More about Grey
Gene or region: STX17
Reference allele: normal STX17 (N)
Mutant allele: duplication within STX17 (G)
Affected Breeds: many
Research Confidence: High confidence, findings reproduced in multiple studies
Grey is a modifier of coat color, resulting in a progressive loss of pigmentation throughout the coat. Foals tend to be born a darker shade than normal for their coat color, and usually begin to display white hairs with the first shedding. Often times, the white hairs are first noticeable around the eyes. The underlying skin remains dark, which distinguishes greys that have lightening completely from horses with significant white spotting. Grey is a dominant trait, signifying that horses with two (G/G) or one (G/N) copy of the allele both display the trait. The rate of greying is highly variable, though some research suggests horses with two copies may grey at a faster rate.
There are several other pigmentation traits associated with greying. While some horses lose pigmentation fairly uniformly, others form light circles with dark borders (dappled grey) or retain dark speckling on a lighter background (flea-bitten grey). Grey is also associated with vitiligo, which is a patchy loss of pigmentation of the skin. Homozygous horses (G/G) tend to show less speckling and are more likely to be affected by vitiligo than heterozygotes (G/N).
Grey is also associated with the development of melanomas, with research indicating an incidence of 70-80% in horses over the age of 15. Most grey melanomas are slow-growing, benign tumors that do not significantly impact the health of the horse. However, some melanomas do convert to malignant, or rarely, are malignant from the onset. Further research has indicated that 66% of grey melanomas will become malignant. Both the G allele of STX17 and the a allele of ASIP (horses with a black base coat as opposed to bay) are associated with a higher melanoma incidence. However, as age is also associated with melanoma incidence, it may be better to think of homozygous greys (G/G) and black-based horses (a/a) as more likely to develop melanomas at a younger age. Other minor genetic factors affect the incidence and severity of melanomas, although the exact genetic loci are not known at this time.
Genotype and Phenotype (Color Names)
* The coat color of a horse with at least one G allele is generally called grey, regardless of the underlying coat color. If the coat color is known, sometimes it is identified with “color gone grey,” for example “chestnut gone grey.”
* Spotting patterns, however, can usually be identified (even in very light greys due to differences in skin color), thus can be included after grey, for example “grey tobiano.”
Not much is known about the function of STX17. The grey duplication has been shown to increase the expression of both STX17 and its neighbor NR4A3 (which is involved in cell cycle regulation), plus contains a regulatory sequence specific to pigment cells (melanocytes). The mutation is believed to increase the rate of normal cell cycling, which both serves to deplete normal pigmentation stem cells (rising to white hairs) and eventually results in an overgrowth of cells leading to tumors (melanomas). Further research has shown that the extracellular signal-regulated kinase (ERK) pathway is continuously activated in Grey melanocytes, which is strongly associated with melanomas in humans.
Rosengren Pielberg G et al., “A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse.” (2008) Nat Genet. 40: 1004-9.
Sundström E et al., “Identification of a melanocyte-specific, microphthalmia-associated transcription factor-dependent regulatory element in the intronic duplication causing hair greying and melanoma in horses.” (2012) Pigment Cell Melanoma Res. 25: 28-36.
Sundström E et al., “Copy number expansion of the STX17 duplication in melanoma tissue from Grey horses.” (2012) BMC Genomics. 13: 365.
Curik I et al., “Complex inheritance of melanoma and pigmentation of coat and skin in Grey horses.” (2013) PLoS Genet. 9: e1003248.
Jiang L et al., “Constitutive activation of the ERK pathway in melanoma and skin melanocytes in Grey horses.” (2014) BMC Cancer. 21: 857.