Toward Meaningful Whole-Genome   Interpretation with Open Access Tools   From the Genome Commons   BioIT World Expo   2010...
What did we learn from their genomes?             Not much.                                        2
Can we agree to disagree? Probably not.    Heart Attack Risk Prediction    from Experimental Man, DE Duncan    Gene       ...
Trouble for direct-to-consumer testing.                      http://blog.navigenics.com/articles/comments/an_open_letter_t...
Theres lots of good news, too.➢   Disease diagnosis & prognosis➢   Drug dosing and side effects➢   Disease variant/gene id...
The Genome Commons seeks to buildopen access, open source tools thatmaximize the predictive, preventative,and personalized...
Collect datain one place.                7
Databases isolation impedes effective use.   Data are studied, compiled, and stored gene-wise.   That makes sense for coll...
GCdb will be a repository of variants and traits.                 OMIM from                 dbSNP     dbSNP               ...
Make genomic datausable and useful.                     10
The Navigator will integrate data and tools.                     Infer variants in LD      Align variants to             I...
Improve variantimpact predictions.                      12
CAGI – Critical Assessment of Genome InterpretationA community assessment of the state-of-the-art in phenotype prediction....
MTHFR and Methylation                                   exogenous                                   folate              fo...
Sequencing 18 Genes of Folate Pathway                   Guthrie-Spot Sequencing Protocol➢   250 NTD children and 250 case ...
MTHFR variants exhibit 3 classes of effects.                             S. cerevisiae growth with MTHFR knock-in mutants ...
Step 1: Collect predictions.mutation     Team 1       Team 2M110I        No Effect    RemediableR134C        Impaired     ...
Step 2: Assess predictions.mutation    Team 1        Team 2       ExperimentM110I      No Effect                         ...
Step 3: Celebrate and learn.               Its not whether you win or lose...mutation     Team 1             Team 2       ...
Be clinically relevant.                          20
Sequencing identifies clinically important associations.                                   Concurrence among cases        ...
Do itethically.             22
A few ineluctable ethical issues.➢   How to fairly acknowledge aggregated    data?➢   Should scientifically suggestive res...
The Genome CommonsJasper Rine    Steven Brenner   Bernie Lo   Robert Nussbaum                                             ...
Nature. 2007 Mar 13;452(7184):151. 25
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Bio-IT 2010 Genome Commons

  1. 1. Toward Meaningful Whole-Genome Interpretation with Open Access Tools From the Genome Commons BioIT World Expo 2010-04-22 Reece Hart, Ph.D. Chief Scientist, Genome Commons QB3 / Center for Computational Biology UC Berkeley reece@berkeley.edu 12010-04-22 11:43
  2. 2. What did we learn from their genomes? Not much. 2
  3. 3. Can we agree to disagree? Probably not. Heart Attack Risk Prediction from Experimental Man, DE Duncan Gene Marker Risk Allele Genotype Risk Company CELSR2/PSEC1 rs599839 G AG 0.86 deCodeMe CDKN2A/CDKN2B? rs10116277 T GT 1 deCodeMe CDKN2A/CDKN2B? rs1333049 C CC 1.72 Navigenics MTHFD1L rs6922269 A AA 1.53 Navigenics CDKN2A/CDKN2B? rs2383207 G GG 1.22 23andme 3
  4. 4. Trouble for direct-to-consumer testing. http://blog.navigenics.com/articles/comments/an_open_letter_to_nature/ 4
  5. 5. Theres lots of good news, too.➢ Disease diagnosis & prognosis➢ Drug dosing and side effects➢ Disease variant/gene identification➢ Technological advances 5
  6. 6. The Genome Commons seeks to buildopen access, open source tools thatmaximize the predictive, preventative,and personalized value of genomic data. ● Technical – organize date and streamline tools ● Scientific – improve predictive accuracy ● Clinical – engage clinicians and counselors ● ELSI – address ineluctable ethical, legal, and social dilemmas 6
  7. 7. Collect datain one place. 7
  8. 8. Databases isolation impedes effective use. Data are studied, compiled, and stored gene-wise. That makes sense for collection, but not for genome-wide use. OMIM GeneTests/ GeneReviews 935 genes  LSDBs1177 Locus-Specific Databases NHGRI GWASSource: http://www.hgvs.org/dblist/glsdb.html on Oct 15.Some genes have multiple LSDBs. PharmGKB Literature Literature dbSNP 8
