor, Melanocortin, Type 1; D018160:Receptors, Cytoplasmic and Nuclear