The Human Variome Project

1
The Human Variome Project

• Richard G.H. Cotton
• Genomic Disorders Research Centre
• Melbourne, Australia
• March 2008
• Human Variome Project Information Seminar
• Melbourne, Australia

2
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
• A community activity to collect for databasing

3
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

4
Why is it important?

• It has been estimated that 60 of all humans will
  be affected by mutation in a lifetime
• 70 of admissions to a major US Paediatric
  hospital had a genetic basis
• 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

5
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

6
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

7
Why are we in this situation

• Divided and no voice Thousands of small
  unrelated voices split by gene, country and
  speciality
• Diagnosis costly and extremely specialised
• Common disease more fashionable
• Databases between research and service
• Maintenance costs into the future

8
Current mutation databases

• 2 major central/general mutation databases
• OMIM/HGMD
• dbSNP - NCBI
• Many conduit databases
• HOWDY
• 683 gene or locus specific databases
• LSDBs
• 2184 Genes with gt1 mutation
• HGMD (public version as at 4th February, 2008)
• Ethnic databases

9
The Cystic Fibrosis Illustration(as at 18th
October, 2007)

• OMIM 136 mutations - 6 linked to dbSNP
• dbSNP 918 variations
• CFTRdb 1556 mutations
• Difficult to place mutation on sequence
• HGMD 1218 mutations (public version)
• 1417 mutations (private version)

10
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

11
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

12
Meeting Recommendations

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

13
HVP related studies initiated and planned
activities

• InSiGHT/colon cancer complete international
  flow. Patient to central database a pilot
• 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 and/or publication of single
  variation
• Collection from countries
• Pathogenicity of variation
• Somatic mutation database
• GEN2PHEN
• Evidence based genetic medicine
• Ongoing projects

14
Curation support for LSDBs

• Aim To sustain data collection and quality
• Updating and quality control essential by experts
• Currently variable due to lack of time/funding
• 10,000 per year (say) expensive for 1,000 or
  20,000 genes
• Need to spread load
• Companies to donate to exchange logos in sites
• Initiated CMO Global
• Discussions Deloittes
• Approved by The Wellcome Trust and NHGRI

15
Collection from countries

• Aim To collect all mutations from all labs
• Pilot 6-8 countries with colon cancer (MMR)
• Submit to LSDB
• Establish/Procedure applicable to all genes
• Human Genetic Societies
• MutDB model also
• HGSA initiating

16
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

17
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

18
Student involvement

• Past
• Crucial in the past e.g. www.pahdb.mcgill.ca/
• Leads to publications, conference
  presentations/attendance, CV items
• Potential activity
• Collect, collect, collect and assist
• Assist with LSDB mutation collection and curation
• Assist with targeting diagnostic and research
  labs
• Visit key labs to assist and obtain experience
• Guidance
• Those interested contact R. Cotton
  (cotton_at_unimelb.edu.au)