GENETIC VARIATION IN THE DOMESTICATED DOG AS A MODEL OF HUMAN DISEASE

One of the greatest challenges facing clinical scientists is a developed understanding of the genetic basis for complex human diseases such as cancer. Despite many technological advances in genetics, progress has been slow. This is owed, in part, to intricate gene-gene interactions as well as poorly understood environmental influences on gene expression and genetic traits. The high level of heterogeneity of the human genome makes identification of these interactions and environmental influences difficult. Recently, the domesticated dog (Canis Lupis Familaris), has demonstrated its powerful applicability to human disease as a new model of genetic variation. Dogs are an excellent model for the study of complex disease in humans for a variety of reasons, including the extensive level of health care they receive, and their phenotypic diversity. Approximately 400 inherited diseases similar to those of humans are characterized in dogs, including complex disorders such as cancers, heart disease, and neurological disorders. The purpose of this dissertation project is to elucidate the role of genetic variation in the domesticated dog as a model for understanding human disease and is comprised of four manuscripts. I establish 1) the utility of the canine model for the study of human disease, 2) the theoretical and empirical establishment of a novel method for genomewide genetic analysis, 3) identification of germline loci associated with the risk for development of Osteosarcoma. Finally, 4) I describe a novel mechanism involving structural variation which results in an epigenetic readout for a highly penetrant Mendelian trait. I discuss how each of these studies stands to broadly accelerate biomedical investigation.