De novo mutations in canine evolution and disease

The domestic dog is an evolutionarily unique animal and has a special niche within genomics research. Since their domestication from the grey wolf, dogs have become one of the most phenotypically diverse living land animals. Man’s desire to create individuals with specialised morphological and behavioural traits has led to the development of over 400 recognised breeds. Dogs share a significant number of inherited disease phenotypes with humans and are regarded as valuable animal models for understanding evolution and disease. New mutations are the ultimate source of new phenotypic diversity and evolutionary change. They can also cause rare spontaneous genetic disorders and collectively, they make a significant contribution to disease burden in managed populations. To comprehensively understand the mechanisms of evolution and disease, discovering the rates of occurrence, type, and patterns of distribution of de novo mutations across the genome is essential. Until recently, the characteristics of de novo mutations could be inferred only using indirect or biased methods. With recent technological advancements, it is now possible to directly observe de novo mutations that occur in a single generation directly through parent-offspring sequencing studies. Whole genome sequencing provides the opportunity for genomic variants associated with rare diseases caused by spontaneous mutations to be identified directly. We are on the brink of the capacity to utilize these technologies more fully in the field of personal medicine. In this thesis, de novo germline mutations affecting the evolution and occurrence of disease in the dog are identified and characterised. The inspiration for this work stemmed from the extraordinary phenotypic diversity in the species and its close relationship to people