International Mouse Phenotyping Consortium Mark Moore,
Ph.D.
Slide 2
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.
Slide 3
Nat Genet. 2004 Sep;36(9):925-7. The European dimension for the
mouse genome mutagenesis program. Auwerx JAuwerx 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, Mller 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.Avner PBaldock
RBallabio ABalling RBarbacid MBerns ABradley ABrown SCarmeliet
PChambon PCox RDavidson DDavies KDuboule DForejt JGranucci FHastie
Nde Angelis MHJackson IKioussis DKollias GLathrop MLendahl
UMalumbres Mvon Melchner HMller WPartanen JRicciardi-Castagnoli
PRigby PRosen BRosenthal NSkarnes BStewart AFThornton
JTocchini-Valentini GWagner EWahli WWurst W
Slide 4
Numbers of KOs reported per gene Number of targeted genes
Number of times each gene KOd
Slide 5
Money lost due to repetitive work 3308 unique genes have been
KOd 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
Slide 6
KOMP Goals: Phase 1 a high-throughput international effort to
produceknockouts 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
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KOMP-IMPC Alleles WTSI (Allan Bradley and Bill Skarnes)
Helmholtz (Wolfgang Wurst)
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KOMP-IMPC Alleles Regeneron Approach
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IKMC Alleles
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The KOMP Repository www.komp.org
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KOMP Repository Activities
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KOMP Customer orders by month Late 2008 early 2010 Each order
saves $20,000-50,000 KOMP is already saving more money than it
spends
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KOMP + Other Goals and Progress
Slide 14
The IKMC have produced over 10,000 KO ES cell lines
Slide 15
IKMC
Slide 16
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)
ECfunded EUMODIC (Helmholtz, Munich; ICS, Strasbourg, MRC Harwell,
WTSI) project is now doing broad-based phenotyping of 500 mutant
lines completion 2011 Phenotyping Background
Slide 17
Why the IMPC Build a resource of KO mice and associated
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
Slide 18
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) The
International Mouse Phenotyping Consortium (IMPC) Steering
Committee Secretariat (Mark Moore, Jrg Robacher)
Slide 19
IMPC Vision IKMC (2006-11) ARRA (2010-11) EUMODIC (2008-11)
IMPC (2011-21) PI Driven
Slide 20
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 Embryology Imaging
Technologies Working to actively manage the coordination and
development of the multiple centres Launch Phase II 2011?
Slide 21
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
Slide 22
Rationale Supporting a broad phenotyping effort would provide
the following advantages: A single cohort of mice would go through
multiple phenotyping 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.
Slide 23
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
Please list the top 3 diseases that have been modeled using
knockout mice. Disease or condition# of votes Cancer21 immune
system diseases7 obesity7 Alzheimers5 atherosclerosis5 diabetes5
ApoE heart disease2 autoimmunity2 cyctic fibrosis2 Huntington
Disease2 Stem cells- bone marrow transplants2
Slide 28
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# of votes cancer15
Aging5 epigenetics4 stem cells4 embryogenesis3 brain function2
consciousness2 degenerative nerve disease2 Heart disease2 Memory2
organogenesis2 regeneration2 schizophrenia2
Slide 29
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 (100s/y). behavior metabolism immuno MMRC Survey
Conducted by Kent Lloyd
Slide 30
Survey Summary Report MMRC Survey Conducted by Kent Lloyd
>2000 e-mails and ~300 respondents
Slide 31
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
Slide 32
IMPC Phenotyping Core group of tests at all centres Agreed upon
minimum cohort size (7?) Test and recommend additions to or
dropping phenotypic 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
Slide 33
Phenotyping Progression Primary Screen (Thousand(s) per years)
Second Level Testing (Hundreds per year ) Tertiary In-Depth (dozens
per year)
Slide 34
Mouse Phenotyping and Production/Distribution Centers Mouse
Clinics ES to mouse Production (optional) Archiving (optional)
Primary Phenotyping Secondary Phenotyping Production Centers
Re-animation Mouse production ArchivingDistribution Secondary
Phenotyping
Slide 35
IMPC Next Steps Form Steering Committee Develop Requirements
Document Informatics Explore new ways to lower mouse costs Continue
exploring commercial options Mice Form Tech Development Group First
Tasks: Imaging Recommendation (&Pathology) Embryonic Lethal
Analysis Tech Dev Develop final plan for IMPC Pipeline Operating
plan for review of pipeline Phenotyping Working groups in each area
Devise how to test models at centers Challenge Models
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IMPC Cost Projections
Slide 40
IMPC Phase II Projections Phenotyping the remaining 15,000 KOs
Project Costs
Slide 41
Next 3 years (2010-2013) EUMODIC project will come to
completion UC, Davis has funding to support the creation and
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
Slide 42
IMPC, a global and still expanding research initiative:
Download link of procedure to join the IMPC