Etalon Equine Genetics Discovers Three New White Marking Variants in a New Gene

Have you ever been told that your horse might carry an “untestable” or “unknown” white gene? Then you are definitely going to want to read this!

Every so often a horse with interesting white markings but no known white variants in their DNA results makes their way to the desks of Etalon Equine Genetics’ researchers. When this scenario occurs, as it does more often than you might think, the team jumps at the opportunity to solve another genetic mystery. And while we get excited about every discovery our team makes, the following lovely horses led our research team to something truly special – three white marking variants on a completely different gene known as HPS5!

Now if you are not up-to-speed on all of your equine genes (we do not blame you - no gene shaming allowed!), you might be thinking, “Okay that sounds cool, but why is this SO exciting?” Because this is the first time that a white marking variant has been found on an entirely new genetic region for color in over 10 years!¹ While the gene itself is not new, it is a newly discovered region for white markings. Plenty of other variants for white markings have been found by Etalon and other equine DNA researchers during the years, but they have all been related to the same old familiar genes (yawn!) - this discovery is special!

White markings, scientifically known as depigmentation, are a common phenotype in horses, but the genetics behind them are quite complicated. There are currently over 50 known variants that cause white spotting on the skin and coat. Previous discoveries were mostly linked to mutations of the KIT gene, which is responsible for Dominant White variants, and the PAX3 and MITF genes, which are associated with different Splashed White variants.

The HPS5 gene, which influences the increase in the number of melanocyte cells, has previously been shown to influence depigmentation in humans, mice, and zebrafish.² ³ ⁴ ⁵ However, its role in horses remained a mystery… until now! In humans, mutations of the HPS5 gene are associated with oculocutaneous albinism, meaning depigmentation of the skin, hair, and eye. This region has also shown an association with Hermansky-Pudlak syndrome (HPS). HPS is a rare genetic disorder that can cause issues with blood clotting. Because this discovery in horses is so new, further studies are needed to determine if horses with HPS5 genetic mutations also experience these health issues other than the known depigmentation of their coats.

Considering his track record when it comes to solving genetic puzzles, it makes sense that it would be Etalon’s very own Research Associate, Aiden McFadden, who helped crack the code on this exciting new discovery. Aiden has played an integral part in many of Etalon’s genetic revelations, from coat colors to health variants. While initially investigating the genetic cause of Cruz's distinctive white patches, along with those of a broader equine cohort, Aiden and his research team found themselves at an impasse. Despite their best efforts, the search for novel KIT mutations, where many white markings originate from, continued to lead to dead ends.

The pivotal breakthrough came when they expanded their investigation to include more diverse populations of horses sporting similar unknown markings. It was then that they made a crucial realization: the answers they were looking for lay in an entirely different gene. This discovery was a game-changer, especially considering Aiden's previous frustration when his research seemed stalled by traditional theories. By shifting their perspective entirely, the team not only cracked the code behind Cruz's markings but also underscored the importance of curiosity and adaptability in scientific exploration. In honor of McFadden’s large role in finding these new variants as a part of the Etalon team, we feel it is only fitting that we christen them the “Eden Whites (EDXW),” where ‘Eden’ is the ethereal fusion of “Etalon” and “Aiden.”

The three identified mutations, named Eden White 1 (EDXW1), Eden White 2 (EDXW2), and Eden White 3 (EDXW3), are associated with significant increases in white markings depending on the specific mutation. To make this exciting discovery even more interesting, EDXW1 and EDXW3 show a rare interaction with MC1R, which is the gene that controls whether a horse will have a black or red base coat color. The dominant E allele, responsible for black pigment, was associated with lower levels of white depigmentation compared to the recessive chestnut genotype. In simple terms: black or bay horses will likely have more or larger white markings than chestnut horses.

The Eden White variants have so far been identified in many different breeds from heavy breed horses such as Gypsy Cobs and Shires, to stock-type breeds like the Paint and Quarter Horse, as well as spanning other breeds like Lusitanos, miniature horses, Paso Finos, and much more. While both EDXW1 and EDXW3 were found in nine major breed groups in the study, it is interesting to note that EDXW2 was absent in Thoroughbred horses. This wide distribution suggests a broad impact of these mutations on depigmentation across equines of various lineages. Long story short, your horse, regardless of their breed, may have inherited one of the Eden White variants!

Want to learn more about the science behind EDWX? Make sure to check out our Genetics Unbridled podcast episode dedicated to this exciting new discovery!

References

McFadden, A., Martin, K., Vierra, M., Robilliard, H., Lundquist, E. W., Everts, R. E., Brooks, S. A., & Lafayette, C. (2024). Three HPS5 mutations associated with depigmentation in diverse horse breeds. Livestock Science, 282, 105454. https://doi.org/10.1016/j.livsci.2024.105454

"Discovery Alert: Join the Nerd Herd to Learn about Eden Whites" on Genetics Unbridled - Horse DNA & Technology Powered by Etalon Equine Genetics

¹ Bellone, R. R., Holl, H., Setaluri, V., Devi, S., Maddodi, N., Archer, S., Sandmeyer, L., Ludwig, A., Foerster, D., Pruvost, M., Reissmann, M., Bortfeldt, R., Adelson, D. L., Lim, S. L., Nelson, J., Haase, B., Engensteiner, M., Leeb, T., Forsyth, G., Mienaltowski, M. J., … Brooks, S. A. (2013). Evidence for a retroviral insertion in TRPM1 as the cause of congenital stationary night blindness and leopard complex spotting in the horse. PloS one, 8(10), e78280. https://doi.org/10.1371/journal.pone.0078280

² Di Pietro, S. M., Falcón-Pérez, J. M., & Dell'Angelica, E. C. (2004). Characterization of BLOC-2, a complex containing the Hermansky-Pudlak syndrome proteins HPS3, HPS5 and HPS6. Traffic (Copenhagen, Denmark), 5(4), 276–283. https://doi.org/10.1111/j.1600-0854.2004.0171.x

³ Huizing, M., Hess, R., Dorward, H., Claassen, D. A., Helip-Wooley, A., Kleta, R., Kaiser-Kupfer, M. I., White, J. G., & Gahl, W. A. (2004). Cellular, molecular and clinical characterization of patients with Hermansky-Pudlak syndrome type 5. Traffic (Copenhagen, Denmark), 5(9), 711–722. https://doi.org/10.1111/j.1600-0854.2004.00208.x

⁴ Hirobe, T., Wakamatsu, K., & Ito, S. (2012). A new mutation of mouse ruby-eye 2, ru2(d)/Hps5(ru2-d) inhibits eumelanin synthesis but stimulates pheomelanin synthesis in melanocytes. Zoological science, 29(10), 652–661. https://doi.org/10.2108/zsj.29.652

⁵ Daly, C. M., Willer, J., Gregg, R., & Gross, J. M. (2013). snow white, a zebrafish model of Hermansky-Pudlak Syndrome type 5. Genetics, 195(2), 481–494. https://doi.org/10.1534/genetics.113.154898