![Charter The MutaDATABASE Charter on Intellectual Property Pertaining to DNA Variants and the Information Embedded Therein We, the undersigned participants in and supporters of the MutaDATABASE, take the position that variants in human DNA are the ultimate open-source resource: they should be freely available for scientists to study, clinicians to test, and patients (and everyone) to derive health and/or other benefits from. Our view is that human DNA and human DNA information are res publicae [1]. As such, there can be no abiding claims on these data, not by clinical testing laboratories, research laboratories, universities, commercial sequencing and/or genomic interpretation enterprises, gene curators, informaticians, insurers, the state, multinational governance organizations, database proprietors, or persons from whom these data are derived. Maximization of benefits from genomic variant data will require successful interactions among all of these entities with as few barriers in place as possible. Accordingly, MutaDATABASE will be completely "Open Access." There will be no restrictions and no usage fees. Each participating laboratory and investigator agrees to these terms and agrees to place no strings whatsoever on any data they deposit into MutaDATABASE. Variants in MutaDATABASE are governed by a Creative Commons CC0 license [2]. Specifically, MutaDATABASE depositors waive all copyrights, intellectual property rights, and related or neighboring rights, such as their moral rights (to the extent waivable), their publicity or privacy rights, rights they have protecting against unfair competition, and database rights and rights protecting the extraction, dissemination and reuse of any and all data deposited into MutaDATABASE. 1. Ossorio, P.N., The human genome as common heritage: Common sense or legal nonsense? J Law Med Ethics, 2007. 35 (3): 425-439. 2. http://creativecommons.org/choose/zero/](https://image.slidesharecdn.com/mutadatabase-110208105017-phpapp01/85/MutaDATABASE-37-320.jpg)
MutaDATABASE
- 1. The MutaDATABASE project Wim Van Criekinge, BIOBIX, Univ Ghent, Belgium Sherri Bale, GENEDX, Gaithersburg, USA Frederik Decouttere, GENOHM, Ghent, Belgium Heidi Rehm, PhD, Harvard Medical Schoool, Boston, USA Bob Nussbaum, Dept Human Genetics, UCSF, USA Johan Den Dunnen, Leiden University, the Netherlands Patrick Willems, GENDIA, Antwerp, Belgium
- 2. The Problem Novel mutations are not being made public through publication or database entry Many remain unclassified variants which is a challenge for genetic counseling
- 3. The problem is being PCR-amplified Genetic testing is moving towards testing of whole populations for multifactorial disease (common and rare variants) Genetic testing is moving towards testing of whole exomes/genomes on next generation sequencing platforms
- 4. Next Generation Sequencing 23.000 WHOLE EXOME 160 RETINAL PATHOLOGY 93 X-LINKED MENTAL RETARDATION 57 FAMILIAL CARDIOMYOPATHY 55 EPILEPSIA 24 CONGENITAL DISORDERS OF GLYCOSYLATION (CDG) 24 FAMILIAL ARRHYTHMIA 23 DILATED CARDIOMIOPATHY (DCM) 19 USHER SYNDROME AND NON-SYNDROMIC DEAFNESS 18 DEMENTIA 17 HYPERTROPHIC CARDIOMIOPATHY (HCM) 14 PARKINSON 12 MUSCULAR DYSTROPHY 10 LONG QT SYNDROME 8 NOONAN, LEOPARD, COSTELLO AND CARDIOFACIOCUTANEOUS SYNDROME 7 FAMILIAL HYPERCHOLESTEROLEMIA 7 AUTOSOMAL RECESSIVE AND SPORADIC RETINITIS PIGMENTOSA 7 ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY (ARVC) 5 BRUGADA SYNDROME 2 CATECHOLAMINERGIC POLYMORPHIC VENTRICULAR TACHYCARDIA (CPVT) Nr genes Next generation sequencing panels
- 5. Mutation Databases < 200.000 3611 TOTAL + 12.000 + + 83 DMuDB + ? Few - 600 HGVS + 163.061 + - 895 LOVD + ? Few + + < 1000 MutDB + ? Few + + < 50 UMD - 96.631 + + 3611 HGMD Free Mutations Standardised Centralised Genes Database
- 6. Nothing new under the sun ?
- 7. Deafness : 50 genes (apart from GJB2) In total literature + databases : 230 mutations 1 single lab : > (unpublished) 1800 mutations Input mutations into public domain
- 8. Input mutations into public domain 538 1305 TOTAL 5 21 MYL3 10 44 MYL2 14 68 TPM1 43 108 TNNT2 41 85 TNNI3 236 480 MYH7 180 463 MYBPC3 9 36 ACTC HGVS DATABASE MutaDATABASE Lab 1 (Harvard) HCM Gene
- 9. BRCA1/2 : +/- 17.000 bp coding sequence 3.500 variations Total genome : +/- 34.000.000 bp coding sequence 7.000.000 variations Estimated number of mutations
- 10. Estimation is that less than 10 % mutations is in public domain Research labs : Many mutations in the past Few mutations over the last years Diagnostic labs: Europe : moderate number USA : few mutations Input mutations into public domain
- 11. TOO DIFFICULT TOO TIME CONSUMING NO EASY GATEWAY Why do we not put mutations into the public domain ?
