Phenomics is a forward genetic approach where researchers start with a particular trait or phenotype and discover the causal gene. Our approach uses genome-wide chemical mutagenesis of mouse spermatogonia with EthylNitrosourea (ENU) that allows a high fraction of mammalian genes to be altered without any prior assumptions or knowledge about their physiological roles. Pedigrees of these gene-variant mice can be scanned for phenotypes of interest in a highly parallel fashion. The point-mutations produced by ENU yield a large range of gene variant alleles, creating loss of function defects in individual protein domains and splice variants, partial function, and overactive versions that can reveal different functional roles that are not revealed by complete absence of a protein product. The APF produces libraries of ENU-gene variant mice on inbred, intercross, or genetically sensitised backgrounds. These libraries are structured for detection of new recessive or dominant alterations in mammalian physiological or pathological processes. The pedigrees are designed so the offspring at the G3 stage from any one G2 breeder pair will carry approximately 20-30 homozygous recessive random gene mutations with each appearing at a modal frequency of 1/4. A minimum of 12 mice in each family are screened so that multiple mice (on average 3/12) will show the same phenotypic trait ensuring reproducibility in this pedigree before being chosen for further analysis.

The APF also offers gene-variant research strains that have already been identified and serve as valuable unique models for investigating allergy, obesity, autoimmunity, neurological, cancer and development.

Why mouse models?

In humans too many genes vary at once between individuals, too many uncontrolled environmental factors vary at once and small family sizes make it difficult or impossible to experimentally interconnect variations in genes with phenotype (biochemistry, cells and whole organism).

Mice are ideal for deciphering how the mammalian genome translate into the phenome as their gene sets match up almost perfectly with the human genome. Mice can be easily inbred into large family sizes with identical genomes so that variation in a gene that alters their phenotype can be found. These gene variant mice can be expanded in a controlled environment and are easily studied by further cell experimental analysis allowing the discovery of mechanism from gene alteration to phenotype that cannot be carried out in humans.

What is phenomics good for?

Advantages of phenomics approach include:

• Understanding causal relationships between genes and traits.
  
• Dissecting protein functions: ~60% of variants are mis-sense alleles with single amino acid substitutions in specific domains.
  
• Revealing completely unknown components and mechanisms.
  
• Revealing different mechanisms compared to knocking out entire gene. (Protein Domain specific effects)
  
• Allows the researcher to focus on his/her relevant disease or pathway relevant gene variants: Sets of gene variant families clustered on a specific process shapes view of process.
  
• Develop pre-clinical animal models of human disease
  

Broader Applications of phenomics research lead to:

• Drug and vaccine development for human health
  
• Develop discovery tools
  
• Health care delivery
  
• Diagnostic testing
  
• Assisted breeding in livestock
  
• Epidemiology in both human and animal health and
  
• Conservation and control of native or feral animals