CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD ARIISEFSINERISINSTITUT CURIEINSTITUT...
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Transcript of CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD ARIISEFSINERISINSTITUT CURIEINSTITUT...
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
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ITMO Génétique, génomiqueet bioinformatique
From population genetics to cellular genomics: a path towards personalised medicine
Lluis Quintana-Murci, Institut Pasteur-CNRS
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
Genetic variation in health and disease
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ACGTGTACAGAAGGGCCATGAACACTGTTATTACTCTTACACAATTGTGAGGCAGCCCTCGAGCCACAGGCGGGTCCAGCTGTTGGCTATAAACGGATAGCCTACCGGTCTCTGATCGGAGATCACCATGTTTCTGGGTCCCTTGTACCCTGGATGCAGTACCTCGCCCCAGTTTCGCATACAAATTCGCATACAAAACGTGTACAGAAGGGCCATGAACACTGTTATTACTCTTACACAATTGTGAGGCAGCCCTCGAGCCACAGGCGGGTCCAGCTGTTGGCTATAAACGGATAGCCTACCGGTCTCTGATCGGAGATCACCATGTTTCTGGGTCCCTTGTACCCTGGATGCAGTACCTCGCCCCAGTTTCGCATACAAATTTCGCATACAAAAA
Genetic Diversity
Inter-Population Variation
Phenotypic DiversityPhenotypic Diversity
Inter-Individual Variation
Personal genomics
Personalised medicine
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
The last decade in human genomics
3
1. The complete sequence of the human genome
2. SNP Discovery and the HapMap Project
3. The 1,000 Genomes Project
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
Lessons from genome diversity
4
tttctccatttgtcgtgacacctttgttgacaccttcatttctgcattctcaattctatttcactggtctatggcagagaacacaaaatatggccagtggcctaaatccagcctactaccttttttttttttttgtaacattttactaacatagccattcccatgtgtttccatgtgtctgggctgcttttgcactctaatggcagagttaagaaattgtagcagagaccacaatgcctcaaatatttactctacagccctttataaaaacagtgtgccaactcctgatttatgaacttatcattatgtcaataccatactgtctttattactgtagttttataagtcatgacatcagataatgtaaatcctccaactttgtttttaatcaaaagtgttttggccatcctagatatactttgtattgccacataaatttgaagatcagcctgtcagtgtctacaaaatagcatgctaggattttgatagggattgtgtagaatctatagattaattagaggagaatgactatcttgacaatactgctgcccctctgtattcgtgggggattggttccacaacaacacccaccccccactcggcaacccctgaaacccccacatcccccagcttttttcccctgctaccaaaatccatggatgctcaagtccatataaaatgccatactatttgcatataacctctgcaatcctcccctatagtttagatcatctctagattacttataatactaataaaatctaaatgctatgtaaatagttgctatactgtgttgagggttttttgttttgttttgttttatttgtttgtttgtttgtattttaagagatggtgtcttgctttgttgcccaggctggagtgcagtggtgagatcatagcttactgcagcctcaaactcctggactcaaacagtcctcccacctcagcctcccaaagtgctgggatacaggtgtgacccactgtgcccagttattattttttatttgtattattttactgttgtattatttttaattattttttctgaatattttccatctatagttggttgaatcatggatgtggaacaggcaaatatggagggctaactgtattgcatcttccagttcatgagtatgcagtctctctgtttatttaaagttttagtttttctcaaccatgtttacttttcagtatacaagactttgacgttttttgttaaatgtatttgtaagtattttattatttgtgatgttatttaaaaagaaattgttgactgggcacagtggctcacgcctgtaatcccagcactttgggaggctgaggcgggcagatcacgaggtcaggagatcaagaccatcctggctaacatggtaaaaccccgtctctactaaaaatagaaaaaaattagccaggcg
3 million differences between individuals
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
Lessons from genome diversity
5
tttctccatttgtcgtgacacctttgttgacaccttcatttctgcattctcaattctatttcactggtctatggcagagaacacaaaatatggccagtggcctaaatccagcctactaccttttttttttttttgtaacattttactaacatagccattcccatgtgtttccatgtgtctgggctgcttttgcactctaatggcagagttaagaaattgtagcagagaccacaatgcctcaaatatttactctacagccctttataaaaacagtgtgccaactcctgatttatgaacttatcattatgtcaataccatactgtctttattactgtagttttataagtcatgacatcagataatgtaaatcctccaactttgtttttaatcaaaagtgttttggccatcctagatatactttgtattgccacataaatttgaagatcagcctgtcagtgtctacaaaatagcatgctaggattttgatagggattgtgtagaatctatagattaattagaggagaatgactatcttgacaatactgctgcccctctgtattcgtgggggattggttccacaacaacacccaccccccactcggcaacccctgaaacccccacatcccccagcttttttcccctgctaccaaaatccatggatgctcaagtccatataaaatgccatactatttgcatataacctctgcaatcctcccctatagtttagatcatctctagattacttataatactaataaaatctaaatgctatgtaaatagttgctatactgtgttgagggttttttgttttgttttgttttatttgtttgtttgtttgtattttaagagatggtgtcttgctttgttgcccaggctggagtgcagtggtgagatcatagcttactgcagcctcaaactcctggactcaaacagtcctcccacctcagcctcccaaagtgctgggatacaggtgtgacccactgtgcccagttattattttttatttgtattattttactgttgtattatttttaattattttttctgaatattttccatctatagttggttgaatcatggatgtggaacaggcaaatatggagggctaactgtattgcatcttccagttcatgagtatgcagtctctctgtttatttaaagttttagtttttctcaaccatgtttacttttcagtatacaagactttgacgttttttgttaaatgtatttgtaagtattttattatttgtgatgttatttaaaaagaaattgttgactgggcacagtggctcacgcctgtaatcccagcactttgggaggctgaggcgggcagatcacgaggtcaggagatcaagaccatcctggctaacatggtaaaaccccgtctctactaaaaatagaaaaaaattagccaggcg
