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).
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.
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