Molecular genetics and mechanisms of pigmentation and melanoma

Ever since man domesticated the first wild animals several thousand years ago, many species have been living in close relationship with humans, being objects for our requests and wishes about any kind of phenotypic traits. As a result, we have by selective breeding created a fascinating spectrum of phenotypes within most species we have domesticated. The broad aim of this thesis has been to investigate the molecular mechanisms causing different colour and pattern phenotypes in domestic animals. In more detail, the mutation causing Greying with age and melanoma in horses and the mutations leading to the Sex-linked barring feather pattern in the domestic chicken have been studied. Grey horses are born any colour, but gradually loose their hair pigmentation and usually become white by the age of 6-8 years. The pigmentation loss only affects the hair, and the skin stays dark throughout life. Melanomas and vitiligo-like depigmentation frequently occur among Grey horses, and it is claimed that 70-80% of Grey horses older than 15 years have melanocytic lesions. The Sex-linked barring pattern in chickens is characterized by black and white stripes on the feathers. Similar barring patterns are found among many bird species, such as the peregrine falcon and the zebra finch. The mutation causing Sex-linked barring has previously been mapped to the q arm of chromosome Z, which explains why the homogametic (ZZ) sex in chickens, males, develop a broader barring pattern. In this thesis, the mutations causing both traits are identified, and their functional properties are investigated. The mutation causing Greying with age and melanoma in horses was identified as a 4.6 kb intronic duplication in the gene STX17, not previously linked either to pigmentation or melanoma. Moreover, it could be shown that the mutation in STX17 has an elevated copy number in melanoma DNA, and that it contains a strong melanocyte specific activating regulatory element residing a MITF binding site. This finding sheds further light on the intriguing molecular processes of melanoma development. The mutations linked to Sex-linked barring could be mapped to the CDKN2A/B tumour suppressor locus, a genetic region commonly associated with familiar forms of melanoma and also implied in the molecular mechanisms of pigmentation regulation