Gene discovery and the genetic basis of inherited disease in non-model organisms

本研究的新重点是揭示非模式生物中遗传性疾病的遗传成分-特别是具有商业和/或保护区域利益的大型哺乳动物。拟议的研究利用基因组资源和生物信息学工具，其直接目标是发现导致银狐破坏性遗传状况的基因，以及更一般的目标是阐明物种的基因型和表型变异之间的关系，尽管在PubMed中缺乏代表性，但与我们自己的进化史相对较近。该研究的具体目标是确定狐狸遗传性增生性牙龈炎（牙龈过度生长）的候选基因，评估这些基因的DNA序列与狐狸疾病状态之间的关系，比较在一个无关联的假定中性遗传位点上受影响和未受影响的狐狸，并测定自然种群中疾病相关遗传变异的频率和分布。另一个目标是研究导致黑熊克莫德病的突变的进化起源（位于与人类红毛相同的基因上）以及它在哺乳动物中的独特性和适应性意义。这项研究意义重大，因为它利用一种人类疾病在分子水平上模拟一种繁殖性食肉动物疾病。除了为毛皮养殖业提供有价值的信息外，它还有助于我们了解令人烦恼的人类状况。识别与细胞周期相关的基因为癌症研究提供了潜在的重要新工具。研究这些基因在繁殖种群和自然种群中的变异将有助于解开基因型和表型之间的复杂关系，并最终有助于解释哺乳动物遗传变异的巨大范围。正是在后一种情况下，阐明克莫德熊黑化的分子遗传机制是重要的。除了科学贡献外，这项研究还涉及开发新的生物技术，如微芯片DNA重测序，并建立区域机构合作。

The novel focus of the present study is to uncover the genetic component of inherited disease in non-model organisms - specifically large mammals that are of commercial and/or conservation interest regionally. The proposed research takes advantage of genomic resources and bioinformatics tools, with the immediate goal of discovering genes responsible for a devastating hereditary condition in silver foxes, and the more general one of illuminating the relationship between genotypic and phenotypic variation in species that, although depauperately represented in PubMed, share a comparatively recent evolutionary history with our own. The specific goals of the research are to determine candidate genes for hereditary hyperplastic gingivitis (gum overgrowth) in foxes, to evaluate the association between the DNA sequence of these genes and disease status of foxes, to compare affected and unaffected foxes at an unlinked putatively neutral genetic locus, and to assay the frequency and distribution of disease-associated genetic variation in natural populations. An additional goal is to investigate the evolutionary origin of the mutation that causes Kermodism in black bears (located on the same gene as red hair in humans) and its uniqueness and adaptive significance among mammals. This research is significant because it uses a human disease to model a furbearing carnivore disease at the molecular level. In addition to providing valuable information to the fur breeding industry, it therefore also contributes to our knowledge of a troublesome human condition. The identification of genes associated with aspects of the cell cycle provides potentially important new tools for cancer research. And studying variation in these genes in both bred and natural populations will contribute to the disentanglement of the complex relationship between genotype and phenotype and ultimately help explain the vast scope of mammalian genetic variation. It is in this latter context that elucidation of the molecular genetic mechanisms of melanism in Kermode bears is important. In addition to its scientific contributions, this research involves the development of new biotechnologies, such as microchip DNA re-sequencing, and forges regional institutional collaborations.