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

Gerli Pielberg ,Fredrik Pontén,Johan Lennartsson,Manfred Grabherr,Leif Andersson,Elisabeth Sundström,Sara Strömberg,Gabriella Lindgren,Anna Golovko,Carolyn Fitzsimmons,Thomas Druml,Johann Sölkner,M Vetterlein ,R Baumung ,Claire M Wade ,Ino Čurik ,Monika Seltenhammer ,M M Binns ,Carl‐Henrik Heldin ,K Sandberg ,Kerstin Lindblad‐Toh

doi:10.1038/ng.185

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.

Highlights

In horses, graying with age is an autosomal dominant trait associated with a high incidence of melanoma and vitiligo-like depigmentation
Southern blot analysis of genomic DNA revealed no polymorphisms for NR4A3, TXNDC4 or INVS, but a B4.6-kb insertion was present in STX17
Cyclin D1 (CCND1) and cyclin D2 (CCND2) have both compared with liver and skin from both Gray and non-Gray horses been identified as targets of NR4A3, which prompted us to (Fig. 4a). To study this differential expression more directly, we investigate whether these genes are upregulated in Gray melanoquantified the relative expression of alleles in melanomas from three mas

Summary

Swedish Warmblood

Horses homozygous for the mutation showed more rapid graying and were more homogenously white in the final stage of the process compared with Gray heterozygotes (Fig. 3a) They had significantly higher incidence of melanoma (Fig. 3b) and vitiligo (Fig. 3c) and almost no speckling (Fig. 3d). The higher incidence of melanomas in horses carrying an ASIP null mutation implies that increased MC1R signaling promotes melanoma development in Gray horses This result was unexpected because the most well-characterized function of agouti is to modulate MC1R signaling and thereby pigment switching in hair-follicle melanocytes[11]. Mice that are homozygous for the null mutation causing extreme agouti have much darker pigmentation in the glabrous skin of their ears and tails This mouse phenotype and our observation that Gray horses carrying the recessive mutant agouti allele have a higher incidence of melanomas in glabrous skin show that ASIP influences dermal melanocytes. Vitiligo grage long form is likely to be differentially expressed

Northern blot analysis revealed high

Melanoma cDNA d

METHODS

Findings

Manuscript ID Author Editor Publisher