Endogenous retrovirus insertion in KIT oncogene determines white and white spotted in domestic cats

The Dominant White locus (W) in the domestic cat demonstrates pleiotropic effects exhibiting complete penetrance for absence of coat pigmentation and incomplete penetrance for deafness and iris hypopigmentation. I preformed linkage analysis using a pedigree segregating White to identify KIT (Chr. B1), as the feline W locus. Segregation and sequence analysis of the KIT gene in two pedigrees (P1 and P2) revealed the remarkable retrotransposition and evolution of a feline endogenous retrovirus (FERV1) as responsible for two distinct phenotypes of the W locus, Dominant White, and White Spotting. The retrotransposition interrupts a DNase I hypersensitive site in KIT intron 1 that was previously demonstrated to regulate temporal and tissue specific expression of KIT in mice. A large population-genetic survey of cats (n=269), supports our findings and demonstrates statistical significance of the FERV1 LTR and full-length element with Dominant White (p < 0.0001) and White Spotting (p< 0.0001), respectively.