Can we exploit the power of NGS to move towards personalized medicine?, Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Elia Stupka Copenhagenomics 2012
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At CPHx Elia Stupka discussed successes, failures and challenges ahead if we want to turn NGS into the holy grail of “personalized medicine”.
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Can we exploit the power of NGS to move towards personalized medicine?, Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Elia Stupka Copenhagenomics 2012
- 1. Can we exploit the power of NGS to move towards personalized medicine? Elia Stupka - stupka.elia@hsr.it giovedì 14 giugno 12
- 2. BACKGROUND • Biology background • Part of the core human genome analysis team within the Ensembl group -> pure bioinformatics • In Singapore, headed the Fugu informatics team, again bioinformatics, involved in Fantom3 project • Since then, tried to get closer to the biology (added a wet lab 8 years ago)... and then to the clinic (added medical staff to the group last year) giovedì 14 giugno 12
- 3. DRIVING QUESTION: GENOME FUNCTION! • Bioinformatics Pipelines can only reflect the current (biased) understanding of what the data should be telling… • Classic examples: –“Surely a gene can’t produce so many transcripts, put a higher cut-off on your predictions” –“Delete all genes which do not encode for a protein” –“Delete all genes which are less than 200nt long” • Thus I grew an interest in… rubbish (US:garbage), or to be more precise, in elements of the genome and its grammar which did not fit accepted rules… giovedì 14 giugno 12
- 4. A VIEW OF THE GENOME... giovedì 14 giugno 12
- 5. A VIEW OF THE GENOME... Coding gene… giovedì 14 giugno 12
- 6. A VIEW OF THE GENOME... RNASeq: Transcripts, splicing, expression profiling Non-coding RNA RNASeq Coding gene… giovedì 14 giugno 12
- 7. A VIEW OF THE GENOME... RNASeq: Transcripts, splicing, expression profiling Promoter CAGE Seq Non-coding RNA RNASeq Coding gene… giovedì 14 giugno 12
- 8. A VIEW OF THE GENOME... RNASeq: Transcripts, splicing, expression profiling Methylation Promoter CAGE Seq Non-coding RNA RNASeq Coding gene… giovedì 14 giugno 12
- 9. A VIEW OF THE GENOME... RNASeq: Transcripts, splicing, expression profiling Methylation Promoter CAGE Seq Non-coding RNA Enhancer RNASeq P300 ChiPSeq Coding gene… giovedì 14 giugno 12
- 10. A VIEW OF THE GENOME... RNASeq: Transcripts, splicing, expression profiling Methylation Promoter Insulator CTCF CAGE Seq ChIP Seq Non-coding RNA Enhancer RNASeq P300 ChiPSeq Coding gene… giovedì 14 giugno 12
- 11. A VIEW OF THE GENOME... RNASeq: Transcripts, splicing, expression profiling Methylation Histone Promoter Insulator CTCF Modifications CAGE Seq ChIP Seq Non-coding RNA Enhancer RNASeq P300 ChiPSeq Coding gene… giovedì 14 giugno 12
- 12. A VIEW OF THE GENOME... RNASeq: Transcripts, splicing, expression profiling Methylation SNP Histone Promoter Insulator CTCF Modifications CAGE Seq ChIP Seq Non-coding RNA Enhancer RNASeq P300 ChiPSeq Coding gene… giovedì 14 giugno 12
- 13. GENETICS... • We are at a crossroads between: • Existing and ongoing GWAS data, based on genotyping microarrays, still cheapest and most mature for studies of 10,000s of cases • Heavy emphasis on exome sequencing, with many projects in completion examining hundreds or low1,000s of samples • BUT, no major breakthroughs in complex disease.... • Whole genome sequencing also ongoing, numbers increasing rapidly, but still quite costly for high coverage giovedì 14 giugno 12
