In other species: taurine cattle , indicine cattle (zebu)

Categories: Pigmentation phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 604204 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal dominant

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2008

Species-specific name: Gray; Grey; Greying with age

Species-specific symbol: G, G2, G3

Species-specific description: Horses are born with normal pigmentation, but gradually lose their pigmentation as they age, until, typically at around 6-8 years old, they become white, while retaining dark skin pigmentation. Included with this phenotype is a relatively high incidence of dermal melanomas, and an associated decrease in life expectancy (see OMIA:002231-9796 : Melanoma, generic in Equus caballus)

History: As summarised by Pielberg et al. (2008), white horses have been favoured by humans for hundreds of years.

Mapping: Rosengren Pielberg et al. (2005) fine-mapped this locus to a region less than 3 cM between two genes (NANS and ABCA1) on ECA25. Comparative mapping with humans and mice suggested no obvious candidate genes in this region, implying that this coat colour is due to a mutation in a gene not yet identified.

Molecular basis: Rosengren Pielberg et al. (2008) presented convincing evidence that this classic phenotype is due to a 4.6kb intronic duplication in the gene for syntaxin-17 (STX17). This duplication appears to increase the expression of both syntaxin-17 and a neighbouring gene NR4A3, which encodes nuclear receptor subfamily 4, group A, member 3. Whilst the details are still to be elucidated, Pielberg et al. (2008) present circumstantial evidence that overexpression of one or both of these two genes leads to a hyperproliferation of hair-follicle melanocytes, leading to a gradual depletion of progenitor stem cells, and hence to a gradual loss of hair pigmentation as the animal ages. At the same time, the overexpression of one or both of these genes leads to a proliferation of dermal melanocytes in glabrous skin (skin that naturally lacks hair), which predisposes to melanoma development. Curik et al. (2013) provided evidence that "the STX17 mutation explains to a large extent the moderate to high genetic correlations among [melanoma grade, grey level, vitiligo grade, and speckling grade] . . . , providing an example of strong pleiotropic effects caused by a single gene". Leeb (2013) provides a very informative summary of the results of Curik et al. (2013).
Nowacka-Woszuk et al. (2021) assessed "the usefulness of droplet digital PCR (ddPCR) in precise genotyping of equine STX17 4.6-kb duplication ... ." Genotyping of 75 horses representing various breeds "revealed that the tested individuals had copy numbers of the 4.6-kb STX17 fragment equal to 6, 4, or 2 for the GG, Gg, and gg gray mutation genotypes, respectively. [Their] results thus suggest that the equine graying with age mutation is a triplication." The authors suggest that "further studies of wider range material are needed to fully understand the molecular structure of the graying with age causative mutation within the equine STX17 gene."
Rubin et al. (2024) "demonstrate the presence of two different Grey alleles, G2 carrying two tandem copies of the duplicated sequence and G3 carrying three. The latter is by far the most common allele, probably due to strong selection for the striking white phenotype. [Their] results reveal a remarkable dosage effect where the G3 allele is associated with fast greying and high incidence of melanoma whereas G2 is associated with slow greying and low incidence of melanoma. The copy number expansion transforms a weak enhancer to a strong melanocyte-specific enhancer that underlies hair greying (G2 and G3) and a drastically elevated risk of melanoma (G3 only)."

Genetic testing: Since exactly the same mutation is completely associated with the grey/gray phenotype in more than 850 horses from numerous breeds (Rosengren Pielberg et al., 2008), it is very likely that a single DNA test will suffice to detect virtually all occurrences of the grey/gray alleles. Kavar et al. (2012) provide details of a robust DNA test. Nowacka-Woszuk et al. (2021) provide methods for using ddPCR to detect copy number which can help in distinguishing between the G1, G2, and G3 alleles.  Horses with only a G1 allele will not be grey, and therefore some testing laboratories report this allele as N (for normal). 

Associated gene: