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Genomics, Cancers & Infectious Diseases

Genomics, Cancers & Infectious Diseases. Qunyuan Zhang Division of Statistical Genomics Washington University School of Medicine. Genomes Sequenced. 1995: H. influenzae, the first sequenced genome of a free-living organism 2011: 11554 bacterial genomes

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Genomics, Cancers & Infectious Diseases

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  1. Genomics, Cancers & Infectious Diseases Qunyuan Zhang Division of Statistical Genomics Washington University School of Medicine

  2. Genomes Sequenced 1995: 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 Project Plan: 2500 samples from about 25 human populations Hundreds have been sequenced

  3. Genome Projects

  4. Omics Genome (variation, polymorphism) Transcriptome (gene expression) Proteome Phenome (diseases) Central dogma Phenotypes Traits

  5. Genomic Variation …GTCAGTATCAGG… (reference) …GTCAGCATCAGG… …GTCAGAATATCAGG… …GTCAGCAGG… (TAT deletion) …GTCAGCAGTATCAGG… …GTCAGCTATAGG… …GTCAGAGG… …CCGCTATCGACC… SNP array SNP Insertion Deletion Duplication Inversion Translocation Copy number (large insertion, deletion, duplication) SNP array, SNP+CN array

  6. SNP Array fluorescence hybridization hybridization washing scanning Intensities genotypes image processing genotype calling

  7. Genotyping BB AB AA

  8. Sequencing Alignment Reference genome Aligned sequences Assembling Assembled sequences Assembled genome

  9. Variant Calling

  10. List of Variants

  11. Variant visualization of a genome

  12. Association between genome and phenome

  13. A case-control design

  14. Mendelian Diseases With disease Disease gene With no disease Non-disease gene

  15. Common/Complex Diseases Higher risk of disease More risk genes Lower risk of disease Less risk genes Linkage Scan GWAS

  16. Cancers (germline variants) High risk of cancer More risk genes Low risk of cancer Less risk genes Linkage Scan GWAS http://www.nature.com/ng/journal/v42/n6/full/ng.586.html

  17. Cancers (somatic mutation) Normal genome Germline risk variant inherited from parents Cancer genome Somatic mutation Cancer

  18. Identifying somatic mutations in a tumourgenome 70% (After QC) 98% 98% 50% 65% 96% Nature456, 66-72 (2008) doi:10.1038/nature07485

  19. 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

  20. DNMT3A Mutations in 188 AML Patients

  21. DNMT3A Mutations in 93 AML Patients

  22. DNMT3A Mutations Significantly Reduce Survival Probability

  23. DNMT3A Mutations Significantly Reduce Many Genes’ Methylation Level N Engl J Med. 2010 Dec 16;363(25):2424-33

  24. Infectious Diseases (gene identification) virulence genes host susceptibility and resistance genes pathogen vaccination-response genes antibiotic sensitivity genes antibiotic resistance/tolerance genes vaccine Medication (antibiotics) 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

  25. Infectious Diseases (other applications) Population Structure, Evolution, and Molecular Epidemiology Pathogen/Strain Detection and Outbreak Investigation Inverse Vaccination Microbiome Metagenome

  26. Whole-Genome Sequencing and Transmission-Network Analysis of a Tuberculosis Outbreak N Engl J Med 2011;364:730-9. An outbreak of tuberculosis occurred over a 3-year period in a medium-size community in British Columbia, Canada

  27. Genomic diversity/similarity

  28. Transmission Networks N Engl J Med 2011;364:730-9.

  29. Inverse Vaccination Serogroup B Neisseria meningitidis (MenB) the most common cause of meningococcal disease in the developed world Nearly 40 years of conventional vaccine development failed to produce a comprehensive vaccine Novartis Vaccines 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

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