- 14. EXOME SEQUENCING IN RARE DISEASES: FUNCTION! Collaboration with Phil A Waters, F Lescai et al, submitted Beales, UCL giovedì 14 giugno 12
- 15. EXOME SEQUENCING IN RARE DISEASES: FUNCTION! Collaboration with Phil A Waters, F Lescai et al, submitted Beales, UCL giovedì 14 giugno 12
- 16. EXOME SEQUENCING IN RARE DISEASES: FUNCTION! Collaboration with Phil A Waters, F Lescai et al, submitted Beales, UCL giovedì 14 giugno 12
- 17. EXOME SEQUENCING IN RARE DISEASES: FUNCTION! Collaboration with Phil A Waters, F Lescai et al, submitted Beales, UCL giovedì 14 giugno 12
- 18. INDELS AND REPAT NUMBERS... IMPORTANT! giovedì 14 giugno 12
- 19. RNA: STILL A LOT OF UNKNOWNS • ncRNAs? We need a real catalogue, so far incomplete! giovedì 14 giugno 12
- 20. Why it matters: an example in a Parkinson locus Collaboration with Stefano Gustincich Lab, SISSA giovedì 14 giugno 12
- 21. A NEW CLASS OF NCRNAS! Nature, 3rd revision giovedì 14 giugno 12
- 22. A NEW CLASS OF NCRNAS! Nature, 3rd revision giovedì 14 giugno 12
- 23. A NEW CLASS OF NCRNAS! Nature, 3rd revision giovedì 14 giugno 12
- 24. A NEW CLASS OF NCRNAS! Nature, 3rd revision giovedì 14 giugno 12
- 25. DNA METHYLATION • Pooled 10 individuals through neurofibroma progression: Collaboration with •Schwann Cells (healthy) Stephan Beck Lab •Benign tumour A Feber et al, •Malignant tumour Genome Research, 2011 • Checked DNA Methylation by Medip-Seq giovedì 14 giugno 12
- 26. REPEAT ELEMENTS... Collaboration with Stephan Beck Lab A Feber et al, Genome Research, 2011 giovedì 14 giugno 12
- 27. EPIGENETICS IN FETAL PROGRAMMING OF DISEASE Collaboration with: Prof. Adrian Clark, Barts and The London School of Medicine Prof. Simon Langley Evans, University of Nottingham giovedì 14 giugno 12
- 28. CARDIOVASCULAR GENETICS AND EPIGENETICS giovedì 14 giugno 12
- 29. giovedì 14 giugno 12
- 30. HOW TO MOVE ALL THIS TO THE CLINIC • Moved to San Raffaele Hospital in Milan, a highly integrated campus with1,600 scientists, 5,000 hospital staff and a University with a Medical Faculty • Primary challenges: • PEOPLE: Cultural barriers, burocratic barriers, etc. • IT: Sharing data, knowledge, databases, etc. • ETHICS and BIOBANKING and CLINICAL CULTURE • EXPERIMENTAL DESIGN: plan early, impossible to fix later! giovedì 14 giugno 12
- 31. MULTIPLE SCLEROSIS FAMILY Collaboration with INSPE Dr Martinelli- Boneschi Prof. Giancarlo Comi giovedì 14 giugno 12
- 32. HETEROGENEITY OF PATIENTS: OK IF KNOWN? Whole genome SNP arrays Gene Expression RNA-Seq Medip-Seq Chip-Seq giovedì 14 giugno 12
- 33. WEIGHTED GENETIC RISK SCORE 1.5 Family cases Family controls HSR cases HSR controls 1.0 Density 0.5 0.0 7 8 9 10 11 12 13 GRS giovedì 14 giugno 12
- 34. GENE EXPRESSION giovedì 14 giugno 12
- 35. INTEGRATION NOT AS SCARY AS IT SEEMS a, Whole-genome view of the gene ranks based on integrating ChIP-on-chip, methylation and gene expression results. The y axis shows −log(P), where P is the P value of the Qstatistic corrected for multiple testing. Significantly (false discovery rate, ≤10%) downregulated (green) or upregulated (red) genes are shown. SNPs, CNVs, DNA Methylation, Histone Methylation, Gene Expression, etc. J Zhang et al, Nature, 2012 ...and... Wilks, S. Order Statistics. Bull Amer Math 54, 6-50 (1948) !!!! :) giovedì 14 giugno 12
- 36. THE TEAM giovedì 14 giugno 12