CottonR HVPsession ASHG2007

The Human Variome Project: 

The Human Variome Project Richard G.H. Cotton Genomic Disorders Research Centre Melbourne, Australia 25 October 2007 ASHG – HVP Session

What is the Human Variome Project?: 

What is the Human Variome Project? Variome – Variation in a genome Human Variome Project – Collection & Distribution of Human Variation & its phenotype Initiated 20-23 June, 2006 in Melbourne, Australia

Vision: 

Vision A public catalogue of curated variation in each of 24,000 genes & associated phenotypes/studies An automated system of submission and review Improved genetic healthcare and research outcomes

Why is it important?: 

Why is it important? Premise I It has been estimated that 60% of all humans will be affected by mutation in a lifetime (Baird P., et al. 1988) [This does not include carers, other members of the family and cancer]

Why is it important?: 

Why is it important? Premise II 70% of admissions to a major US Paediatric hospital had a genetic basis (S.E. McCandless et al, 2004)

Why is it important?: 

Why is it important? Premise III For Proper and efficient health care and research instant access is needed to up-to-date and accurate lists of mutations/variations in genes which affect human health A diagnostic laboratory dealing with colon cancer suggests 1 Senior staff salary could be saved (C. Meldrum)

When did work start?: 

When did work start? 1949 First globin mutations 1970’s McKusick collected mutations – OMIM 1980’s Cooper collecting mutations – HGMD 1994 Agreement – curation of best done by experts in a gene 1995 HUGO Mutation Database Initiative 2003 Human Genome Variation Society 2006 Human Variome Project

Problems faced – Mendelian disorders: 

Problems faced – Mendelian disorders Variable curation software Literature errors – e.g. 43% Different nomenclatures Lack of funding User interfaces poor Lack of coordination Lack of recognition Confidentiality/privacy aspects Information about each variable

Problems faced – Mendelian disorders (cont.): 

Problems faced – Mendelian disorders (cont.) Different levels of curation No formal collection required Patchy reporting of phenotype Lack of incentive, time & software to report Commercial protection of data Difficulty of publishing mutations Variable cross searchability Excellent efforts to contribute but in isolation Little biochemical expression work

Why are we in this situation: 

Why are we in this situation Divided and no voice – Thousands of small unrelated voices Diagnosis costly and extremely specialised Common disease more fashionable Databases between research and service Maintenance costs into the future

Current mutation databases: 

Current mutation databases 2 major central/general mutation databases OMIM/HGMD dbSNP - NCBI Many “conduit” databases HOWDY 683 gene or locus specific databases LSDBs 2056 Genes with >1 mutation HGMD (public version as at 14th August, 2007) Ethnic databases

The Cystic Fibrosis Illustration(as at 18th October, 2007): 

The Cystic Fibrosis Illustration (as at 18th October, 2007) OMIM – 136 mutations - – 6 linked to dbSNP dbSNP – 926 variations CFTRdb – 1547 mutations – Difficult to place mutation on sequence HGMD – 1208 mutations (public version) – 1298 mutations (private version)

Problems faced – SNP/Association studies: 

Problems faced – SNP/Association studies Variable reporting of specific association No reporting of negative association studies Gene specific summaries not available Common disease specific summaries difficult to obtain e.g. HUGE Reviews

Solution to Raise Profile: 

Solution to Raise Profile The activity has been named the Human Variome Project Involvement of major bodies: WHO, UNESCO, OECD, EC, CDC (USA), Nature Genetics, Science/AAAS, etc. WHO and ACMG co-sponsored planning/resolution meeting held June 2006, Melbourne Australia, which initiated the project www.humanvariomeproject.org

Organisations Represented: 

Organisations Represented American College of Medical Genetics, U.S.A. ASHG, U.S.A. CDC, U.S.A. CLIA, U.S.A. EBI, Europe EuroGentest European Commission European Genetic Quality Control Group ESHG, Europe Google HapMap HGVS HuGENet HUGO HUGO - Gene Nomenclature Committee HGSA, Australia Human Genome Project International Federation of Human Genetic Societies March of Dimes, U.S.A. NCBI, U.S.A. NIH (Nat. Inst. on Aging) OECD WHO UNESCO Victorian Partnership for Advanced Computing

Journals Represented: 

Journals Represented American Journal of Human Genetics American Journal of Medical Genetics Annals of Human Genetics (Editor) Clinical Genetics European Journal of Human Genetics Genetics in Medicine Genome Research Genomics Human Genetics Human Genomics (Editor) Human Molecular Genetics Human Mutation (Editor) Journal of Inherited Metabolic Disease Nature Genetics (Editor)

Databases Represented: 

Databases Represented Locus Specific Databases: Breast Cancer: Larry Brody Duchenne Muscular Dystrophy: Johan den Dunnen Fanconi Anemia: Arleen Auerbach HLA: Steve Marsh InSiGHT: Annika Lindblom PAH: Charles Scriver Ethnic Specific Databases: United Arab Emirates: Ghazi Tadmouri General Databases: OMIM: Ada Hamosh dbSNP: Donna Maglott, Steve Sherry MutationView: Nobuyoshi Shimizu, Shinsei Minoshima HGVbase: Anthony Brookes HGMD: David Cooper represented by Anthony Brookes

