Mouse Models of Neurological Disease

描述(由申请人提供)：本申请旨在扩大杰克逊实验室(JAX)和华盛顿大学(WASH U)临床与翻译科学研究所(ICTS)之间的合作努力，以建立与神经系统疾病相关的小鼠和人类遗传学之间的综合、互惠渠道。为此，我们建议将杰克逊实验室由NCRR资助的动物和生物材料资源(ABMR)(P40 RR001183，小鼠突变资源)和Wash U ICTS结合起来，使用高通量测序来识别多达40个具有神经系统疾病临床表现的突变的致病突变。这一试点项目证明了高通量测序可以提供一条途径，通过避免位置克隆过程，以前所未有的速度定义突变等位基因。我们建议建立一个用于自发突变鉴定的高通量测序管道，关键的是，我们建议开发所需的序列分析工具，不仅应用于神经疾病的模型，而且应用于由自发突变小鼠适当建模的其他疾病领域(即视觉、听力、前庭功能、颅面畸形等)。 与公共卫生相关：该试点项目中开发的技术将允许在小鼠基因组中进行高通量突变检测，这是在人类疾病的小鼠模型中发现表型驱动的基因的关键一步。由于99%的小鼠基因在人类基因组中具有同源性，在具有临床表型的突变体中识别小鼠自发突变往往直接导致随后的人类疾病基因的识别。因此，在这个项目中发现的突变是这些假定的疾病模型发展到适合于转化性研究的程度的关键。此外，这组神经学突变将提供一个测试平台，在此平台上可以开发分析工具。由于小鼠群体中的自发突变与人类群体中的等位基因变异/突变发生的方式完全相同，华盛顿大学基因组技术访问中心(GTAC)正在开发的用于患者高通量测序数据的分析工具也可用于分析来自自发小鼠突变的测序数据。反过来，老鼠突变体集合将为这些分析工具的改进提供必要的测试用例。

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.