A Variant Associated with Increased White Spotting Epistatic to Genotype in Horses ().

Over 40 identified genetic variants contribute to white spotting in the horse. White markings and spotting are under selection for their impact on the economic value of an equine, yet many phenotypes have an unknown genetic basis. Previous studies also demonstrate an interaction between MC1R and ASIP pigmentation loci and white spotting associated with KIT and MITF. We investigated two stallions presenting with a white spotting phenotype of unknown cause. Exon sequencing of the KIT and MITF candidate genes identified a missense variant in KIT (rs1140732842, NC_009146.3:g.79566881T>C, p.T391A) predicted by SIFT and PROVEAN as not tolerated/deleterious. Three independent observers generated an Average Grade of White (AGW) phenotype score for 147 individuals based on photographs. The KIT variant demonstrates a significant QTL association to AGW (p = 3.3 × 10−12). Association with the MC1R Extension locus demonstrated that, although not in LD, MC1R e/e (chestnut) individuals had higher AGW scores than MC1R E/- individuals (p = 3.09 × 10−17). We also report complete linkage of the previously reported KIT W19 allele to this missense variant. We propose to term this variant W34, following the standardized nomenclature for white spotting variants within the equine KIT gene, and report its epistatic interaction with MC1R.