Revolutionizing the Fight Against Cancers and Infectious Diseases
Genomics, Cancers & Infectious Diseases
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Genomics, Cancers & Infectious Diseases
Qunyuan ZhangDivision of Statistical Genomics
Washington University School of Medicine
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Genomes Sequenced1995: H. influenzae, the first sequenced genome of a free-living
organism
2011:11554 bacterial genomes 41 eukaryotic genomes (19 from fungi)2675 viral species~ 40,000 strains of influenza virus~ 300,000 strains of HIV
2003: the first complete human genome sequences
2008: The 1000 Genomes ProjectPlan: 2500 samples from about 25 human populationsHundreds have been sequenced
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Genome Projects
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Omics
Genome(variation, polymorphism)
Transcriptome (gene expression)
Proteome
Phenome (diseases)
PhenotypesTraits
Centraldogma
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Genomic Variation
SNP
Insertion
Deletion
Duplication
Inversion
Translocation
…GTCAGTATCAGG… (reference)
…GTCAGCATCAGG…
…GTCAGAATATCAGG…
…GTCAGCAGG… (TAT deletion)
…GTCAGCAGTATCAGG…
…GTCAGCTATAGG…
…GTCAGAGG… …CCGCTATCGACC…
Copy number (large insertion, deletion, duplication)
SNP array
SNP array, SNP+CN array
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SNP Array hybridization
fluorescence hybridization
scanning
washing
image processingIntensities genotypes
genotype calling
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Genotyping
BB
AB
AA
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Sequencing
Aligned sequences
Referencegenome
Assembled genome
Assembled sequences
Assembling
Alignment
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Variant Calling
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List of Variants
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Variant visualization of a genome
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Association between genome and phenome
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A case-control design
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Mendelian Diseases Disease gene With disease
Non-disease gene With no disease
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Common/Complex DiseasesMore risk genes Higher risk of disease
Less risk genes Lower risk of disease
Linkage Scan
GWAS
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Cancers (germline variants)
More risk genes High risk of cancer
Less risk genes Low risk of cancer
Linkage ScanGWAS
http://www.nature.com/ng/journal/v42/n6/full/ng.586.html
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Cancers (somatic mutation)
Germline risk variantinherited from parents
Somatic mutation
Normal genome
Cancer genome
Cancer
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Nature 456, 66-72 (2008) doi:10.1038/nature07485
Identifying somatic mutations in a tumour genome
(After QC)
98%
50%
98%
65%
70%
96%
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DNMT3A mutation in a patient with Acute Myeloid Leukemia (AML)
116.4 billion base pairs with paired-end 99.6% coverage of the genome.
1-base-pair deletion in DNMT3A at the amino acid position 723
DNMT3A encodes DNA methylation enzymes that catalyze the addition of a methyl group to the C residue of CpG nucleotides, which is often associated with reduced expression of the downstream gene.
DNA methylation has long been hypothesized to contribute to cancers, no evidence.
A total of 62 of 281 patients (22%) had mutations in DNMT3A.
N Engl J Med. 2010 Dec 16;363(25):2424-33
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DNMT3A Mutations in 188 AML Patients
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DNMT3A Mutations in 93 AML Patients
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DNMT3A Mutations Significantly Reduce Survival Probability
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DNMT3A Mutations Significantly Reduce Many Genes’ Methylation Level
N Engl J Med. 2010 Dec 16;363(25):2424-33
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Infectious Diseases (gene identification)
vaccine Medication (antibiotics)
hostpathogen
susceptibility and resistance genes
virulence genes
vaccination-response genes
antibiotic sensitivity genes
antibiotic resistance/tolerance genes
Host/pathogen genes of interest can be identified by comparing genomic differences between two groups of host/pathogen samples
(case vs. control, responsive vs. non-responsive, resistant vs. sensitive ….)
Pathogenesis Vaccine/Drug Discovery
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Infectious Diseases (other applications)
Population Structure, Evolution, and Molecular Epidemiology
Pathogen/Strain Detection and Outbreak Investigation
Inverse Vaccination
Microbiome
Metagenome
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An outbreak of tuberculosis occurred over a 3-year period in a medium-size community in British Columbia, Canada
Whole-Genome Sequencing and Transmission-Network Analysis of a Tuberculosis Outbreak
N Engl J Med 2011;364:730-9.
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Genomic diversity/similarity
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Transmission Networks
N Engl J Med 2011;364:730-9.
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Inverse VaccinationSerogroup B Neisseria meningitidis (MenB)the most common cause of meningococcaldisease in the developed world
Nearly 40 years of conventional vaccinedevelopment failed to produce a comprehensive vaccine
2000, complele genome sequences of the virulent MenB strain MC58
Induced a protective immune response against three diverse MenB strains in 89%–96% of subjects
outer membrane vesicles (OMV) containing PorA
Novartis Vaccines