Genomics, Cancers & Infectious Diseases

Qunyuan ZhangDivision of Statistical Genomics

Washington University School of Medicine

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

Genome Projects

Omics

Genome(variation, polymorphism)

Transcriptome (gene expression)

Proteome

Phenome (diseases)

PhenotypesTraits

Centraldogma

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

SNP Array hybridization

fluorescence hybridization

scanning

washing

image processingIntensities genotypes

genotype calling

Genotyping

BB

AB

AA

Sequencing

Aligned sequences

Referencegenome

Assembled genome

Assembled sequences

Assembling

Alignment

Variant Calling

List of Variants

Variant visualization of a genome

Association between genome and phenome

A case-control design

Mendelian Diseases Disease gene With disease

Non-disease gene With no disease

Common/Complex DiseasesMore risk genes Higher risk of disease

Less risk genes Lower risk of disease

Linkage Scan

GWAS

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

Cancers (somatic mutation)

Germline risk variantinherited from parents

Somatic mutation

Normal genome

Cancer genome

Cancer

Nature 456, 66-72 (2008) doi:10.1038/nature07485

Identifying somatic mutations in a tumour genome

(After QC)

98%

50%

98%

65%

70%

96%

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

DNMT3A Mutations in 188 AML Patients

DNMT3A Mutations in 93 AML Patients

DNMT3A Mutations Significantly Reduce Survival Probability

DNMT3A Mutations Significantly Reduce Many Genes’ Methylation Level

N Engl J Med. 2010 Dec 16;363(25):2424-33

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

Infectious Diseases (other applications)

Population Structure, Evolution, and Molecular Epidemiology

Pathogen/Strain Detection and Outbreak Investigation

Inverse Vaccination

Microbiome

Metagenome

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.

Genomic diversity/similarity

Transmission Networks

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

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