Knockout Mouse Phenotyping Project (KOMP2)

1. Design, produce and systematically phenotype a null mutation mouse line across the mouse–human orthologous genome to provide insights into gene function, disease genetics, pleiotropy and co-morbidity.
    
   • KOMP2 and IMPC have developed standardized pipelines for phenotyping knockout mouse strains at embryo, early adult and late adult stages. Null alleles are produced in numerous ways, with an expanded focus on CRIPSR technology to increase the output of mouse mutants.
      
2. Prioritize mouse–human orthologous genes and their proteins that are poorly understood with no or minimal knowledge on biological function and limited tools for their analysis (the “dark genome”).
    
   • Over 16,000 genes in mice have been identified as existing in both humans and mice. KOMP2 and IMPC have produced at least 9,700 of the approximately 13,000 knockout strains that currently exist, leaving 3,000 genes to be prioritized in the mutagenesis effort.  
      
3. Partner with the human genetics and clinical community to produce bespoke mouse mutants with human disease-associated coding variants to confirm pathogenicity, susceptibility or resistance to infection and accelerate research and discovery.
    
   • KOMP2 extends its impact through several collaborations with large-scale research projects and programs, including:
      
     1. Gabriella Miller Kids First Pediatric Research Program (NIH Common Fund): KOMP2 and Kids First are collaborating on a pilot project to create mouse strains to study, phenotype and validate coding and non-coding genetic variants (e.g., missense, structural variants, copy number variants, INDELS and frameshifts) identified from Kids First datasets. The IMPC and Kids First will continue to collaborate, investigating more genes to find links between birth defects and childhood cancer.
         
     2. Illuminating the Druggable Genome (NIH Common Fund): KOMP2 is generating knockout mouse strains for the IDG project. The IDG project is studying human genes that can be mapped to mouse orthologues. The IMPC can then generate and phenotype knockout mouse models for these orthologues. The IMPC currently has data for 41% of IDG’s target genes across 25 groups of phenotypes, including ageing, reproductive, immunity, craniofacial, nervous, renal, cardiovascular and others.
         
     3. Undiagnosed Disease Network (NIH Common Fund): The UDN uses KOMP2/IMPC data and mouse models to assist diagnoses. The phenotype data can provide evidence to support the pathogenicity of variants associated with rare and undiagnosed disease cases, and mouse models provide resources for functional studies for pathogenicity and therapeutic approaches.
         
4. Develop and distribute technology and resources that can enhance understanding of the functional relationship between human genetic variation (coding and non-coding), environment and disease. It will also explore in vivo the mechanisms of genetic variation in health and disease.
    
   • KOMP2 and IMPC research yields valuable insights across biomedical research, made evident through over 4700 publications, the accessibility of information through multiple open-access resources and the use of knockout data in pre-clinical studies and therapeutic target discovery.

For more information about the International Mouse Phenotyping Consortium (IMPC), please visit IMPC Consortium and IMPC Workshops.

To learn more about the Mutant Mouse Resource and Research Centers (MMRRC), please visit the MMRRC website.