The objective of this K0MP2 project is to provide comprehensive phenotyping of 200 KOMP mutant mouse lines each year for five years. This will provide significant new information regarding gene function, especially for un-annotated genes, to the research community and will accelerate our understanding of the genetic basis of disease. This goal will be achieved by a consortium having a significant track-record in mutant mouse production, phenotyping, technical innovation and working together on collaborative projects. The UCD-TCP-CHORI consortium consists of the Mouse Biology Program at U. California Davis (UCD), the Toronto Center for Phenogenomics (TCP), and Children's Hospital of Oakland Research Institution (CHORI). In this application, we propose phenotyping 200 homozygous K0MP2 mutant lines each year: 150 adult mutant lines will be phenotyped at the UCD - CHORI site using a single pipeline approach and integrating molecular phenotyping into the assessment;and 50 sub-viable lines will be phenotyped at TCP along with adult phenotyping of heterozygotes for a subset of the embryonic lethal lines. In addition, TCP will assess homozygous mutant adult lung function using a well established challenge test in a subset of the adult-viable mutant lines. Methods, procedures-and best practices for adult phenotypes shared among the UCD-TCP-CHORI consortium members will be harmonized. The plan integrates well with the recommendations of the International Mouse Phenotyping Consortium, but we have recommended changes that will save significant resources, and provide rich novel datasets. Innovations include: A) a single pipeline approach for the adult-viable lines;B) intensive and detailed embryonic lethal phenotyping that incorporates several imaging modalities;C);targeted sub-viable mutant phenotyping;and D) intelligent transcriptome analyses in homozygous adult. Also, we propose an intensive technology development program to apply the revolutions in DNA sequencing technology to refine, tailor and optimize RNAseq for transcriptome analyses and to explore other molecular phenotypes such as micro RNA profiling, and metabolomics for future incorporation into the phenotype screens.
Mutant mice are an essential tool for understanding the function of genes and the mechanisms by which genetic variation affects disease risk in humans. This project will generate valuable data about gene function by characterizing the changes due to mutations in specific genes.
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