  9. 9. GCdb will be a repository of variants and traits. OMIM from dbSNP dbSNP Genome Commons GO Database LSDBs ⋮ variants pheno- types ICD-10 GeneTests PharmGKB Automated bulk Curated, high-quality, UMLS loading of and traceable structured data association data ➢ Genotypes in standard ➢ Up-to-date coordinates ➢ Quality-controlled ➢ Phenotype ontologies ➢ Open access ➢ Asociations with ➢ Based on Unison likelihood, confidence, evidence, and severity 9
  10. 10. Make genomic datausable and useful. 10
  11. 11. The Navigator will integrate data and tools. Infer variants in LD Align variants to Identify variants with Facile user interfaces for basic research, with typed markers specified genome known phenotypic impact clinical application, drug development, epidemiology, and other uses. Genome Commons Navigator V Genotypes (e.g., a Imputer Remapper Annotator by hybridization) r Variant i Annotation a Integrator Whole Genome/ Assembler/ Variant n ImpactExome Sequences Aligner Caller t Predictor s Assemble genome Phased, aligned variants, Infer effect of unclassified Integrate and reconcile all sequence and call variants from genotyping, genetic variants classified variants into a (separately or jointly) imputation, or sequencing comprehensive report External Data and Tools Genome Commons Database 11
  12. 12. Improve variantimpact predictions. 12
  13. 13. CAGI – Critical Assessment of Genome InterpretationA community assessment of the state-of-the-art in phenotype prediction.➢ Follow the successful CASP framework ● Solicit unpublished data ● Collect blind predictions from participants ● Assess against revealed annotations, mechanisms, and phenotypes➢ Prediction Domains: Molecular phenotype Cellular phenotype Organismal phenotype A A A T T T With John Moult & Steven Brenner 13
  14. 14. MTHFR and Methylation exogenous folate fol3 met135,10-Methylene tetrahydrofolate (TH4) is required for the synthesis of nucleic acids, while 5-methyl TH4is required for the formation of methionine from homocysteine. Methionine, in the form of S-adenosylmethionine, is required for many biological methylation reactions, including DNA methylation.Methylene TH4 reductase is a flavin-dependent enzyme required to catalyze the reduction of 5,10-methylene TH4 to 5-methyl TH4. Linus Pauling Institute http://lpi.oregonstate.edu 14
  15. 15. Sequencing 18 Genes of Folate Pathway Guthrie-Spot Sequencing Protocol➢ 250 NTD children and 250 case matched controls➢ Protocol ● 2mm punch ● Isolate genomic DNA ● Amplification ● Purification ● Sequencing by JGI➢ Variant calls of 238 exons in 18 genes ● Analysis ● Curate ● QC Jasper Rine 15
  16. 16. MTHFR variants exhibit 3 classes of effects. S. cerevisiae growth with MTHFR knock-in mutants Severely Impaired Folate Remedial No Effect e.g., R134C e.g,. M110I, D223N e.g., R519C 0.6 0.7 0.6 M110I MTHFR 0.5 0.6 0.5 MTHFR 0.5 50 µg/ml 0.4 0.4 OD 0.4 600 600 600 0.3 D223N 0.3 OD OD 0.3 OD R134C MTHFR R519C [FOLINIC ACID] 0.2 0.2 0.2 0.1 0.1 0.1 met13 0 0 0 0 6 0 6 0 6 12 18 24 30 36 42 48 54 60 12 18 24 30 36 42 48 54 60 12 18 24 30 36 42 48 54 60 HOURS HOURS HOURS 0.7 0.7 0.7 0.6 0.6 0.625 µg/ml 0.5 0.5 0.5 OD 0.4 0.4 0.4 600 600 600 OD 0.3 OD 0.3 OD 0.3 0.2 0.2 0.2 0.1 0.1 0.1 0 0 0 0 6 0 6 0 6 12 18 24 30 36 42 48 54 60 12 18 24 30 36 42 48 54 60 12 18 24 30 36 42 48 54 60 HOURS HOURS HOURS Time Jasper Rine 16
  17. 17. Step 1: Collect predictions.mutation Team 1 Team 2M110I No Effect RemediableR134C Impaired RemediableD223N RemediableR519C No Effect No Effect 17
  18. 18. Step 2: Assess predictions.mutation Team 1 Team 2 ExperimentM110I No Effect Remediable RemediableR134C Impaired Remediable ImpairedD223N Remediable RemediableR519C No Effect  Effect No No Effect 18
  19. 19. Step 3: Celebrate and learn. Its not whether you win or lose...mutation Team 1 Team 2 ExperimentM110I  No Effect  Remediable RemediableR134C  Impaired  Remediable ImpairedD223N  Remediable RemediableR519C  No Effect  Effect No No Effect 19
  20. 20. Be clinically relevant. 20
  21. 21. Sequencing identifies clinically important associations. Concurrence among cases databases Intersection among 21
  22. 22. Do itethically. 22
  23. 23. A few ineluctable ethical issues.➢ How to fairly acknowledge aggregated data?➢ Should scientifically suggestive results be used for clinical care?➢ What is the balance between openness and preventing misinterpretation?➢ What happens to confidentiality agreements during bankruptcy?➢ How do we balance personal privacy with opportunities for public health advances? Bernard Lo 23
  24. 24. The Genome CommonsJasper Rine Steven Brenner Bernie Lo Robert Nussbaum 24
  25. 25. Nature. 2007 Mar 13;452(7184):151. 25
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