Genetics of breed susceptibility to canine diabetes mellitus and insulinoma: From one extreme to the other

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Pet dogs exhibit tremendous diversity across different breeds, not only in physical appearance but also in disease susceptibility. Diabetes mellitus (DM), affects 1 in 300 dogs and results from destruction of pancreatic beta-cells, leading to insulin deficiency. Samoyed dogs are highly susceptible to DM (OR = 21.7), whereas Boxer dogs are resistant (OR =0.06), suggesting that beta-cells in the former breed are more 'fragile'. However, Boxers are susceptible to developing insulinomas (INSA), implying that the price paid for improved beta-cell survival is the potential for malignant transformation and tumour formation. The genetic risk associated with these two disease syndromes is likely to be 'fixed' within each breed. We propose an approach whereby we compare whole genome sequences (WGS) in dogs at the extremes of the pancreatic beta cell phenotype.HYPOTHESISWe hypothesise that comparison of the Boxer genome to the Samoyed genome will reveal unique variations in genes critical for beta-cell health and survival. Such variants may protect from DM, but predispose to INSA and vice versa. Identification of genes and mechanisms involved in beta-cell health and resilience will reveal new pathways for intervention in prevention or treatment of DM and INSA.AIMSTo undertake WGS (Illumina HiSeqX) of at least 10 Samoyeds and 10 Boxers (10x to 30x coverage, dependent on pilot work), with a focus on cases of DM and INSA. Labrador retrievers will be used as a reference breed, with a neutral risk of both diseases. To identify breed-specific variants with relevance to pancreatic beta-cell biology and investigate these in a larger cohort of dogs (n=100) affected with DM and INSA across a range of breeds METHODSDNA samples for this project are already available. A bespoke bioinformatic pathway will be used for analysis, utilising the high-performance computer cluster at the Wellcome Trust Centre for Human Genetics, University of Oxford.