The domestic dog encompasses hundreds of genetically isolated breeds, many of which show an increased risk for certain diseases. With the canine genome sequence, an understanding of the haplotype structure and availability of disease gene mapping tools, we are now in a unique position to map canine disease genes to inform human biology and medicine. So far we have mapped monogenic traits as well as >40 loci for >10 complex traits. We now propose to map genes for key diseases using many breeds to dissect a larger number of genes underlying the specific disease. We further plan to evaluate the functional consequences of mutations and pilot personalized treatment strategies based on genetic risk. The specific aims are:1.Characterization of disease phenotypes, breed predisposition and sample acquisition. We are currently collecting samples from >20 diseases and will expand our phenotypic classification and sample collection to a larger number of breeds for some key diseases such as osteosarcoma, breast cancer, behavior and atopy or lymphocytic thyroiditis.2.Identification and functional characterization of canine disease genes and pathways. We will perform genomewide association mapping followed by targeted resequencing for mutation detection. Pathway analysis will be performed to understand the disease mechanisms mostly contributing to the disease. For select mutations, we will use state of the art molecular biology to provide detailed functional characterization of selected genes revealed by our gene discovery platform.3.Piloting canine personalized treatment strategies based on inherited risk factors.For a few diseases we will pilot personalized treatment strategies based on inherited risk factors, utilizing the genetic information gathered in aim 2. Available or novel drugs acting on the identified pathways will be tested in dogs with specific risk factors using a veterinary network for clinical trials.Knowledge gained should inform human personalized medicine.