International Mouse Phenotyping Consortium
Mark Moore, Ph.D.
A meeting at the Banbury Centre, Cold Spring
Harbor in 2003 published a proposal for high
throughput Gene Knockouts and Phenotyping for
every gene in the mouse genome.
Nat Genet. 2004 Sep;36(9):925-7.
The European dimension for the mouse genome mutagenesis program.
Auwerx J, Avner P, Baldock R, Ballabio A, Balling R, Barbacid M, Berns
A, Bradley A, Brown S, Carmeliet P, Chambon P, Cox R, Davidson D, Davies
K, Duboule D, Forejt J,Granucci F, Hastie N, de Angelis MH, Jackson I, Kioussis
D, Kollias G, Lathrop M, Lendahl U, Malumbres M, von Melchner H, Müller
W, Partanen J, Ricciardi-Castagnoli P,Rigby P, Rosen B, Rosenthal N, Skarnes
B, Stewart AF, Thornton J, Tocchini-Valentini G, Wagner E, Wahli W, Wurst W.
Numbers of KOs reported per gene
Number of targeted genes
140
120
100
80
60
40
20
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
Number of times each gene KO’d
Money lost due to repetitive work

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3308 unique genes have been KO’d
6310 total number of mice (all alleles)
Approximately 3,000 re-hits
Assume a cost of $50,000/KO
 repeats of no additional value
 10% represents 300 = $15,000,000
 25% represents 750 = $37,500,000
 50% represents 1,500 = $75,000,000
 80% represents 2,400 = $120,000,000
KOMP Goals: Phase 1
•
“…a high-throughput international effort to produce…knockouts for all mouse
genes, and place these resources into the public domain.”
• KO alleles
– null, ideally “conditional-ready” (loxP or flp)
– contain reporter (LacZ or EGFP)
• Methods
– combination of targeting and trapping
• Deliverables
– mutant ES cell lines, sperm, frozen embryos
– Public domain resource
• Beyond Phase 1
– histochemical analysis of transgene expression
– phenotypic data
– searchable database
KOMP-IMPC Alleles
WTSI (Allan Bradley and Bill Skarnes)
Helmholtz (Wolfgang Wurst)
KOMP-IMPC Alleles
 Regeneron Approach
IKMC Alleles
The KOMP Repository
www.komp.org
KOMP Repository Activities
KOMP Customer orders by month
Late 2008 – early 2010
180
R2 = 0.6
Each order saves $20,000-50,000
KOMP is already saving more
money than it spends
160
140
168
160
143
139
132
121
104
103
Jun-09
Jul-09
98
100
87
89
92
90
115
85
80
60
45
40
20
Feb-10
Jan-10
Dec-09
Nov-09
Oct-09
Sep-09
Aug-09
May-09
Apr-09
Mar-09
Feb-09
Jan-09
Dec-08
Nov-08
Sep-08
0
Oct-08
Number of orders
115
114
120
KOMP + Other Goals and Progress
The IKMC have produced over 10,000 KO ES cell
lines
IKMC
Phenotyping Background
• 3 workshops: Rome in 2007, Bar Harbor and Toronto in
2008 to establish vision for an IMPC & discuss
international, coordinated phenotyping efforts –
agreed that the way forward is to develop a business
plan
• Medical Research Council/Wellcome Trust workshops
in Nov 2008 and Oct 2009 to engage UK scientific
community
• NIH Phenotyping meeting, Bethesda October 2009
(survey)
• EC–funded EUMODIC (Helmholtz, Munich; ICS,
Strasbourg, MRC Harwell, WTSI) project is now doing
broad-based phenotyping of 500 mutant lines –
completion 2011
Why the IMPC
 Build a resource of KO mice and associated
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encyclopedia of gene functions
Free thousands of researchers from tool generation
This resource will be revolutionize research for the
next 20-30 years
Novel genes will be brought to light that would
otherwise be ignored
Potential for breakthrough discoveries
The International Mouse Phenotyping Consortium
(IMPC) Steering Committee
• MRC Harwell (Steve Brown, current Chair, Tom Weaver)
• MRC (Nathan Richardson, Paula Clements)
• NIH (Jane Peterson, Eric Green, Jim Battey, Colin Fletcher,
Martin Guyer)
• Sanger Institute (Alan Bradley, Karen Kennedy)
• Wellcome Trust (Michael Dunn, Clare McVicker)
• Infrafrontier (Martin Hrabe de Angelis)
• Helmholtz Zentrum Munich (GMC) (Martin Hrabe de Angelis)
• Toronto Centre for Phenogenomics (TCP) (Colin McKerlie)
• Institut Clinique de la Souris (ICS) (Yann Herault)
• Australian Phenomics Network (Adrienne McKenzie)
• European Commission (Jacques Remacle, observer)
• Secretariat (Mark Moore, Jörg Roßbacher)
IMPC Vision
PI Driven
IMPC (2011-21)
ARRA (2010-11)
EUMODIC (2008-11)
IKMC (2006-11)
IMPC Progress
 Addition of new members bringing total to 10
 4 Funding Organizations
 6 Mouse phenotyping Centers
 Response to community-wide surveys
 Development of workshops
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Embryology
Imaging Technologies
 Working to actively manage the coordination
and development of the multiple centres
 Launch Phase II 2011?
