Genetic and genomic investigations of hereditary and infectious wildlife diseases in non-model organisms

本研究的目的是在犬模型中阐明与两种野生动物疾病相关的遗传/基因组因素。传染性和遗传性野生动物疾病造成经济和文化损失，并对人类健康构成潜在威胁。纽芬兰岛上的本土犬类，红狐和郊狼，为研究野生动物疾病的遗传相关性，包括宿主和疾病基因组的相互作用提供了一个理想的模式系统。狐狸和郊狼是通过基因表达和单核苷酸多态(SNP)微阵列等犬类基因组资源实现的。这两种犬类也为野生动物疾病遗传学提供了截然不同的时间窗口，因为狐狸在冰川后定居在岛上，而郊狼是最近迁徙的。首先，纽芬兰是北美唯一的犬类内寄生线虫法国心虫的地方性疫源地。由于狐狸向郊狼和家犬传播，这种寄生虫引起了极大的关注。在这里，我建议使用靶标丰富的序列捕获、候选基因测序和全基因组SNPs来研究宿主易感性/抗性的遗传相关性，并使用SNP面板来绘制宿主和寄生虫的共同系统学图，以确定疾病传播和流行的人口统计学、空间和历史相关性，并识别与宿主相互作用相关的寄生虫标记。其次，纽芬兰和欧洲饲养的银狐患有遗传性增生性牙周炎(HHG)，这是一种阻碍繁殖计划的牙周病。利用犬类基因表达微阵列，我的实验室已经确定了与这种遗传性疾病有关的细胞信号通路，我打算通过目标丰富的基因组测序进一步探索这一途径。目标是发现这种疾病的基因和致病突变，确定这种疾病在野外的发生情况和频率，并开发一种诊断测试。我提议的研究将促进纪念大学和纽芬兰动物健康部门之间的合作，并将对毛皮饲养者协会、加拿大国内外的野生动物管理官员和狗主人以及人类疾病和哺乳动物生长和发育的基础研究人员具有重要意义。HHG致病突变的发现将为研究类似的人类疾病提供一个切入点；通过使用一种毛茸茸的食肉动物疾病来模拟人类疾病，人类和动物的健康问题都得到了解决。细胞周期中致病基因突变的鉴定也将为癌症研究提供信息。法国心虫的工作将有助于建立寄生虫在野生犬科动物中传播和维持的时空模型，有助于防止这种传染病的进一步传播，并作为了解宿主/寄生虫遗传多样性的基础和哺乳动物遗传变异的主要未知范围的模型。

The objectives of this research are to elucidate genetic/genomic factors associated with two wildlife diseases in canid models. Infectious and inherited wildlife diseases cause economic and cultural losses and pose potential health threats to humans. The indigenous canids of the island of Newfoundland, red foxes and coyotes, present an ideal model system in which to investigate genetic correlates of wildlife disease, including host and disease genome interactions. Foxes and coyotes are "genomically enabled" by canid genome resources like gene expression and single nucleotide polymorphism (SNP) microarrays. These two canids also provide distinct time windows into wildlife disease genetics as foxes colonized the island post-glacially whereas coyotes are recent migrants. First, Newfoundland is the only endemic focus in North America of the canid endoparasitic nematode French heartworm. This parasite is of significant concern due to intraguild transmission from foxes to coyotes and domestic canines. Here I propose to use target-enriched sequence capture, candidate gene sequencing, and genomewide SNPs to investigate genetic correlates of host susceptibility/resistance, and SNP panels to map host and parasite co-phylogeographies to determine demographic, spatial and historical correlates of disease transmission and prevalence, and identify parasite markers related to host interactions. Second, farmed silver foxes in Newfoundland and Europe experience hereditary hyperplastic gingivitis (HHG), a gum disease that hinders breeding programs. Using canine gene expression microarrays, my laboratory has identified the cell signalling pathway involved in this inherited disease, which I intend to further explore via target-enriched genome sequencing. The goal is to discover the gene and causative mutation of this condition, determine occurrence and frequency in the wild, and develop a diagnostic test. My proposed research forges collaborations among Memorial University and Newfoundland’s Animal Health Division, and will be important to Fur Breeder’s Associations, wildlife management officials and dog owners throughout Canada and abroad, and basic researchers of human disease and mammalian growth and development. The discovery of the causative mutation of HHG will provide an entry point into a similar human disease; by using a furbearing carnivore disease to model a human one, both human and animal health issues are addressed. The identification of pathogenic mutations of genes in the cell cycle will also be informative to cancer research. The French heartworm work will help develop a spatio-temporal model of parasite spread and maintenance in wild canids, contribute to prevention of further spread of this infectious disease, and serve as a model for understanding the basis of host/parasite genetic diversity and the largely unexplained scope of mammalian genetic variation.