ga
gc
gc
ga
ga
ga
ga
tc
tc
tc
ga
ga g
c
tc
tc
tc
Most mutations have no (known) phenotypic effects
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
Lessons from genome diversity
6
tttctccatttgtcgtgacacctttgttgacaccttcatttctgcattctcaattctatttcactggtctatggcagagaacacaaaatatggccagtggcctaaatccagcctactaccttttttttttttttgtaacattttactaacatagccattcccatgtgtttccatgtgtctgggctgcttttgcactctaatggcagagttaagaaattgtagcagagaccacaatgcctcaaatatttactctacagccctttataaaaacagtgtgccaactcctgatttatgaacttatcattatgtcaataccatactgtctttattactgtagttttataagtcatgacatcagataatgtaaatcctccaactttgtttttaatcaaaagtgttttggccatcctagatatactttgtattgccacataaatttgaagatcagcctgtcagtgtctacaaaatagcatgctaggattttgatagggattgtgtagaatctatagattaattagaggagaatgactatcttgacaatactgctgcccctctgtattcgtgggggattggttccacaacaacacccaccccccactcggcaacccctgaaacccccacatcccccagcttttttcccctgctaccaaaatccatggatgctcaagtccatataaaatgccatactatttgcatataacctctgcaatcctcccctatagtttagatcatctctagattacttataatactaataaaatctaaatgctatgtaaatagttgctatactgtgttgagggttttttgttttgttttgttttatttgtttgtttgtttgtattttaagagatggtgtcttgctttgttgcccaggctggagtgcagtggtgagatcatagcttactgcagcctcaaactcctggactcaaacagtcctcccacctcagcctcccaaagtgctgggatacaggtgtgacccactgtgcccagttattattttttatttgtattattttactgttgtattatttttaattattttttctgaatattttccatctatagttggttgaatcatggatgtggaacaggcaaatatggagggctaactgtattgcatcttccagttcatgagtatgcagtctctctgtttatttaaagttttagtttttctcaaccatgtttacttttcagtatacaagactttgacgttttttgttaaatgtatttgtaagtattttattatttgtgatgttatttaaaaagaaattgttgactgggcacagtggctcacgcctgtaatcccagcactttgggaggctgaggcgggcagatcacgaggtcaggagatcaagaccatcctggctaacatggtaaaaccccgtctctactaaaaatagaaaaaaattagccaggcg
ga
gc
gc
ga
ga
ga
ga
tc
tc
tc
ga
ga g
c
tc
tc
tc
Some variants can explain phenotypic variation (in health and disease)
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CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
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Lessons from genome diversity
The burden of deleterious mutations in the human genome
•10,000 amino-acid altering mutations
•300-400 stop/splice/indels disrupting 200-300 genes
•heterozygous at 50-100 mutations associated with an inherited disorder
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CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
Impact of genetic variation on phenotypes
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ACGTGTACAGAAGGGCCATGAACACTGTTATTACTCTTACACAATTGTGAGGCAGCCCTCGAGCCACAGGCGGGTCCAGCTGTTGGCTATAAACGGATAGCCTACCGGTCTCTGATCGGAGATCACCATGTTTCTGGGTCCCTTGTACCCTGGATGCAGTACCTCGCCCCAGTTTCGCATACAAATTCGCATACAAAACGTGTACAGAAGGGCCATGAACACTGTTATTACTCTTACACAATTGTGAGGCAGCCCTCGAGCCACAGGCGGGTCCAGCTGTTGGCTATAAACGGATAGCCTACCGGTCTCTGATCGGAGATCACCATGTTTCTGGGTCCCTTGTACCCTGGATGCAGTACCTCGCCCCAGTTTCGCATACAAATTTCGCATACAAAAA
Genetic Diversity
Inter-Population Variation
Phenotypic DiversityPhenotypic Diversity
Inter-Individual Variation
Personal genomics
Personalised medicine
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
Genome-wide association studies - GWAS
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By September 2013:11,304 SNPs associated with 891 traits/diseases (1,701 studies)
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CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
GWAS results in personalised medicine
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Thomas et al. Nature. 2009
• High p-values do not translate to clinically useful diagnostic assays• Strong population variation (only useful in European populations)
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CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
Healthy-based population approaches
