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ITMO Genetics, Genomics and Bioinformatics

ITMO Genetics, Genomics and Bioinformatics. Personalized medicine in the Next Generation Sequencing (NGS) era: Scientific and Medical challenges, Ethical considerations September 24, 2013 / Bruxelles Thierry Frebourg. CEA. CHRU. CNRS. CPU. INRA. INRIA. INSERM. INSTITUT PASTEUR.

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ITMO Genetics, Genomics and Bioinformatics

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  1. ITMO Genetics, Genomics and Bioinformatics Personalized medicine in the Next Generation Sequencing (NGS) era: Scientific and Medical challenges, Ethical considerations September 24, 2013 / Bruxelles Thierry Frebourg CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD ARIIS CIRAD EFS FONDATION MERIEUX INERIS INSTITUT CURIE INSTITUT MINES-TELECOM IRBA IRSN UNICANCER

  2. A SHORT HISTORY OF HUMAN GENETICS 2009 New generationSequencing (NGS) 2004 End of sequencing of the humangenome 1953 DNA Structure Watson and Crick 1975 Southern 1993 Automatedsequencers Beginning of sequencing of the humangenome 1865 Mendel 1985 PCR (Mullis) 1959 Trisomy21 Lejeune Turpin Jacobs Sanger sequencing 2007 Wholegenome analyses: CGH 1865 – 1975 Pre-molecularera 1975 – 2004 Molecularera 2004- Genomicera

  3. THE NGS REVOLUTION : FROM TARGETED TO GLOBAL SEQUENCING The humangenome : 3 Gb (3.109 ) Sanger sequencing on amplicons : 500 bp 1000 Kb (106bp) sequencedwithin 7 days Humanexomesequencing160.000 exons = 30 Mb (30 106) 1.2% of the humangenome 3 Gb 100x 3000 Mb = 3 Gb X 100 000 50 Gb (50. 109pb) sequencedwithin 7 days

  4. NGS : BIOINFORMATICS EXPERTISE pb -Kb X 1 000 000 Gb Quality - Alignment - Annotation - Filtration - Comparison - Storage

  5. UNDERESTIMATED VARIABILITY OF THE HUMAN GENOME • Perexome • 34 Mb : 1.2% of the total genome: • 17000 Single Nucleotide Variations (SNV) • 50% non synonymous • 500 rare (<0.1%) SNVsnot present in the data bases • 1 de novo SNV withpotential impact pergeneration

  6. MAIN CHALLENGE OF NGS : INTERPRETATION OF GENETIC VARIATIONS • 1995-2010 • Detection of mutations Discovery of the DNA polymorphismcomplexity SNV, SNP, CNV….. • Since 2010 • Interpretationof mutations Statistical analyses Animal models Phenotypicevaluation Biological and medicalinterpretation

  7. EXTENSIVE CHARACTERIZATION OF THE GENETIC DETERMINISM OF DISEASES Single case Extremephenotype September 2013 : 900 publications Familial cases Substractive exomes in trio Comparative exomes between relatives Comparative exomes inter-families 17000 SNVs Exclusion of non genic– intronic – synonymous SNPs : 5000 SNVs Exclusion of SNVs from dbSNP131 -1000 genome project - in house exomes - 5379 exomes* 400 non-synonymous/splice acceptor donor site/frameshift coding indels Subtraction of inherited SNVs De novo mutations : 0-10 Genes affected by identical variations : 20 Altered genes in common *NHLBI Grand Opportunity Exome Sequencing Project

  8. OPTIMIZATION OF PERSONALIZED MEDICINE • High throughput • Simultaneousanalysis of genes • Reduction of delay Hereditarycolorectal cancer : 1/500 Colon cancer 62 years WT/ mt Wt/ Wt WT/WT WT/ mt Colon cancer 36 years Colon cancer 32 years Suppression of an illegitimate anxiety and inappropriate medical follow-up in non mutation carriers Colonoscopysince 20 years of ageevery 2 years MSH2, MLH1, MSH6 ,PMS2, APC, MUTYH, SMAD4, BMPR1A, STK11, PTEN

  9. NGS HIGHLIGHTS THE COMPLEXITY OF THE GENETIC DETERMINISM OF DISEASES Age Personalizedmedicine 100% 80% Monogenicdiseases 60% Biologicaltolerance Risk of disease Oligogenic diseases 40% Multigenic diseases 1 5 100 Number of genetic variations

  10. ETHICAL ISSUES OF NGS IN THE CONTEXT OF PERSONALIZED MEDICINE • Mis-interpretation of the medical significance of the genetic variations • - Genomic reductionism “and tomorrow, everyone in this room will be able to hold their genome in their iPad and You will be able to surf your genome and find out everything about yourself.“ Senior VP , Illumina, June 2013 • - Development of Direct-to-consumer (DTC) genetic testing services • - No medical value of genetic analyses without clinical evaluation • Accessto genome data : the global alliance white paper • “Cancers, rare diseases, common diseases infectious diseases” • “Serving the needs of the entire biomedical ecosystems: patients, researchers hospitals, biopharma, institutions, clinical trials, governments” • Cloud computing for storage controlled access CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD ARIIS CIRAD EFS FONDATION MERIEUX INERIS INSTITUT CURIE INSTITUT MINES-TELECOM IRBA IRSN UNICANCER 10

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