Studies in model organisms can help elucidate the molecular mechanisms causing disease, and the dog is an excellent example as it shares many of the same environment, diseases and genes with humans. With mapping tools available, we are in a unique position to map canine disease genes to learn about human biology and medicine. The genetic homogeneity within dog breeds yields a cleaner picture of disease risk and greater ease at finding these risk factors. To date, we have identified >40 associated loci for >10 complex traits. For several diseases we find different genes and pathways predisposing to the disease in each breed. The major aim of our work is to continue to dissect the genetic components of important complex diseases in dog breeds and to utilize this information to understand and dissect the genetic components of the corresponding human diseases. We are focusing on three key disease groups of high relevance to both dogs and people: cancer, immunological disease and neuropsychiatric disorders, as well as on behavior. Emphasis will be placed on discovering as many risk factors and pathways as possible for the diseases under study, with the goal of creating a greater and more complete understanding of each disease (similar to that of a more diverse human population). We believe that regulatory mutations (in regulatory DNA elements as well as non-coding RNAs) play a major role in complex disease in both dogs and humans. We will therefore continue our previous efforts to annotate the human and canine genomes using comparative genomics (analysis of evolutionary constraint in 240 mammals), RNA-seq and epigenomics, specifically applying this information to deepen our understanding of the identified disease loci. Once canine disease genes and pathways have been identified, we will perform functional characterization (bioinformatic and wet lab functional analysis) of disease genes as well as perform follow-up genetic analysis in human patients.