Search

In many mammalian species, depigmentation phenotypes are widely known, but are rare in the wild, as unpigmented animals usually have a disadvantage in survival. Depigmentation phenotypes are sometimes associated with pleiotropic effects, resulting in severe pathological conditions such as e.g. the overo lethal white foal syndrome in horses. As abnormal coat color phenotypes are easily recognized in domestic animals they provide a good system to identify genetic variants affecting fundamental processes of life. This includes melanocyte development, migration, survival, and proliferation. Said special coat color phenotypes are mostly due to spontaneous mutations. The resulting mutant alleles, are often kept in the population and positively selected due to the striking appearance and special value of fully or partially depigmented animals to their owners. In this thesis, I contributed to the identification of candidate causative genetic variants of various coat color phenotypes in a range of domestic animals, by applying different genetic approaches and with the help of next generation sequencing technologies. One approach was based on the calculation of selection signatures in various goat breeds from Switzerland and Pakistan. In two Pakistani goat breeds, complex structural variants at the KIT locus were identified potentially explaining the observed breed-defining depigmentation phenotypes. In the same study, multiple structural variants at the ASIP locus in Swiss goat breeds were found. RNA sequencing results of the caprine ASIP locus, revealed a high number of non-coding 5’-exons which were not observed in other mammals so far. Further analysis of one particular Swiss goat breed, the Valais Blackneck, revealed introgression events of some aforesaid ASIP alleles into the breed accounting for the rare coat color phenotypes segregating in the breed. Variation of ASIP could also be found in rabbits being a plausible cause for the black and tan phenotype further giving insight into the variable regulation of ASIP in multiple species. A heterozygous deletion affecting KIT was identified in a young German Riding Pony showing an interesting white spotting phenotype. It has most likely arisen by a de novo mutation event as the parents did not show any comparable phenotype. Lastly, a deletion in the MITF gene was found in a family of American Paint Horses, displaying variable white spotting phenotypes associated with deafness. Additional known white spotting alleles further increased the risk for deafness as six of the eight family members were deaf and carried multiple additional white spotting alleles. The identification of these candidate causative variants not only enabled genetic testing and targeted breeding. They also gave insights into underlying mechanisms of the spatial and temporal regulation of pigment production as well as on the complex regulatory network involved in melanocyte development. Additionally, they help us in better understanding of breed history.

White spotting phenotypes in horses may be caused by developmental alterations impairing melanoblast differentiation, survival, migration and/or proliferation. Candidate genes for white-spotting phenotypes in horses include EDNRB, KIT, MITF, PAX3 and TRPM1. We investigated a German Riding Pony with a sabino-like phenotype involving extensive white spots on the body together with large white markings on the head and almost completely white legs. We obtained whole genome sequence data from this horse. The analysis revealed a heterozygous 1273-bp deletion spanning parts of intron 2 and exon 3 of the equine KIT gene (Chr3: 79 579 925-79 581 197). We confirmed the breakpoints of the deletion by PCR and Sanger sequencing. Knowledge of the functional impact of similar KIT variants in horses and other species suggests that this deletion represents a plausible candidate causative variant for the white-spotting phenotype. We propose the designation W28 for the mutant allele.