Jivanji SWilkinson ETang LTiplady KMYeates AHarland CGray CCouldrey CWorth GGamache IDesjardins JTabares JAAYamanaka NMcNaughton LBrennan LCloutier M-PCowan MEllison RFransen TMonehan TSpelman RJSnell RGCharlier CYamanaka YGarrick DMort RLittlejohn MD2025-12-082025-11-14Jivanji S, Wilkinson E, Tang L, Tiplady KM, Yeates A, Harland C, Gray C, Couldrey C, Worth G, Gamache I, Desjardins J, Tabares JAA, Yamanaka N, McNaughton L, Brennan L, Cloutier MP, Cowan M, Ellison R, Fransen T, Monehan T, Spelman RJ, Snell RG, Charlier C, Yamanaka Y, Garrick D, Mort R, Littlejohn MD. (2025). Structural and epistatic regulatory variants cause hallmark white spotting in cattle. Science Advances. 11. 46. (pp. eadt5913-).https://mro.massey.ac.nz/handle/10179/73923Despite being one of the most iconic and immediately recognizable traits in domestic cattle, the variants underpinning the white-spotted coat pattern of Holstein-Friesian and related breeds remain uncharacterized. Here, we report two variants modulating these effects, comprising intronic and long-distance-acting regulatory variants of the MITF and KIT genes. We confirm causality through "Holsteinized" mouse models edited for these alleles and show that these variants are likely responsible for spotting traits in other bovine breeds. These effects include epistatic impacts on other bovine coat patterns, such as fine-scale speckling, "black socks," and reversal of the otherwise dominant, "white-face" trait characteristic of Hereford cattle.CC BY(c) 2025 The Author/shttps://creativecommons.org/licenses/by/4.0/Journal article10.1126/sciadv.adt59132375-2548journal-articleeadt5913-eadt5913