- 12. Where do we go fishing for mutations ?
- 13. GENEDX LABCORP CORRELAGEN ATHENA DIAGNOSTICS GENZYME QUEST ARUP MAYO HOUSTON EMORY DUARTE CHICAGO GREENWOOD BOSTON MYRIAD ?? Input mutations into public domain by US labs
- 14. MutaDATABASE An international project to get standardized gene mutation databases on a central database platform (MutaDATABASE) by converting existing gene databases to a standardized format by addition of new gene databases
- 15. Website MutaDATABASE Gene curators MutaCURATORS Mutation collectors MutaADMINISTRATORS Clinical info MutaCLINICIANS Software MutaREPORTER Lab circles MutaCIRCLES Journal MutaREVIEWS Entities
- 16. MutaREVIEWS MutaCURATORS PUBLIC MutaCIRCLES MutaDATABASE MutaCLINICIANS MutaADMINISTRATORS
- 17. MutaDATABASE collects all human gene variations related to monogenetic disease into a database which is : centralized (server University Ghent) standardized freely available open access freely exportable to other databases
- 18. MutaDATABASE 1. Provides general information on human disease genes 2. Provides overviews of all mutations in these genes 3. Provides overviews of diseases associated with these genes 3. Provides tables of : cDNA sequence Amino acid sequence Exon-intron sequences Disease mutations 4. Provides figures of : Cytogenetic localization Physical map Genomic structure Mutations listed as observations in single patients together with clinical info 5. Allows easy submission of molecular and clinical info
- 19. MutaDATABASE - LOVD MutaDATABASE and LOVD are collaborating through Johan Den Dunnen
- 20. Control gene databases in MutaDATABASE Review all info submitted to MutaDATABASE Supervise MutaCIRCLES Write gene reviews for MutaREVIEWS MutaCURATORS
- 21. Travel to large test labs to put info into MutaDATABASE Contact small test labs to put info into MutaDATABASE Teach labs how to put information into MutaDATABASE MutaADMINISTRATORS
- 22. Labs that work on the same gene form a gene circle The exchanged info is available on the website Questions automatically go to all members of the circle The lab circles joinedly write the gene reviews for the Journal The lab circles joinedly write the gene reviews for the Website MutaCIRCLES
- 23. Lab 1 Lab 2 Lab 3 Lab 4 MutaCIRCLES MutaCIRCLES
- 24. MutaCIRCLES -- X -- -- -- -- -- -- --- -- INSIGHT -- x -- x -- x -- -- -- -- Duarte x x -- x -- -- x -- -- -- Emory x x -- -- -- x x -- -- -- Arup x -- -- -- x -- X -- -- -- Athena -- -- -- -- x x X X x X Correlagen x -- X -- x X X X X Partners -- - x x x -- X X X X GeneDx 10 6 9 10 6 6 9 10 10 7 GENES Deaf Colon Usher MR MODY Aorta Noonan Arrhyth Long QT HCM DISEASE
- 25. Online journal, no hard copy Free access Only gene reviews, 300 genes per year Within 5 years most important genes (1500) are covered All papers have the same lay out MutaCURATORS coordinate Every year all reviews are updated MutaREVIEWS
- 26. MutaREPORTER
- 27. MutaREPORTER Is software interface between lab sequencers and website Imports patient’s gene sequence into database Picks up gene variations Generates the correct nomenclature for the variation Qualifies variations into known or novel Uses software prediction programs to estimate pathogenicity of novel mutations Generates a report for the variation with known or predicted functional significance, gene figure with mutation location, surrounding sequence, references Submits novel variations to gene master that evaluates before entering variation into database
- 28. MutaREPORTER
- 29. MutaREPORTER Access to all info in MutaDATABASE A genome browser with track-based sequence views A variation checker for HGVS nomenclature Facilitated access to prediction tools (Splice site, SIFT, POLYPHEN) Possibility to automatically import variants from in-house databases Possibility to submit variants into MutaDATABASE Possibility to communicate with other genetic labs (MutaCIRCLES)
- 30. MutaREPORTER key principles Facilitates data input of variants with a few keystrokes Visualizes all variant related information in 1 comprehensive, dynamic view Includes gene analyses & qualification tools Operates seamless across MutaDATABASE projects and participants
