Mouse Models of Neurological Disease

描述（由申请方提供）：本申请旨在扩大杰克逊实验室（JAX）和华盛顿大学（Wash U）临床和转化科学研究所（ICTS）之间的合作，以在小鼠和人类神经系统疾病相关遗传学之间建立一个集成的互惠管道。为此，我们建议将杰克逊实验室（P40 RR 001183，小鼠突变体资源）的NCRR资助的动物和生物材料资源（ABMR）与华盛顿大学ICTS结合起来，共同努力使用高通量测序来鉴定多达40种具有神经系统疾病临床表现的突变体中的致病突变。该试验项目证明了高通量测序可以提供一种途径，通过该途径，可以通过避免定位克隆过程以前所未有的速度定义突变等位基因。我们建议建立一个高通量的测序管道自发突变识别，关键是，我们建议开发应用这个管道所需的序列分析工具，不仅神经系统疾病的模型，而且其他疾病领域，适当地模仿自发小鼠突变（即视觉，听力，前庭功能，颅面畸形等）。 公共卫生相关性：该试点项目开发的技术将允许在小鼠基因组中进行高通量突变检测，这是在人类疾病小鼠模型中发现表型驱动基因的关键步骤。由于99%的小鼠基因在人类基因组中具有同源物，因此在具有临床表型的突变体中识别自发的小鼠突变通常直接导致随后识别人类疾病基因。因此，在该项目中发现的突变是将这些假定的疾病模型发展到非常适合转化研究的程度的关键。此外，这组神经突变体将提供一个测试平台，在此基础上可以开发分析工具。由于小鼠群体中自发突变的发生方式与人类群体中等位基因变异/突变的发生方式非常相似，因此华盛顿大学正在开发的分析工具。用于患者高通量测序数据的基因组技术访问中心（GTAC）也可用于分析来自自发小鼠突变体的测序数据。反过来，小鼠突变体收集将为这些分析工具的改进提供必要的测试案例。

DESCRIPTION (provided by applicant): This request seeks to extend a collaborative effort between The Jackson Laboratory (JAX) and the Washington University (Wash U) Institute for Clinical and Translational Sciences (ICTS) to establish an integrated, reciprocal pipeline between mouse and human genetics related to neurological disease. Toward this end, we propose to bring together the NCRR funded Animal and Biological Materials Resource (ABMR) at The Jackson Laboratory (P40 RR001183, Mouse Mutant Resource) and Wash U ICTS in a combined effort to use high throughput sequencing to identify the causative mutations in up to 40 mutants with clinical manifestations of neurological disease. This pilot project is a proof of principle that high throughput sequencing can provide a path by which mutant alleles can be defined at an unprecedented rate by obviating the positional cloning process. We propose to establish a high-throughput sequencing pipeline for spontaneous mutation identification, and critically, we propose to develop the sequence analysis tools needed to apply this pipeline, not only to models of neurological disease, but also to other disease areas that are appropriately modeled by spontaneous mouse mutants (i.e. vision, hearing, vestibular function, craniofacial dysmorphology, etc). PUBLIC HEALTH RELEVANCE: The technologies developed in this pilot project will allow for high throughput mutation detection in the mouse genome, which is a critical step for phenotype driven gene discovery in mouse models of human disease. Since 99% of mouse genes have a homolog in the human genome, the identification of spontaneous mouse mutations in mutants with clinical phenotypes often directly leads to the subsequent identification of human disease genes. Therefore, the mutations found in this project are key to the advancement of these putative disease models to the point where they are ideally suited for translational research. Moreover, this set of neurological mutants will provide a test platform upon which analysis tools can be developed. Because spontaneous mutations in mouse populations arise in the very same manner as allelic variation / mutations arise in human populations, the analysis tools that are under development at the Wash U. Genome Technology Access Center (GTAC) for patient high throughput sequencing data can also be used to analyze sequencing data from spontaneous mouse mutants. In turn, the mouse mutant collection will provide essential test cases for refinement of these analysis tools.