Molecular characterization of rare forms of canine neurological diseases as potential models for similar human diseases

• Main Author: Letko, Anna
• Format: Doctoral or Postdoctoral Thesis
• Language: English
• Published: Universität Bern
• Subjects: 570 Life sciences; biology; 590 Animals (Zoology); 610 Medicine & health; 630 Agriculture; Canis lupus
• Online Access: http://boristheses.unibe.ch/2789/; http://boristheses.unibe.ch/2789/1/21letko_a.pdf; https://doi.org/10.48549/2789

Canis lupus familiaris, the domestic dog, possesses a huge variability in traits such as size, conformation, coat color, or character, which reflects the generations of targeted human selection after the dog's domestication thousands of years ago. The phenotypic differences naturally reflect the underlying, often breed-specific, genetic variation. While heterogeneity between breeds is large, at the same time, the individuals within one breed are usually very homogeneous. This specific population structure of modern dog breeds with low genetic diversity favors the propagation of spontaneous occurrences of genetic mutations that might lead to the development of diseases, and thus makes the dog a valuable animal model. Inherited neurological disorders in animals as well as in human patients are incurable, often severe, and result in progressively worsening quality of life; early diagnosis is therefore beneficial for managing the disease development. DNA-based precision medicine using state-of-the-art methods, e.g. whole-genome sequencing (WGS) has been successfully utilized in recent years for routine diagnosis of rare diseases in human as well as in veterinary medicine. Identification of disease-causing variants allows dog breeders to avoid the spread of such variants in the affected dog breed, ultimately improving the health of the whole population through better breeding management, as well as to advance the understanding of the molecular mechanisms involved in corresponding human disease, and may be useful for the development of novel therapeutic strategies. In this thesis, I took part in the analysis of seven specific canine neurological phenotypes applying different genetic mapping methods, candidate gene analysis, and WGS. I also generated and analyzed extensive genealogical and genomic data on the worldwide Leonberger dog population in regards to its diversity and disease prevalence. Despite its increasing size in recent years, the population lost considerable genetic diversity due to a bottleneck in the ...