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• Understanding patterns of population variation of our genomes • Searching for the signatures of selection in the genome
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CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
Population and evolutionary genetics
12
Variation in biological relevance in host defence of immune receptors
Positive selection targeting protective mutations in Europeans
Type-III IFNs and hepatitis CInnate immunity to infection
Quintana-Murci & Clark. Nat Rev Immunol, 2013
Manry et al., J Exp Med, 2011
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CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
Principles of cellular genomics
InfectionDrugs
RadiationUntreated cells Treated cells
Variation in gene expressionGenetic/epigenetic markers
Gene-environment interactions
Complex phenotypesLack of mechanistic understanding
Simpler phenotypesFocus on mechanisms
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CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
Cellular genomics complementing GWAS
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• GWAS of TB have mostly failed in identifying susceptibility genes
• A recent cellular genomics study has identified >100 mutations that affect expression only after infection (response eQTLs)
• These mutations may contribute in an additive manner to susceptibility to develop TB - > added value of cellular genomics
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CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
Integrative genomics
• Importance of taking first basic science approaches
• Need for understanding how genotypes affect phenotypes in BOTH
health and disease
• Need for complementary approaches based on model systems
• Opportunities to tackle these questions at the highest resolution (e.g.,
NGS, rare variants, epigenetics)
• Improve methods in statistical genetics and computational biology
(e.g., epistasis)
15
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CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
A path towards personalised medicine
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ENVIRONMENTSLIFESTYLE
GENETICScomplete sequences
EPIGENETICSMethylation, Histone modification
HEALTH and DISEASE
BIOMARKERSResponses to treatment Vaccine efficiency, doses
PHENOTYPESMolecular phenotypes (expression)
Cellular phenotypesOrganismal phenotypes (traits or diseases)
Model systems
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CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
17
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
Population and evolutionary genetics
18
Barreiro & Quintana-Murci, Nat Rev Genet, 2010
180 immunity-related genes targeted by positive selection
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
Disease-based approaches
19
Approach Clinical genetics Epidemiological genetics
Phenotype Severe/acute(children)
Milder/chronic(adults)
Tools Mendelian Genetics Linkage/association
Sample Small Large
Rare mutationsStrong individual effect
Common polymorphismsModest individual effect
Little public health impact Strong public health impact
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
Limitations of “disease-only”-based approaches
• Associations based on strict statistic thresholds• Disease is a complex “phenotype”• Odds ratios remain rather low• Assumption of genes acting “alone”• Causal mutations remain mostly unidentified
-> Need for complementary approaches
20
CEA
CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRDARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCERIRBA IRSNCIRAD
FONDATION MERIEUX
Using “simpler” phenotypes (molecular)
• Expression is a molecular phenotype that varies between individuals and populations
• Levels of expression can be under genetic control (eQTL)
21
Genotype mRNA
M. tuberculosis
• 1/3 of the world’s population infected with Mycobacterium tuberculosis (MTB)
• Only 10% of infected individuals will develop the active form of the disease
Environment