Novel Brown Coat Color (Cocoa) in French Bulldogs Results from a Nonsense Variant in HPS3

Brown or chocolate coat color in many mammalian species is frequently due to variants at the B locus or gene. In dogs, five different loss-of-function alleles have been described, which explain the vast majority of dogs with brown coat color. Recently, breeders and genetic testing laboratories identified brown French Bulldogs that did not carry any of the known mutant alleles. We sequenced the genome of a brown French Bulldog and compared the data to 655 other canine genomes. A search for private variants revealed a nonsense variant in , c.2420G>A or p.(Trp807*). The brown dog was homozygous for the mutant allele at this variant. The gene encodes a protein required for the correct biogenesis of lysosome-related organelles, including melanosomes. Variants in the human gene cause Hermansky-Pudlak syndrome 3, which involves a mild form of oculocutaneous albinism and prolonged bleeding time. A variant in the murine gene causes brown coat color in the mouse mutant. We genotyped a cohort of 373 French Bulldogs and found a strong association of the homozygous mutant genotype with the brown coat color. The genotype-phenotype association and the comprehensive knowledge on function from other species strongly suggests that :c.2420G>A is the causative variant for the observed brown coat color in French Bulldogs. In order to clearly distinguish -related from the -related brown coat color, and in line with the murine nomenclature, we propose to designate this dog phenotype as "cocoa", and the mutant allele as .