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) Phenotypes Traits Central dogma

5. 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

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

7. Genotyping BB AB AA

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

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 Disease gene With disease Non-disease gene With no disease

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

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

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

18. Nature 456, 66-72 (2008) doi:10.1038/nature07485 Identifying somatic mutations in a tumour genome (After QC) 98% 50% 98% 65% 70% 96%

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) vaccine Medication (antibiotics) host pathogen 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

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

26. 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.

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 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