ITMO Genetics Genomics and Bioinformatics Personalized medicine in
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 ARIIS CIRAD EFS CEA CHRU CNRS FONDATION MERIEUX CPU INRA INRIA INSERM INSTITUT PASTEUR INERIS INSTITUT CURIE INSTITUT MINES-TELECOM IRD IRBA 1 IRSN UNICANCER
A SHORT HISTORY OF HUMAN GENETICS 1953 DNA Structure 1865 Watson and Crick Mendel 1975 Southern 2009 2004 New generation End of sequencing Sequencing of the human 1993 (NGS) genome Automated sequencers 1985 1959 PCR Beginning of Trisomy 21 Sanger (Mullis) sequencing Lejeune of the human sequencing Turpin genome Jacobs 1865 – 1975 Pre-molecular era 1975 – 2004 Molecular era 2007 Whole genome analyses: CGH 2004 Genomic era
THE NGS REVOLUTION : FROM TARGETED TO GLOBAL SEQUENCING The human genome : 3 Gb (3. 109 ) X 100 000 Sanger sequencing on amplicons : 500 bp 1000 Kb (106 bp) sequenced within 7 days Human exome sequencing 160. 000 exons = 30 Mb (30 106) 1. 2% of the human genome 3 Gb 100 x 3000 Mb = 3 Gb 50 Gb (50. 109 pb) sequenced within 7 days
NGS : BIOINFORMATICS EXPERTISE pb -Kb X 1 000 Gb Quality - Alignment - Annotation - Filtration - Comparison - Storage
UNDERESTIMATED VARIABILITY OF THE HUMAN GENOME Per exome 34 Mb : 1. 2% of the total genome : ü 17000 Single Nucleotide Variations (SNV) ü 50% non synonymous ü 500 rare (<0. 1%) SNVs not present in the data bases ü 1 de novo SNV with potential impact per generation
MAIN CHALLENGE OF NGS : INTERPRETATION OF GENETIC VARIATIONS Ø 1995 -2010 Detection of mutations Discovery of the DNA polymorphism complexity SNV, SNP, CNV…. . Ø Since 2010 Interpretation of mutations Statistical analyses Phenotypic evaluation Biological and medical interpretation Animal models
EXTENSIVE CHARACTERIZATION OF THE GENETIC DETERMINISM OF DISEASES Single case Extreme phenotype Substractive exomes in trio September 2013 : 900 publications Familial cases Comparative exomes between relatives Comparative exomes inter-families 17000 SNVs Exclusion of non genic– intronic – synonymous SNPs : 5000 SNVs Exclusion of SNVs from db. SNP 131 -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
OPTIMIZATION OF PERSONALIZED MEDICINE üHigh throughput üSimultaneous analysis of genes ü Reduction of delay Hereditary colorectal cancer : 1/500 Colon cancer 62 years WT/ mt Colon cancer 32 years Wt/ Wt WT/ mt WT/WT Colon cancer 36 years Suppression of an illegitimate anxiety and inappropriate medical follow-up in non mutation carriers MSH 2, MLH 1, MSH 6 , PMS 2, APC, MUTYH, SMAD 4, BMPR 1 A, STK 11, PTEN Colonoscopy since 20 years of age every 2 years
NGS HIGHLIGHTS THE COMPLEXITY OF THE GENETIC DETERMINISM OF DISEASES Age 100% Personalized medicine 60% Biological tolerance Risk of disease 80% Monogenic diseases Oligogenic diseases 40% Multigenic diseases 1 5 Number of genetic variations 100
ETHICAL ISSUES OF NGS IN THE CONTEXT OF PERSONALIZED MEDICINE ü 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 i. Pad 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 ü Access to 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 ARIIS CIRAD EFS CEA CHRU CNRS FONDATION MERIEUX CPU INRA INRIA INSERM INSTITUT PASTEUR INERIS INSTITUT CURIE INSTITUT MINES-TELECOM IRD IRBA 10 IRSN UNICANCER
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