Countries Represented: 

Countries Represented Argentina Australia Belgium Brazil Canada China France India Japan Mexico Netherlands Philippines South Africa Switzerland Tunisia United Arab Emirates United Kingdom United States of America Zimbabwe

Meeting Recommendations: 

Meeting Recommendations Recommendations from sessions Overall 96 recommendations (6th Oct 06) Published in Nature Genetics April 07 (free access on www.nature.com.ng/)

Planning Group: 

Planning Group Richard Cotton Russ Altman Arleen Auerbach Walter Bodmer Samir Brahmachari Anthony Brookes John Burn Peter Byers Jose-Maria Cantu Steve Chanock Pat Concannon Johan den Dunnen Richard Gibbs Li Jin Michael Katz Muin Khoury Mary-Claire King Pui-Yan Kwok Annika Lindblom Raj Ramesar C. (Sue) Richards David Rimoin Nobuyoshi Shimizu Graham Taylor Gert-Jan van Ommen Michael Watson

Planning Group – Observers & Consultants: 

Planning Group – Observers & Consultants Consultants Ewan Birney Aravinda Chakravarti Victor McKusick Neil Risch Charles Scriver Lincoln Stein Douglas Wallace David Weatherall Yusuke Nakamura Observers Victor Boulyjenkov (WHO) Julia Hasler (UNESCO) Jacques Remacle (EC) Christina Sampogna* (OECD)

Draft Working Groups based on headings of recommendations: 

Draft Working Groups based on headings of recommendations Coordination The Clinic and Phenotype Diagnostic Laboratories Variation/Linkage of Common Diseases/Research Laboratory Informatics and Central Databases Curation, Collection and Locus specific databases Developing Countries International Liaison Funding and Sustainability Nomenclature and Standards Ethics and Education Publication and Credit Translation

Current Statusas at 18th October2007: 

Current Status as at 18th October2007 Recommendations from sessions – 28th Aug 06 Consolidated recommendations – 6th Oct 06 Concept Plan – 12th Dec 06 Deliverables - 12th Jan 07 Planning Group – 2nd Feb 07 Working Groups – 2nd Feb 07 (still in progress) Deloittes Business Plan - available (completed March 07) Major European Consortium application to EC Major application to Australian Governments Approaches to NHGRI, Wellcome and others Nature Genetics April 07 Editorial, Recommendations, Database of LSDBs article Arab & Japanese HVP initiated Pilot projects planned

Pilot studies initiated and planned activities: 

Pilot studies initiated and planned activities InSiGHT/colon cancer – complete international flow. Patient to central database Specific corporate/support group/charity funding of each LSDB Mounting of 10 LSDBs to NCBI Disease specific form for each disease Ethics of databasing mutations Microattribution of single variation Ongoing projects

Ideal mutation Flow: 

Ideal mutation Flow Patient phenotype Patient genotype Patient profile LSDB Central database browsers Pathology Publication Clinic file

Some guidelines & help: 

Some guidelines & help 96 Recommendations of the Human Variome Project Meeting June 2006 Derived deliverables from these recommendations HGVS published material (www.hgvs.org) Outcomes should be portable/useful worldwide

Potential ideas and aids to data collection: 

Potential ideas and aids to data collection Reporting of each instance of mutation to CDC as per Cancer. Reporting of mutation as part of QC Reporting of mutation requirement of licensing Inducement by PubMed ID / Publication Forms & software for each disease to automate collection Disease specific committees/curators Country/state specific efforts

Activities of a Consortium of Members HGVS members and others: 

Activities of a Consortium of Members HGVS members and others Mailing list Newsletter Working Groups 2 Meetings per year Nomenclature standards Quality standards Database content standards Entry form Guidelines to create Database Ethical guidelines List of mutation databases 683 Encouragement of 100 databases Review of LSDBs Central database – concept Gene editors 390 LSDB software WayStation pilot Coordination Survey of curators

Planning: 

Planning Formation of Planning Group and Working Groups Business Plan Completed Board Action Plan/Roadmap Detailed Plans for Groups/Grants Scientific Committee

Acknowledgments: 

Acknowledgments Stylianos E. Antonarakis Arleen D. Auerbach Arthur Beaudet Christophe Beroud Ernest Beutler Anthony Brookes Lisa Brooks Alastair F. Brown Aravinda Chakravarti Francis Collins David Cooper A. Jamie Cuticchia Raymond Dalgleish Matthew Darlison Johan T. Den Dunnen Mary Fujiwara Bruce Gottlieb Ada Hamosh Rania Horaitis Val Hyland Michael Katz Haig H. Kazazian Jr. Heikki Lehväslaiho Donna Maglott Stephen Maurer Victor A. McKusick Shinsei Minoshima William S. Oetting Manyphong Phommarinh Christopher Porter Charles R. Scriver Steve Sherry Nobuyoshi Shimizu Thomas Shows C. Conover Talbot Jr. Peter Tarczy-Hornoch Graham Taylor Lap-Chee Tsui Edward Tuddenham Gert-Jan van Ommen David Valle Mauno Vihinen Douglas C. Wallace