Different Founding Effects Underlie Dominant Blue Eyes (DBE) in the Domestic Cat.

Simple Summary: Aesthetic traits are major components of modern feline breeds. Each breed is defined by a standard specifying morphology; coat length, texture, and colour; and eye colour. Considering the coat and eye colour may help breeders in managing their breeding stocks to optimise their mating, but it also has an impact on the health and well-being of cats. Indeed, some colours and patterns may be associated with deleterious traits. Recently, a new coat and eye pattern has been described in cats. It has been called "dominant blue eyes (DBE)" and includes one or two blue eyes or particolored eyes and minimal white spotting. Different feline breeding lines were developed for DBE, and in some lineages, deafness has been identified as being associated with this trait. The Altai and Topaz breeds were created using DBE founding cats found in Kazakhstan and Russia. The Celestial breed, recognised in France, was created using a DBE outbred male from Kazakhstan and British shorthair and longhair cats. Other breeds, including the Maine Coon, British, Persian, Siberian, Sphynx, and Munchkin cats, introduced DBE. We have previously identified two variants associated with DBE, and here, we report the discovery of a third DBE variant. Finally, we review the presence of the three DBE variants in 14 feline breeding lines. During the last twenty years, minimal white spotting associated with blue eyes was selected by feline breeders to create the Altai, Topaz, and Celestial breeds. Additionally, certain breeders introduced this trait in their lineages of purebred cats. The trait has been called "dominant blue eyes (DBE)" and was confirmed to be autosomal dominant in all lineages. DBE was initially described in outbred cats from Kazakhstan and Russia and in two purebred lineages of British cats from Russia, as well as in Dutch Maine Coon cats, suggesting different founding effects. We have previously identified two variants in the Paired Box 3 (PAX3) gene associated with DBE in Maine Coon and Celestial cats; however, the presence of an underlying variant remains undetermined in other DBE breeding lines. Using a genome-wide association study, we identified a single region on chromosome C1 that was associated with DBE in British cats. Within that region, we identified PAX3 as the strongest candidate gene. Whole-genome sequencing of a DBE cat revealed an RD-114 retrovirus LTR (long terminal repeat) insertion within PAX3 intron 4 (namely NC_018730.3:g.206975776_206975777insN[433]) known to contain regulatory sequences. Using a panel of 117 DBE cats, we showed that this variant was fully associated with DBE in two British lineages, in Altai cats, and in some other DBE lineages. We propose that this NC_018730.3:g.206975776_206975777insN[433] variant represents the DBEALT (Altai Dominant Blue Eye) allele in the domestic cat. Finally, we genotyped DBE cats from 14 lineages for the three PAX3 variants and showed that they were not present in four lineages, confirming genetic heterogeneity of the DBE trait in the domestic cat. [ABSTRACT FROM AUTHOR]