- 31. MutaREPORTER Assembly aware storage, reference database independent (Ensembl / Genbank) meaning variants will be named according to user preference Submits novel variations to MutaCURATORS who evaluates before accepting variation into MutaDATABASE Generates the correct nomenclature for the variation (HGVS, BIG, …)
- 32. Offered as a “Software as a Service” or SaaS Centrally managed on mutareporter servers, configured on a high-availability linux cluster Fine-grained security model: public – curator – circle – lab Client requirement: every web browser with flash support built with java and flex (adobe) technologies Supports simultaneous login & real-time variant updates within 1 lab and/or MutaCIRCLE: easy collaboration amongst your colleagues Open data access (nightly database exports) Import/export functions for other popular databases like LOVD, … MutaREPORTER Technical background
- 33. MutaREPORTER Final goal Recording variants directly from sequencer Interpretation variants using algorithm Ranking variants in order of importance Issuying result report Input info into MutaDATABASE
- 34. Early Adopter program (EAP) Early Adopter program (EAP) for MutaREPORTER Proof-of-principle for MutaREPORTER, MutaCIRCLES and MutaDATABASE This will also facilitate grant applications to NIH and EU/EBI The EAP program could be presented to +/- 10 labs for +/- 10 heterogenic diseases for +/- 50 genes The choice of labs and genes-diseases is based upon the amount of variants expected (Large US labs, labs doing next generation sequencing)
- 36. MutaCURATORS Patients MutaDATABASE Clinicians Labs MutaREPORTER Input Mutation information MutaADMINISTRATORS
- 37. Charter The MutaDATABASE Charter on Intellectual Property Pertaining to DNA Variants and the Information Embedded Therein We, the undersigned participants in and supporters of the MutaDATABASE, take the position that variants in human DNA are the ultimate open-source resource: they should be freely available for scientists to study, clinicians to test, and patients (and everyone) to derive health and/or other benefits from. Our view is that human DNA and human DNA information are res publicae [1]. As such, there can be no abiding claims on these data, not by clinical testing laboratories, research laboratories, universities, commercial sequencing and/or genomic interpretation enterprises, gene curators, informaticians, insurers, the state, multinational governance organizations, database proprietors, or persons from whom these data are derived. Maximization of benefits from genomic variant data will require successful interactions among all of these entities with as few barriers in place as possible. Accordingly, MutaDATABASE will be completely "Open Access." There will be no restrictions and no usage fees. Each participating laboratory and investigator agrees to these terms and agrees to place no strings whatsoever on any data they deposit into MutaDATABASE. Variants in MutaDATABASE are governed by a Creative Commons CC0 license [2]. Specifically, MutaDATABASE depositors waive all copyrights, intellectual property rights, and related or neighboring rights, such as their moral rights (to the extent waivable), their publicity or privacy rights, rights they have protecting against unfair competition, and database rights and rights protecting the extraction, dissemination and reuse of any and all data deposited into MutaDATABASE. 1. Ossorio, P.N., The human genome as common heritage: Common sense or legal nonsense? J Law Med Ethics, 2007. 35 (3): 425-439. 2. http://creativecommons.org/choose/zero/
- 38. Charter DNA variants are public property
- 39. TOO DIFFICULT TOO TIME CONSUMING NO EASY GATEWAY Why do we not put clinical info into the public domain ?
- 40. PHENEXPLORER Patients MutaDATABASE Clinicians Labs Input Clinical information
- 41. Mutation X in L1CAM Observation Lab Dr Patient Features using Phenexplorer Hydrocephalus Macrocephaly Paraparesis 1 A X 098765 + - + 2 B Y 012387 - - + 3 C X 945628 + + - 4 A Z 126784 + + + 5 C T 453986 + - - TOTAL 80 % 40 % 60 % Real - time genotype - phenotype correlation
- 42. Review all clinical info submitted Contact clinicians Contact patient groups Make phenotype-genotype correlations MutaCLINICIANS