IMPC Activities
 Six mouse clinics so far; anticipate 10-12 worldwide.
 Phase I (2011-2016) of the preparatory/development
period ~4,000
 Work to actively manage the coordination and
development of the multiple centres
 Evaluate a final scientific, management and
governance plan for the full scale programme to
commence in 2016
 Launch Phase II 2016-2021 Completion of the
Genome
Rationale
 Supporting a broad phenotyping effort would
provide the following advantages:
 A single cohort of mice would go through multiple phenotyping
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assays, so the cost of producing multiple cohorts in different
laboratories for phenotyping would be eliminated.
Each mutant mouse strain would be characterized for a broad set of
phenotypes in a way that will allow direct comparisons and result in
a more thorough description of gene function.
Quality standards will be established and maintained, so the data
will be of the highest reliability.
The risk of not finding a phenotype will be greatly reduced.
Important, but unpublishable, negative results will be captured.
IMPC Phenotyping Proposal
The proposal will be shaped by:
 EUMODIC results
 The Sanger MGP
 Publicly available data (Lexicon and Deltagen)
 ENU screens phenotyping results
 Survey Results from UK, NIH, EU
 Recommendations from workshops in the UK
and US
 Future workshops in Europe, US, Canada and UK
EMPReSSslim Primary Phenotyping Pipelines
20 phenotyping platforms
406 phenotype parameters
155 metadata parameters
WTSI Mouse Genetics Program
If No, then why? Limited
Challenge
Models
(e.g.
infectious
agents)
Area not
covered
Funding
Tests
Superficial
and
Insensitive
2009 Mouse Pipeline Survey
Please list the top 3 diseases that have been
modeled using knockout mice.
Cancer
immune system diseases
Disease or condition
# of votes
Cancer
21
immune system diseases
7
obesity
7
Alzheimers
5
atherosclerosis
5
diabetes
5
ApoE heart disease
2
autoimmunity
2
cyctic fibrosis
2
Huntington Disease
2
Stem cells- bone marrow transplants
2
obesity
Alzheimers
atherosclerosis
diabetes
ApoE heart disease
autoimmunity
cyctic fibrosis
Huntington Disease
Stem cells- bone marrow
transplants
Others
Please list the top 3 questions in biology or medicine that you
feel remain to be answered...and that you think could best be
studied using knockout mice.
Topic of question
cancer
# of votes
Aging
cancer
15
Aging
5
epigenetics
4
stem cells
4
embryogenesis
3
brain function
2
consciousness
2
degenerative nerve disease
2
Memory
Heart disease
2
organogenesis
Memory
2
regeneration
organogenesis
2
schizophrenia
regeneration
2
Others
schizophrenia
2
epigenetics
stem cells
embryogenesis
brain function
consciousness
degenerative nerve disease
Heart disease
Survey Summary Report
Question #2: Thinking beyond your laboratory, what do you see as the 3 essential tests, analyses,
and/or examinations that would most likely reveal the utility of a mutant mouse line in your
field? Two caveats: the numbers of mice used per test are limited to 5-10 and the tests must be high
throughput (100’s/y).
