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

宠物狗在不同的品种中表现出巨大的多样性，不仅在外表上，而且在疾病易感性上。糖尿病(DM)，每300只狗中就有1只受到影响，原因是胰岛β细胞被破坏，导致胰岛素缺乏。萨摩亚犬对DM高度敏感(OR=21.7)，而拳击犬则具有抵抗力(OR=0.06)，这表明前者的β细胞更脆弱。然而，拳击手容易患上胰岛素瘤(INSA)，这意味着为提高β细胞存活率所付出的代价是潜在的恶性转化和肿瘤形成。与这两种疾病综合征相关的遗传风险很可能在每个品种内都是“固定的”。我们提出了一种方法，通过比较狗的全基因组序列(WGS)在胰腺β细胞表型的极端。HYPOTHESIS我们假设，将拳击手的基因组与萨摩亚人的基因组进行比较，将揭示对β细胞健康和生存至关重要的基因的独特变异。这些变异体可能会预防DM，但易患INSA，反之亦然。识别与β细胞健康和复原力有关的基因和机制将为糖尿病和INSA的预防或治疗提供新的干预途径。AIMST对至少10名Samoyeds和10名拳击手进行WGS(Illumina HiSeqX)(10倍至30倍的覆盖范围，取决于试点工作)，重点是DM和INSA病例。拉布拉多寻回犬将被用作参考品种，两种疾病的风险都是中性的。为了识别与胰腺β细胞生物学相关的品种特异性变异，并在一系列品种的受DM和INSA影响的狗的更大队列(n=100)中研究这些变异，本项目的METHODSDNA样本已经可用。利用牛津大学惠康信托人类遗传学中心的高性能计算机集群，将使用一种定制的生物信息路径进行分析。

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.