W22 Discovery Solves Long-Standing Mystery

In 2016, Etalon Diagnostics researchers collaborated with Airdrie Apache breeders and Dr. Tosso Leeb’s team at the University of Bern to solve a long-standing mystery. Together they discovered a unique phenomenon of horses carrying two KIT W20/W20 variants along with a third, new KIT variant, which we named “W22” (aka. Airdrie Apache White Gene). This 3 KIT phenomenon is possible because the W22 allele is “within” or “on” the W20 allele as a haplotype, creating the gorgeous, all-white thoroughbreds seen below. To learn more about this discovery and amazing phenomenon, read on!

https://pubmed.ncbi.nlm.nih.gov/28444912/

Thoroughbreds of Distinction in Lexington KY 's stallion, Artic Ice. He's a rare white (W22!) Thoroughbred racing in KY.

White spotting on domesticated animals is common and can range from tiny, unpigmented spots to completely white animals. In the past, it was recognized that semi-dominant genetic variants can lead to white horses in the heterozygous state and embryonic lethality in the homozygous state (1). Among domesticated animals, the horse currently represents the species with the largest number of molecularly defined white spotting alleles. Variants in MITF and PAX3 cause the so-called splashed white phenotype syndrome (2), variants at the equine TRPM1 gene causes the so-called leopard complex spotting (3), and more. Before discovery of the new W22 variant, 23 different functional alleles at the equine KIT gene had been described so far. These include the alleles for sabino-1 and tobiano spotting, and an allelic series termed W1–W21 (4).

While analyzing horses with white spotting phenotypes, researchers encountered a family of horses exhibiting a dominant white spotting phenotype that resembled the phenotypes of other horses with KIT variants, however failed to identify the causative variant. They re-sequenced the genome of a white-spotted thoroughbred horse and searched for an explanation, but again failed to uncover its cause. Searching for large structural variants, they visually inspected the sequence of the genes. This revealed a large heterozygous deletion spanning across exons 10-13 of the KIT gene in the white spotted horse. A deletion allele, or “null” allele, is a mutation in a gene that results in total loss of the normal function of the gene product encoded by that gene, resulting in a null phenotype (5).

As the study moved forward, researchers identified a total of 21 horses carrying the W22 allele. Their phenotypes were quite varied and ranged from a solid-colored body with a broad blaze and high white legs up to completely white horses (Fig. 2). The degree of white spotting is a trait with complex inheritance, and numerous variants at several genes have an influence on depigmentation. The W22 allele probably represents a null allele at the KIT gene. The W20 allele (KIT:p.Arg682His) probably leads to only a minor reduction in KIT function (6). W20 is a very common allele segregating in many diverse horse breeds. The W22 variant was found on a haplotype with the W20 allele (Fig. S1). A haplotype is “a group of alleles of different genes on a single chromosome that are closely enough linked to be inherited usually as a unit” (7). We determined the W20 genotypes in all 21 horses carrying the W22 variant (Table S2). Four of them were homozygous for W20, and all four horses with the W20/W22 genotype were completely white. Not only are these four horses with W20/W20 AND W22 proof of incredible genetic discovery, they are also stunning horses to experience firsthand.

References

_(1) Pulos & Hutt 1969 _ _(2) Pingault et al. 2010; Hauswirth et al. 2012, 2013 _ _(3) Bellone et al. 2013 _ _(4) Brooks & Bailey 2005; Brooks et al. 2007; Haase et al. 2007, 2008, 2009, 2011, 2015; Holl et al. 2010; Hauswirth et al. 2013 _ _(5) Springer-Verlag 2005 _ _(6) Hauswirth et al. 2013 _ (7) Merriam-Webster