immunity/infection/inflammation/arthritis/a…
diabetes/metabolism/mitochondrial/endocri…
behavior/neurology/sleep
histology/morphology
hematology/FACS/bleeding
embryonic…
blood chemistry/lipid levels
body composition/diet/growth…
reproduction/litter size/puberty
gene expression
bone density/bone morhology/bone strength
EKG/cardiac defects/cardiovascular…
cancer
proteomics/genotyping/gene…
retina/vision/ophthalmology
imaging/microCT
lacZ
hypertension
hearing
muscle
aging
GI
urinalysis
genotoxic sensitivity/radiation…
biochemistry/cell biology
respiratory
dermatology/hair
karyotype/stem cells
oral/teeth
olfactory
exercise
pharmacodynamics
renal function
vocalization
wound healing
secretory gland
function tests
thrombosis
immuno
behavior
174
205
181
metabolism
MMRC Survey Conducted by
Kent Lloyd
Survey Summary Report
What is missing?
Circ/sleep
Diet challenge
Eye/retina
Behavior
CVS
Fertility
Auditory
Immune challenge
M/S soft
Urinalysis
Gene expression
Histopath
Learn/memory
Cancer
Embryogenesis
MMRC Survey Conducted by Kent Lloyd
>2000 e-mails and ~300 respondents
Key Areas of Unmet Need
Cancer
• Need longer time
line to study
• Fits with aging
• Challenge?
Aging
• Critical need cited
in all surveys and
workshops
• Strongly augments:
Cancer,
Cardiovascular,
Metabolic,
Neurodegeneration
and Bone Research
Embryology
• A rich source of
phenotype data
• ~30% KOs E.L.
• Very Specialized
Skill Sets Req.
• Need HTP
approach
• Meeting at TCP
April 9-10
IMPC Phenotyping
 Core group of tests at all centres
 Agreed upon minimum cohort size (7?)
 Test and recommend additions to or dropping phenotypic
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tests from the pipeline
Groups are encouraged to add tests to the phenotyping
platform where possible
Each centre is encouraged to incorporate a challenge assay
or assays to the platform
Each centre should develop networks of collaborators
MRI and/or micro CT likely to be added
Incorporate study of embryonic lethals
Phenotyping Progression
Primary Screen
(Thousand(s) per years)
Second Level Testing
(Hundreds per year)
Tertiary In-Depth
(dozens per year)
Mouse Phenotyping and
Production/Distribution Centers
Mouse
Clinics
Production
Centers
ES to mouse
Production
Re-animation
(optional)
Archiving
(optional)
Primary
Phenotyping
Secondary
Phenotyping
Mouse
production
Archiving
Distribution
Secondary
Phenotyping
IMPC Next Steps
Informatics
Mice
Tech Dev
• Form Steering Committee
• Develop Requirements Document
• Explore new ways to lower mouse costs
• Continue exploring commercial options
• Form Tech Development Group
• First Tasks: Imaging Recommendation (&Pathology)
•
Embryonic Lethal Analysis
Phenotyping
• Develop final plan for IMPC Pipeline
• Operating plan for review of pipeline
Challenge Models
• Working groups in each area
• Devise how to test models at centers
IMPC Cost Projections
IMPC Phase II Projections
Project Costs
Phenotyping the
remaining 15,000 KOs
Next 3 years (2010-2013)
 EUMODIC project will come to completion
 UC, Davis has funding to support the creation and
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limited analysis of 312 KO mouse lines
The WTSI is funded to analyse 200 KO lines per year
MLC Harwell planning to analyse 100 KO lines per year
Toronto Centre for Phenotyping (TCP) has capacity to
produce and analyse 100-200 KO mouse lines per year.
InfraFrontiers is developing the vital infrastructure for
the continuation and expansion of mouse
Phenotyping New centres at UAB (Barcelona) and the
Czech Republic will be constructed and come online
NIH has raised funding to launch Phenotyping
IMPC, a global and still expanding research initiative:
Download link of procedure to join the IMPC