EuroPhenome and the International Mouse Phenotyping Consortium John Hancock MRC Harwell

1. EuroPhenome and the International Mouse Phenotyping Consortium John Hancock MRC Harwell

2. “High throughput” phenotyping • Systematic phenotyping of a mouse line using a battery of simple tests to detect defects in as many body systems as possible • e.g. SHIRPA • Obtains the maximum coverage of phenotype in the shortest possible time • Still takes c. 15 weeks

3. High Throughput Phenotyping • EUMODIC • Generate knockout ES cells (EUCOMM, KOMP, NorCOMM) • Make mice • Carry out high throughput phenotyping using standardised protocols (SOPs) • Provide data to wider community via a database

4. EMPReSS-slim - Pipeline for High Throughput Phenotyping

5. EMPReSS • 86 Standard operating procedures (SOPs) • (Dys)morphology • Cardiovascular • Metabolic • Haematology/Clinical Chemistry • Allergy/Immunology • Behaviour • Sensory • Pathology • http://empress.har.mrc.ac.uk

7. EuroPhenome - Data Capture • MIMPP-compliant data files (XML) • Nightly XML file upload from phenotyping centres Validation • Validation with EMPReSS e.g. Parameters/units/bounds

8. EuroPhenome http:www.europhenome.eu

9. The EQ + PATO Approach • E = Entity, e.g. tail, derived from an ontology such as anatomy • Q = Quality, derived from the Quality Ontology PATO • Can be used to build up a description of an atom of phenotypic data…

10. E+Q - An Example Currently in use in EuroPhenome DB

11. “Mine for a Mutant” in EuroPhenome

12. Finding Phenodeviants via MouseBook

13. View from EuroPhenome

14. International Mouse Phenotyping Consortium • 1st Aim: To characterise the phenotype of c. 20,000 mouse gene knockouts in the next 10 years • Establish new phenotyping centres (Infrafrontier) • Develop the EMPReSSslim pipeline to provide the best possible first-line screen • Informatics Discussion…

15. IMPC Informatics EUMODIC as a model What lessons can be learnt? Tear it up and start again? Access to data As quick as possible QC? Single IMPC portal (but DB should provide WS access) Big Question: One single database? (location?) Continental level repositories (identical infrastructure?) Many individual, interlinked DBs

16. Protocols Phenobabelomics Need Efforts To Facilitate The Linking Of These Data Sets Detailed Descriptions Mutant Data Baseline Data

17. Interphenome (MPDIC) Consortium Mammalian Genome18, 157-163 (2007)

18. Three broad requirements • Common data description • Common protocol description • Standard for data exchange Interphenome discussion are ongoing Last meeting in Prague (2 Nov 08)

19. Mouse Models, Human Disease How to we relate mouse phenotypes to human diseases? • Diseases are made up of individual phenotypes, as we understand them • Presence of only a subset of phenotypes may be enough to diagnose a disease • Phenotype -> OMIM mapping not good enough

20. Human DISEASE Interpreter Phenotypic Attributes Phenotypic Attributes Phenotypic Attributes Phenotypic Attributes Mouse Phenotypic Attributes Phenotypic Attributes Phenotypic Attributes Phenotypic Measures Phenotypic Measures Phenotypic Measures PHENOTYPING Mouse Phenotype to Human Disease

21. Ann-Marie Mallon Andy Blake Simon Greenaway Tim Beck Hugh Morgan Octavio Espinosa Georgios Gkoutos Eain Green Joe Weekes Paul Schofield Christoph Lengger Hiroshi Masuya EUMORPHIA EUMODIC The Interphenome group CASIMIR Thanks To… MRC and the EU for funding

23. Use of Ontologies in EuroPhenome:What is an Ontology? Essentially a controlled vocabulary with defined relationships and definitions, e.g.: Head Sensory Organ {Is_A} {Part_Of} Ear Nose Brain Ear Nose Tongue Allows us, for example, to identify other parts of the head that might be affected

24. E: tail + Q: length [assayed by] measurement of tail length by ruler [unit] cm returns value Q: increased length 5 Inferred qualitative description Long tail MP:0002758 Normal value, e.g. from EuroPhenome E+Q - An Example Currently in use in EuroPhenome DB

25. High Throughput Phenotyping - EUMORPHIA and EUMODIC EUMORPHIA • FP5 project involving 19 partners • Generate standard set of phenotyping SOPs • EMPReSS: European Mouse Phenotyping Resource for Standardised Screens • EMPReSS online resource

26. IMPC Informatics • Compatibility between centres - schemas for exporting data into compatible format - share software • Single site for user to view data - raw data, analysis tools • Dedicated group (neutral?) • Unified, central database? • Build on current efforts/rebuild? • Networked closely to phenotyping centres - responsible for information standards, ontology development etc. • Dissemination • Genome browser • Search on phenotype ontology terms e.g. at MGI • Links with OMIM, search from human phenotypes (mapping mouse phenotypes onto human and vice versa)

27. IMPC Informatics • Analysis • Many tools already available • Compare allele to allele to wild type • Internal organisation - coordination • Cross-talk - committees/groups (including external experts) to leverage and learn from ongoing efforts in data outputs/capture/data structure… • InterPhenome as an example - extend, introduce experts and advisory board • Wikis for genes • Need dollars/euros • Data release • As the data is generated - need formal agreement • Resources: 20-40 people? Need considerable investment