Genes Phenotypes

What is IMPC?


IMPC Members

The IMPC is currently composed of 19 research institutions and 5 national funders from 11 countries.

What does IMPC do?

Mouse production and phenotyping
  • Standardized allele production and phenotyping pipelines
Data analysis
  • Quality control
  • Statistical analysis
  • Disease association
Data distribution
  • Free data access and visualizationl
  • Embryonic and adult data
  • Human disease association
  • ES cells and mouse ordering

How does IMPC work?

Allele design
The IMPC consortium is using different targeting strategies that have different and complementary properties to produce Knockout alleles. Below is a general outline of all the targeting strategies used by IMPC teams.

This strategy relies on the identification of a 'critical' exon common to all transcript variants that, when deleted, creates a frame-shift mutation. The Knockout first allele is flexible and can produce reporter knockouts, conditional knockouts, and null alleles following exposure to site-specific recombinases Cre and Flp. Promoterless and promoter-driven targeting cassettes are used for the generation of a 'Knockout-first allele' in C57BL/6N embryonic stem cells (Pettitt et al., 2009).
These two strategies have been shown to yield different targeting efficiencies (Skarnes et al., 2011).
"Targeted, non-conditional " alleles (tm1e) are missing the downstream loxP site. The 3’ loxP site is often lost due to recombination events in the homology region between the targeting cassette and 3’ loxP site. These mutations cannot be converted to conditional alleles following Flp treatment.

Standard deletion alleles with the promoter-driven targeting cassette:
Number of available derivative alleles:
  • tm1a: KO first allele (reporter-tagged insertion allele): 0
  • tm1b: Reporter-tagged deletion allele (post-Cre): 0
  • tm1c: Conditional allele (post-Flp): 0
  • tm1d: Deletion allele (post-Flp and Cre with no reporter): 0
  • tm1e: targeted, non-conditional allele: 0
  • tm1: Reporter-tagged deletion allele (with selection cassette): 0
  • tm1.1: Reporter-tagged deletion allele (post Cre, with no selection cassette): 0
  • tm1.2: Reporter-tagged deletion allele (post Flp, with no reporter and selection cassette): 0
In most cases this design will result in complete null alleles that delete the entire protein coding sequence of the target gene. This allele design can be applied to any gene transcribed by RNA polymerase II regardless of its size, intron-exon structure, RNA splicing pattern, or protein-coding capacity (Valenzuela et al., 2003).

VelociGene lines available:

IMPC alleles viable for high throughput pipieline

  • (i) Small Deletions (single cut strategy)
  • (ii) Exon Deletion / large Deletions (2 cut strategy)

Alleles on request

  • (i) Loxp-flanked critical regions
  • (ii) Point Mutations
  • (iii) Conditional & lacZ reporter Allele - Insertion of dsVector

CRISPR alleles available:
  • Total:
  • NHEJ Alleles (small deletions):
  • Large Deletion/ Exon deletion:
Coordinated production

Coordination

The IMPC is a confederation of international mouse phenotyping projects working towards the agreed goals of the consortium: To undertake the phenotyping of 20,000 mouse mutants over a ten year period, providing the first functional annotation of a mammalian genome.

The IMPC Steering Committee provides the governance for the overall consortium. Participants are tasked with making key strategic decisions including selection of participating organizations, approving and coordinating key operational decisions such as phenotyping platforms and pipeline used, quality assurance and operating standards, and IT organization. Membership provides stakeholders with an opportunity to influence key activities as they develop.

Embryo and Adult Mouse phenotyping protocols

The Adult and Embryonic Phenotype Pipeline

The IMPC (International Mouse Phenotyping Consortium) core pipeline describes the phenotype pipeline that has been agreed by the research institutions. The pipeline is currently in development. The protocols in the core IMPC Pipeline are currently being developed by the IMPC phenotyping working groups and the current versions on this site are still under final review. The phenotyping working groups are working closely with the data wranglers to complete an agreed first version. Updates on the progress of this will be available through IMPReSS.

You can click on the protocols below for more information.