- 43. Group of supervising dysmorphologists : Raoul Hennekam, Les Biesecker, Peter Robinson, Ada Hamosh, Patrick Willems Phenotype ontology (Clinical coding features) is integrating: Elements of Morphology ( http:// research.nhgri.nih.gov/morphology/index.cgi ) London Dysmorphology database (LDDB) HPO - Human Phenotype Ontology (Phenexplorer) MutaDATABASE uses Phenexplorer for input of clinical info MutaCLINICIANS
- 44. Listing mutations as “OBSERVATIONS” will allow to : Determine the frequency of mutations Add clinical features from each individual patient Refer the diagnosing lab and clinician Automatically extract frequency of features for each mutation Input clinical info
- 45. MutaDATABASE Clinical info Input information Molecular info PHENEXPLORER MutaREPORTER
- 46. Labs through MutaDATABASE MutaREPORTER MutaCURATORS through MutaREPORTER MutaADMINISTRATORS through MutaREPORTER MutaCLINICIANS through MutaREPORTER Clinicians through MutaDATABASE Patients through MutaDATABASE Input mutations
- 47. MutaREVIEWS MutaCURATORS PUBLIC MutaCIRCLES MutaDATABASE MutaCLINICIANS MutaADMINISTRATORS
- 48. 1. Wim Van Criekinge, PhD University of Ghent, Belgium 2. Sherri Bale, PhD GENEDX, Gaithersburg, USA 3. Frederik Decouttere, PhD GENOHM , Ghent, Belgium 4. Heidi Rehm, PhD Harvard Medical Schoool, Boston, USA 5. Bob Nussbaum, MD UCSF, USA 6. Johan Den Dunnen, PhD Leiden University, The Netherlands 7. Patrick Willems, MD, PhD GENDIA, Antwerp, Belgium Principal Investigators
- 49. Short term : GHENT University GENEDX GENDIA Long term : NIH ? Funding
- 50. Address : MutaDATABASE BIOBIX Dept of Molecular Biotechnology University of Ghent Coupure Links 653 9000 Ghent, Belgium Phone : + 32 495250382 Email : info@ mutaDATABASE.org Website : www.mutaDATABASE.index.php www.mutaDATABASE.org (june) Contact
- 51. Advisory Board Abbaszadegan Iran (Mashhad) Algazali Lihadh UAE (Al Ain city) Angrist Misha USA (Durham) Auerbach Marleen USA (New York) Antonarakis Stylianos Switzerland (Geneve) Bale Sherri USA (Gaithersburg) Batish Sat Dev USA (Worcester) Baumgart Karl Australia (Sidney) Beales Philip UK (London) Beaudet Art USA (Houston) Biesecker Leslie USA (NIH) Brais Bernard Canada (Montreal) Braverman Nancy Canada (Montreal) Brice Alexis France (Paris) Brody Lawrence USA (Bethesda) Burn John UK (Newcastle) Byers Peter USA (Seattle) Carson Nancy Canada (Ottawa) Chakravarti Aravinda USA (Baltimore) Chelly Jamel France (Paris) Church George USA (Boston) Corey Braastad USA (Worcester) Cutting Garry USA (Baltimore) Dallapicolla Bruno Italy (Rome) Das Soma USA (Chicago) De La Chapelle Albert USA (Columbus) Decouttere Frederik Belgium (Ghent) Eng Charis USA (Cleveland) Fiorentino Francesco Italy (Rome) Friez Michael USA (Greenwood) Garcia-Planells Javier Spain (Valencia) Gecz Jozef Australia (Adelaide) Grosfeld Frank The Netherlands (Rotterdam) Hahn Sihoun USA (Seattle) Hamosh Ada USA (OMIM) Hegde Mathuri USA (Atlanta) Hennekam Raoul The Netherlands (Amsterdam) Heinz Gabriel Germany (Osnabrueck) Holinski Elke Germany (Munchen) Kaluzewski Bogdan (Poland) Lodz Kimberling Bill USA (Iowa City) Klinger Katherine USA (Cambridge) Kohlhase Juergen Germany ( Freiburg) Lane Birgit Singapore Lennon Greg USA (Potomac) Levett Lisa UK (London) Lyon Elaine USA (Salt Lake City) Matsubara Yoichi Japan (Sendai) Melegh Bela Hungary (Pecz) Milunski Jeff USA (Boston) Ming Qi China (Bejing) Mortier Geert Belgium (Antwerp) Morton Cynthia USA (Boston) Mukerji Mitali India (Delhi) Mundlos Stefan Germany (Berlin) Nelson Tanya Canada (Vancouver) Nussbaum Bob USA (San Francisco) Ostrer Harry USA (New York) Pena Sergio Brasil (Belo Horizonte) Petersen Michael Greece (Athens) Pratt Vicky USA (Chantilly) Preising Marcus Germany (Giessen) Rehm Heidi USA (Cambridge) Restrepo Carlos Colombia (Bogota) Richards Sue USA (Portland) Rogaev Evgeny Russia (Moscow) Rouleau Guy Canada (Quebec) Saldivar Sebastian USA (Duarte) Scott Patrick Canada (Edmonton) Shaffer Lisa USA (Spokane) Sunyaev Shamil USA (Boston) Tadmouri Ghazi UAE (Dubai) Tavares Purita Portugal (Porto) Tsuji Lap-Chee China (Hongkong) Van Criekinge Wim Belgium (Ghent) Van de Spek Peter Netherlands (Rotterdam) Warren Steve USA (Atlanta) Waterham Hans (The Netherlands (Amsterdam) Willems Patrick Belgium (Antwerp)
- 52. DO NOT LITTER