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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
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ARIIS CIRAD EFS FONDATION MERIEUX INERIS INSTITUT CURIE INSTITUT MINES-TELECOM IRBA IRSN UNICANCER
1985 PCR (Mullis)
2004- Genomic era
2004 End of sequencing of
the human genome
2007
Whole genome analyses: CGH
1865 – 1975 Pre-molecular era
1975 – 2004 Molecular era
1865 Mendel
1953 DNA Structure Watson and
Crick
1959 Trisomy 21
Lejeune Turpin
Jacobs
A SHORT HISTORY OF HUMAN GENETICS
1975 Southern
1993 Automated sequencers
Beginning of sequencing of the human
genome Sanger
sequencing
2009
New generation Sequencing
(NGS)
THE NGS REVOLUTION : FROM TARGETED TO GLOBAL SEQUENCING
Human exome sequencing 160.000 exons = 30 Mb (30 10
6)
1.2% of the human genome 3 Gb 100x 3000 Mb = 3 Gb
50 Gb (50. 10
9pb) sequenced within 7 days Sanger sequencing on amplicons : 500 bp
1000 Kb (10
6bp) sequenced within 7 days
X 100 000
The human genome : 3 Gb (3.109 )
NGS : BIOINFORMATICS EXPERTISE
Quality - Alignment - Annotation - Filtration - Comparison - Storage
pb -Kb
Gb
X 1 000 000
Per exome
34 Mb : 1.2% of the total genome :
17000 Single Nucleotide Variations (SNV)
50% non synonymous
500 rare (<0.1%) SNVs not present in the data bases
1 de novo SNV with potential impact per generation
UNDERESTIMATED VARIABILITY OF THE HUMAN GENOME
MAIN CHALLENGE OF NGS :
INTERPRETATION OF GENETIC VARIATIONS
1995-2010
Detection of mutations
Since 2010
Interpretation of mutations
Discovery of the DNA polymorphism complexity SNV, SNP, CNV…..
Biological and medical interpretation Phenotypic evaluation
Statistical analyses Animal models
EXTENSIVE CHARACTERIZATION OF THE GENETIC DETERMINISM OF DISEASES
Single case Extreme phenotype
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 Substractive
exomes in trio Comparative exomes
inter-families Familial cases
Comparative exomes between relatives
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
September 2013 : 900 publications
Colon cancer 62 years
WT/ mt Wt/ Wt WT/WT
Suppression of an illegitimate anxiety and inappropriate medical follow-up
in non mutation carriers
WT/ mt
Colonoscopy since 20 years of age every 2 years
Colon cancer 32 years Colon cancer 36 years
OPTIMIZATION OF PERSONALIZED MEDICINE
Hereditary colorectal cancer : 1/500
High throughput
Simultaneous analysis of genes
Reduction of delay
MSH2, MLH1, MSH6 ,PMS2, APC, MUTYH,
SMAD4, BMPR1A, STK11, PTEN
R is k o f d is e as e
100%
40%
60%
80%
Number of genetic variations 100 Oligogenic
diseases
Age
Multigenic diseases Monogenic diseases
B io lo gi ca l t o le ra n ce
NGS HIGHLIGHTS THE COMPLEXITY
OF THE GENETIC DETERMINISM OF DISEASES Personalized medicine
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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
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
ETHICAL ISSUES OF NGS IN THE CONTEXT OF PERSONALIZED MEDICINE
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CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD
ARIIS CIRAD EFS FONDATION MERIEUX INERIS INSTITUT CURIE INSTITUT MINES-TELECOM IRBA IRSN UNICANCER