The IMPC Pipeline Fertility Viability Histopathology Embryo Histopathology Placenta Gross Morphology Embryo Gross Morphology Placenta Viability Embryo LacZ Embryo LacZ Gross Morphology Embryo Gross Morphology Placenta Viability Gross Morphology Embryo Gross Morphology Placenta Viability Gross Morphology Embryo Gross Morphology Placenta Viability Body Weight Open Field CSD Grip Strength Acoustic Startle Calorimetry Echo ECG Challenge IPGTT X-ray ABR Body Composition Eye Morphology Hematology Adult LacZ Clinical Chemistry Insulin Blood Level Immunophenotyping Heart Weight Gross Pathology Tissue Embedding Histopathology OPT E9.5 MicroCT E14.5-E15.5 MicroCT E18.5
Statistics to Phenotype

Statistics to Phenotype

The selection of the statistical method is an important step in the process of phenotype data analysis and is dependent on the experimental implementation, and the variable characteristics (e.g. continuous or categorical).

The statistical analysis was done using an R package developed for IMPC called PhenStat.
PhenStat is a statistical analysis tool suite developed based on known variation in experimental workflow and design of phenotyping pipelines (Kurbatova N et al, 2015).

• Categorical data analysis was performed using a Fisher’s Exact test. Concerning continuous data, it has been shown that gender, weight, and environmental effects (batch) are a significant source of variation. See

• Continuous data analysis was performed with the PhenStat Mixed Model (MM) framework which uses linear mixed models where batch is treated as a random effect. Details of the implementation, including decision tree and models descriptions, are available in the PhenStat package user's guide.
 
• For viability and fertility data, the center conducting the experiment use a statistical method appropriate for the breeding scheme used (exact details are available on the IMPC data portal) and supplied the analysis results to the IMPC.

Following statistical assessment, if the mutant genotype effect represents a significant change from the control group, then the IMPC pipeline will attempt to associate a Mammalian Phenotype (MP) term to the data. The particular MP term(s) defined for a parameter are maintained in IMPReSS. Frequently, the term indicates an increase or decrease of the parameter measured. more details about how IMPC uses statistics and call for phenotypes can be found in the documentation section.
Human disease association

More information about the way IMPC uses disease data.

Explore Disease Data

The ultimate goal of studying model organisms is to translate what is learned into useful knowledge about normal human biology and disease.

The IMPC disease details page contains known gene associations (via orthology to human disease genes) and known mouse models from the literature (from MGI) for the disease as well as predicted gene candidates and mouse models based on the phenotypic similarity of the disease clinical symptoms and the mouse phenotype annotations. The phenotypic similarity is calculated using the PhenoDigm algorithm (Phenotype comparisons for DIsease Genes and Models) developed by the Monarch Initiative which will allow integration of data from model organisms to identify data-supported gene candidates for human genetic diseases (Link to Methods). Mouse Genotype-Phenotype and Human disease resources are described below.

Disease details pages

Results are broken down in 2 parts, depending on the association methodology (by gene orthology or by phenotypic similarity).

Clicking the row for a disease/gene will expand the row to show the details of the phenotype terms involved in the association between the disease and the mouse model. The orange number next to the genotype is the PhenoDigm score (see below) which is a percentage-based score . These are ranked from highest to lowest in two groups. The first group will show the manually curated mouse models from MGI. The second group will list the purely phenodigm predicted associations.

1: By Gene Ortholgy
Human genes/regions causing human disease were extracted from human disease resources described above. Matching mouse orthologues were identified from HomoloGene and associated mouse models were retrieved from IMPC and MGI resources. Phenotypes corresponding to mouse models were then compared to human phenotypes gene matched human disease using PhenoDIgm. Depending on the similarity between the phenotypes, a PhenoDigm score is calculated based on the number and specificity of the matches between the human and mouse phenotypes where 100% represents a perfect match and 0% no match.

2: By Phenotypic Similarity
We compared Mouse and Human Phenotypes using Phenodigm to provide evidence about gene-disease associations. Mouse phenotypes were extracted from mouse models from the IMPC and MGI repositories. Mouse phenotypes were then compared with human disease/phenotypes extracted from human disease resources (OMIM, ORPHANET, DECIPHER) using PhenoDigm as above. In this interface, we only display high-scoring (> 60%) matches that show a reasonable phenotypic similarity between the two species.

Human disease resources

Source Description
OMIM (Online Mendelian Inheritance in Man) An Online Catalog of Human Genes and Genetic Disorders
Orphanet The portal for rare diseases and orphan drugs
DECIPHER (DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resource) Interactive web-based database which incorporates a suite of tools designed to aid the interpretation of genomic variants

Mouse Genotype-Phenotype resources

Source Description
IMPC (International Mouse Phenotyping Consortium) Functional catalogue of mouse mammalian genome
MGI (Mouse Genome Informatics) International database resource for the laboratory mouse

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