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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
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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

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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”.

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 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 Presentation Transcript

  • Can  we  exploit  the  power  of  NGS   to  move  towards  personalized   medicine? Elia Stupka - stupka.elia@hsr.itgiovedì 14 giugno 12
  • 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
  • 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
  • A VIEW OF THE GENOME...giovedì 14 giugno 12
  • A VIEW OF THE GENOME... Coding gene…giovedì 14 giugno 12
  • A VIEW OF THE GENOME... RNASeq: Transcripts, splicing, expression profiling Non-coding RNA RNASeq Coding gene…giovedì 14 giugno 12
  • A VIEW OF THE GENOME... RNASeq: Transcripts, splicing, expression profiling Promoter CAGE Seq Non-coding RNA RNASeq Coding gene…giovedì 14 giugno 12
  • A VIEW OF THE GENOME... RNASeq: Transcripts, splicing, expression profiling Methylation Promoter CAGE Seq Non-coding RNA RNASeq Coding gene…giovedì 14 giugno 12
  • 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
  • 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
  • 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
  • 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
  • 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 coveragegiovedì 14 giugno 12
  • EXOME SEQUENCING IN RARE DISEASES: FUNCTION! Collaboration with Phil A Waters, F Lescai et al, submitted Beales, UCLgiovedì 14 giugno 12
  • EXOME SEQUENCING IN RARE DISEASES: FUNCTION! Collaboration with Phil A Waters, F Lescai et al, submitted Beales, UCLgiovedì 14 giugno 12
  • EXOME SEQUENCING IN RARE DISEASES: FUNCTION! Collaboration with Phil A Waters, F Lescai et al, submitted Beales, UCLgiovedì 14 giugno 12
  • EXOME SEQUENCING IN RARE DISEASES: FUNCTION! Collaboration with Phil A Waters, F Lescai et al, submitted Beales, UCLgiovedì 14 giugno 12
  • INDELS AND REPAT NUMBERS... IMPORTANT!giovedì 14 giugno 12
  • RNA: STILL A LOT OF UNKNOWNS • ncRNAs? We need a real catalogue, so far incomplete!giovedì 14 giugno 12
  • Why it matters: an example in a Parkinson locus Collaboration with Stefano Gustincich Lab, SISSAgiovedì 14 giugno 12
  • A NEW CLASS OF NCRNAS! Nature, 3rd revisiongiovedì 14 giugno 12
  • A NEW CLASS OF NCRNAS! Nature, 3rd revisiongiovedì 14 giugno 12
  • A NEW CLASS OF NCRNAS! Nature, 3rd revisiongiovedì 14 giugno 12
  • A NEW CLASS OF NCRNAS! Nature, 3rd revisiongiovedì 14 giugno 12
  • 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-Seqgiovedì 14 giugno 12
  • REPEAT ELEMENTS... Collaboration with Stephan Beck Lab A Feber et al, Genome Research, 2011giovedì 14 giugno 12
  • EPIGENETICS IN FETAL PROGRAMMING OF DISEASE Collaboration with: Prof. Adrian Clark, Barts and The London School of Medicine Prof. Simon Langley Evans, University of Nottinghamgiovedì 14 giugno 12
  • CARDIOVASCULAR GENETICS AND EPIGENETICSgiovedì 14 giugno 12
  • giovedì 14 giugno 12
  • 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
  • MULTIPLE SCLEROSIS FAMILY Collaboration with INSPE Dr Martinelli- Boneschi Prof. Giancarlo Comigiovedì 14 giugno 12
  • HETEROGENEITY OF PATIENTS: OK IF KNOWN? Whole genomeSNP arrays GeneExpressionRNA-SeqMedip-Seq Chip-Seqgiovedì 14 giugno 12
  • 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 GRSgiovedì 14 giugno 12
  • GENE EXPRESSIONgiovedì 14 giugno 12
  • 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
  • THE TEAMgiovedì 14 giugno 12