Mice and humans share approximately 20,000 genes. To date, little data exists for more than half of these genes and nearly one third have no functional annotation. Because of the high degree of similarity between the mouse and human gene set, genetic data generated in mice can often be extrapolated to human gene function. Mouse models of genes with common functionality between mice and men can lead to new models of human disease, which are useful for drug screening, preclinical studies and deeper understanding of biological and disease mechanism. The goal of the Knockout Mouse Phenotyping Program (KOMP2) is to generate lines of mice that carry knockouts (KOs) for a genome-wide collection of mouse genes and subject the mice to broad based phenotyping. The Jackson Laboratory (JAX) proposes to merge its currently funded KOMP2 Mouse Production and Cryopreservation (U42) and Knockout Mouse Phenotyping (U54) operations as part of RFA-RM-15-017 Limited Competition: Knockout Mouse Production and Phenotyping Project (UM1). JAX KOMP2 proposes to use cutting-edge and cost-effective Cas9 RNA-guided nuclease (Cas9 RGN, also called CRISPR/Cas9) technology to generate, breed, cryopreserve and phenotype1500 lines of mice during the project period. Continued effort will be made to improve the Cas9 RGN technology so as to reduce costs, increase targeting efficiency, and create more complex mutant alleles. Genes will be selected in coordination with our KOMP2 and IMPC partners, and will focus on those with poor annotation, genes that have significant community demand and integrate with other NIH-support programs, and genes predicted to function in select pathways. To guarantee ready access to the community, we will ship mice to outside investigators while they are alive on the shelf and deposit the lines into the Mouse Mutant Regional Resource Center (MMRRC) repositories for future use. Broad based phenotyping on juvenile animals up to 18 weeks of age will be performed on all 1500 lines of mice using International Mouse Phenotyping Consortium (IMPC)-required and JAX-specific protocols. We will assess body weight and composition, metabolic and physiological parameters, and behavioral and cognitive function. To detect age-dependent phenotypes, we will use the same pipeline to phenotype 20% (300 total) of the lines between 15-18 months of age. Based on data generated from the current phase of KOMP2, we expect about 30% of lines to be non-viable. We will characterize the non-viable mutants using high-throughput imaging modalities at three embryonic time points. All data generated from embryonic, juvenile and adult mice will be rapidly deposited into the Data Coordination Center (DCC) that supports KOMP2 and the IMPC. Lastly, JAX will work collaboratively with the KOMP2 Regional Network and with member organizations of the IMPC to share protocols, innovation, and new technology and to broadly and openly disseminate our findings to the international community through publication, presentations at meetings, web activities and social media.

Public Health Relevance

The Knockout Mouse Phenotyping Program (KOMP2) seeks to create an encyclopedia of gene function for the ~20,000 genes in the mouse and to ultimately create a resource for understanding gene function in humans. The Jackson Laboratory (JAX) will contribute to this goal by efficiently generating knockout lines and sharing functional data for 1,500 mouse genes. The JAX team will enhance the value of these data by linking them with current genetic and biological knowledge, enabling the scientific community to discover the roles of these genes in human health and disease.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Research Project with Complex Structure Cooperative Agreement (UM1)
Project #
9UM1OD023222-06
Application #
9192907
Study Section
Special Emphasis Panel (ZHG1-HGR-M (M1))
Program Officer
Mirochnitchenko, Oleg
Project Start
2011-09-16
Project End
2021-07-31
Budget Start
2016-08-02
Budget End
2017-07-31
Support Year
6
Fiscal Year
2016
Total Cost
$4,861,047
Indirect Cost
$2,079,020
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Rozman, Jan; Rathkolb, Birgit; Oestereicher, Manuela A et al. (2018) Identification of genetic elements in metabolism by high-throughput mouse phenotyping. Nat Commun 9:288
Meehan, Terrence F; Conte, Nathalie; West, David B et al. (2017) Disease model discovery from 3,328 gene knockouts by The International Mouse Phenotyping Consortium. Nat Genet 49:1231-1238
Karp, Natasha A; Mason, Jeremy; Beaudet, Arthur L et al. (2017) Prevalence of sexual dimorphism in mammalian phenotypic traits. Nat Commun 8:15475
Samuelov, Liat; Li, Qiaoli; Bochner, Ron et al. (2017) SVEP1 plays a crucial role in epidermal differentiation. Exp Dermatol 26:423-430
Bowl, Michael R; Simon, Michelle M; Ingham, Neil J et al. (2017) A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction. Nat Commun 8:886
Sundberg, John P; Dadras, Soheil S; Silva, Kathleen A et al. (2017) Systematic screening for skin, hair, and nail abnormalities in a large-scale knockout mouse program. PLoS One 12:e0180682
Snyder, Elizabeth M; McCarty, Christopher; Mehalow, Adrienne et al. (2017) APOBEC1 complementation factor (A1CF) is dispensable for C-to-U RNA editing in vivo. RNA 23:457-465
Peterson, Kevin A; Beane, Glen L; Goodwin, Leslie O et al. (2017) CRISPRtools: a flexible computational platform for performing CRISPR/Cas9 experiments in the mouse. Mamm Genome 28:283-290
Teboul, Lydia; Murray, Stephen A; Nolan, Patrick M (2017) Phenotyping first-generation genome editing mutants: a new standard? Mamm Genome 28:377-382
Brophy, Patrick D; Rasmussen, Maria; Parida, Mrutyunjaya et al. (2017) A Gene Implicated in Activation of Retinoic Acid Receptor Targets Is a Novel Renal Agenesis Gene in Humans. Genetics 207:215-228

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