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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
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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
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The last decade in human genomics
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1. The complete sequence of the human genome
2. SNP Discovery and the HapMap Project
3. The 1,000 Genomes Project
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Lessons from genome diversity
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tttctccatttgtcgtgacacctttgttgacaccttcatttctgcattctcaattctatttcactggtctatggcagagaacacaaaatatggccagtggcctaaatccagcctactaccttttttttttttttgtaacattttactaacatagccattcccatgtgtttccatgtgtctgggctgcttttgcactctaatggcagagttaagaaattgtagcagagaccacaatgcctcaaatatttactctacagccctttataaaaacagtgtgccaactcctgatttatgaacttatcattatgtcaataccatactgtctttattactgtagttttataagtcatgacatcagataatgtaaatcctccaactttgtttttaatcaaaagtgttttggccatcctagatatactttgtattgccacataaatttgaagatcagcctgtcagtgtctacaaaatagcatgctaggattttgatagggattgtgtagaatctatagattaattagaggagaatgactatcttgacaatactgctgcccctctgtattcgtgggggattggttccacaacaacacccaccccccactcggcaacccctgaaacccccacatcccccagcttttttcccctgctaccaaaatccatggatgctcaagtccatataaaatgccatactatttgcatataacctctgcaatcctcccctatagtttagatcatctctagattacttataatactaataaaatctaaatgctatgtaaatagttgctatactgtgttgagggttttttgttttgttttgttttatttgtttgtttgtttgtattttaagagatggtgtcttgctttgttgcccaggctggagtgcagtggtgagatcatagcttactgcagcctcaaactcctggactcaaacagtcctcccacctcagcctcccaaagtgctgggatacaggtgtgacccactgtgcccagttattattttttatttgtattattttactgttgtattatttttaattattttttctgaatattttccatctatagttggttgaatcatggatgtggaacaggcaaatatggagggctaactgtattgcatcttccagttcatgagtatgcagtctctctgtttatttaaagttttagtttttctcaaccatgtttacttttcagtatacaagactttgacgttttttgttaaatgtatttgtaagtattttattatttgtgatgttatttaaaaagaaattgttgactgggcacagtggctcacgcctgtaatcccagcactttgggaggctgaggcgggcagatcacgaggtcaggagatcaagaccatcctggctaacatggtaaaaccccgtctctactaaaaatagaaaaaaattagccaggcg
3 million differences between individuals
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Lessons from genome diversity
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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
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Lessons from genome diversity
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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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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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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
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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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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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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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Population and evolutionary genetics
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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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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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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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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)
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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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Population and evolutionary genetics
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Barreiro & Quintana-Murci, Nat Rev Genet, 2010
180 immunity-related genes targeted by positive selection
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Disease-based approaches
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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
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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
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Using “simpler” phenotypes (molecular)
• Expression is a molecular phenotype that varies between individuals and populations
• Levels of expression can be under genetic control (eQTL)
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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