Bio-IT 2010 Genome Commons
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The document summarizes a presentation about developing open access tools to maximize the value of genomic data through the Genome Commons. The Genome Commons Database will be a repository of variants and associated traits. The Genome Commons Navigator will integrate this data and external tools to facilitate basic research, clinical applications, and more. Participation in the Critical Assessment of Genome Interpretation initiative aims to improve predictions of variant impacts on molecular, cellular and organismal phenotypes. Analysis of variants in folate pathway genes found classes of effects on yeast growth and folate remediation.
![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 0.6
25 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](https://image.slidesharecdn.com/t34221500rhartv2-13041334375944-phpapp02/85/Bio-IT-2010-Genome-Commons-16-320.jpg)
Bio-IT 2010 Genome Commons
- 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 [email protected] 1 2010-04-22 11:43
- 2. What did we learn from their genomes? Not much. 2
- 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. Trouble for direct-to-consumer testing. http://blog.navigenics.com/articles/comments/an_open_letter_to_nature/ 4
- 5. There's lots of good news, too. ➢ Disease diagnosis & prognosis ➢ Drug dosing and side effects ➢ Disease variant/gene identification ➢ Technological advances 5
- 6. The Genome Commons seeks to build open access, open source tools that maximize 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. Collect data in one place. 7
- 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 LSDBs 1177 Locus-Specific Databases NHGRI GWAS Source: http://www.hgvs.org/dblist/glsdb.html on Oct 15. Some genes have multiple LSDBs. PharmGKB Literature Literature dbSNP 8
- 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. Make genomic data usable and useful. 10
- 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 Impact Exome 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
- 13. CAGI – Critical Assessment of Genome Interpretation A 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. MTHFR and Methylation exogenous folate fol3 met13 5,10-Methylene tetrahydrofolate (TH4) is required for the synthesis of nucleic acids, while 5-methyl TH4 is 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. 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. 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 0.6 25 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. Step 1: Collect predictions. mutation Team 1 Team 2 M110I No Effect Remediable R134C Impaired Remediable D223N Remediable R519C No Effect No Effect 17
- 18. Step 2: Assess predictions. mutation Team 1 Team 2 Experiment M110I No Effect Remediable Remediable R134C Impaired Remediable Impaired D223N Remediable Remediable R519C No Effect Effect No No Effect 18
- 19. Step 3: Celebrate and learn. It's not whether you win or lose... mutation Team 1 Team 2 Experiment M110I No Effect Remediable Remediable R134C Impaired Remediable Impaired D223N Remediable Remediable R519C No Effect Effect No No Effect 19
- 20. Be clinically relevant. 20
- 21. Sequencing identifies clinically important associations. Concurrence among cases databases Intersection among 21
- 22. Do it ethically. 22
- 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. The Genome Commons Jasper Rine Steven Brenner Bernie Lo Robert Nussbaum 24
- 25. Nature. 2007 Mar 13;452(7184):151. 25