1115 Sham

Genome Research at HKUBeyond the HapMap: 

Genome Research at HKU Beyond the HapMap Pak C. Sham The University of Hong Kong NRPGM Workshop, Jan 2007

Outline: 

Outline HKU Genome Rsearch Centre International HapMap Project Development of Software Tools Genome-Wide Association Studies

Slide3: 

Mission: To lead the genome research in Hong Kong and South China region To provide the expertise and infrastructure for studies in genomics, proteomics, and bioinformatics To develop evidence-based medicine To enhance the understanding of disease mechanisms for better healthcare To provide education and training and enhance the public awareness in genome research Established in 2002 with seed funding of HK$ 120M from UDF

Executive Committee: 

Executive Committee Lap-Chee Tsui Paul K.H. Tam Si Lok Pak C. Sham Robert Curtain

Slide5: 

Pyrosequencing MassArray Genotyping Oligosynthesis DNA Sequencing & Gene Scan Quantitative PCR PCR Farm Fluorescence Polarization Mass spectrometry and Protein profiling 2D Gel and DiGE Bioplex cytokine & phosphoprotein assays MDLC

Slide6: 

Pathway Assist Genotype data management system, linkage and association analyses Gene expression profiling Bioanalyzer Affymetrix microarray system Pathway analysis

Slide7: 

The International HapMap Project aimed to create a genome-wide database of common genetic variation. Prof. Lap-Chee Tsui and the GRC led the Hong Kong HapMap Group (HKHMG) and secured HK$ 35M funding (UGC and ITF) to perform the genotyping of the short arm of Chromosome 3. The GRC established the Sequenom MassArray platform for high-throughput genotyping, and generated the required 10 million genotypes within 18 months.

Slide8: 

Lung Cancer Hirschsprung’s disease Colorectal cancer L-SIGN (SARS) Bioinformatics Proteomics

Slide9: 

Skeletal development and degeneraton from infancy to old age Mouse models for studying the genomics and proteomics of normal and abnormal skeletal development UGC-funded HK$ 50M research program led by Professor Kathy Cheah Candidate gene and genome-wide approaches for identifying genes and gene networks involved in degeneration of intervertebral discs Integration of modern genomic science and technology with clinical practice.

Slide10: 

Training The GRC provides a training ground for graduates students, postdoctoral fellows, clinician-scientists and biotechnologists. The GRC Inaugural Symposium (2004) The Croucher Foundation Advanced Study Institute 2006: “Statistical Genetics: From Haplotype Maps to Disease Susceptibility Genes” The International Proteomics Symposium (IPS2006) The 8th International Meeting on Human Genome Variation and Complex Genome Analysis (HGV2006) The Croucher Foundation Advanced Study Institute 2007: “Genome Informatics: From Gene Finding to Systems Biology”

Slide11: 

University of Oxford Harvard University International Partnership The Centre for Applied Genomics (TCAG) at the Hospital for Sick Children, Toronto King’s College University of London Yale University

Outline: 

Outline HKU Genome Rsearch Centre International HapMap Project Development of Software Tools Genome-Wide Association Studies

HapMap Project Launch: 

HapMap Project Launch WASHINGTON, Oct 2002 “An international research consortium today launched an approximately $100 million public-private effort to create the next generation map of the human genome.” “The International HapMap Project builds on the freely available sequence of the human genome produced by the International Human Genome Sequencing Consortium.” "The HapMap will provide a powerful tool to help us take the next quantum leap toward understanding the fundamental contribution that genes make to common illnesses like cancer, diabetes and mental illness."

The Hong Kong HapMap Group: 

The Hong Kong HapMap Group University of Hong Kong Lap-Chee Tsui Paul Tam William Mak You-Qiang Song Pak C. Sham Chinese University of Hong Kong Mary Waye Stephen Tsui Hong Kong University of Science and Technology Jeffery Wong Hannah Xue

Study Design: 

Study Design Samples CEPH (30 trios) “Europeans” Nigeria (Yoruba; Ibadan: 30 trios) “Africans” Han Chinese (Beijing 45 unrelateds) “East Asians” Japanese (Tokyo; 44 unrelateds) “East Asians” Genotyping All ‘common’ SNPs (> 5% frequency) Phase I: 5 kb initial density across genome (1 million SNPs) Phase II: ~ 1 kb density (> 2.5 million SNPs) Deep resequencing of 10 x 500 kb regions (48 individuals; 1 SNP/300 bp): “ENCODE”

Genotyping Platforms: 

Genotyping Platforms Illumina BeadArrays Sequenom MassExtend (Hong Kong) ParAllele MIP Third Wave Invader Perkin-Elmer AcycloPrime-FP High-density oligonucleotide array

Genotype Data Quality: 

Genotype Data Quality Blinded quality assessment exercise: Very high overall genotyping accuracy (99.7%) All centres contributing data of high (>99%) quality.

Phase 1 HapMap Paper: 

Phase 1 HapMap Paper International HapMap Consortium, Oct 2005

Slide19: 

Allele Frequencies Differences in Populations

Slide20: 

LD patterns in Beijing /Tokyo samples

Tag SNP Information Capture: 

Tag SNP Information Capture Curves right to left: Random Selected by pairwise tagging Selected by multi-marker tagging

Slide22: 

Haplotype Diversity and Ancestral Recombination

Slide23: 

80% recombination occurs in 15% sequence

The HapMap Homepage: 

The HapMap Homepage

Empirical assessment of ancestry: 

Empirical assessment of ancestry ~2K SNPs CEPH/European Yoruba Han Chinese Japanese

Slide26: 

Entire Phase I HapMap Empirical assessment of ancestry

Empirical assessment of ancestry: 

Han Chinese Japanese ~10K SNPs Empirical assessment of ancestry

Outline: 

Outline HKU Genome Rsearch Centre International HapMap Project Development of Software Tools Genome-Wide Association Studies

Slide29: 

Summary: Cluster and set-cover algorithms are developed to obtain a set of tag SNPs that can represent all the known SNPs in a chromosomal region, subject to the constraint that all SNPs must have a squared correlation R2 > C with at least one tag SNP, where C is specified by the user. Bioinformatics (2005)

Slide30: 

Sham et al (2006) Bioinformatics Tag SNP selection using both LD and functional information

Data Management System for Affy 500K: 

Data Management System for Affy 500K Database system with web-based interface Automated genotype calling using DM and BLRMM algorithms Quality control checks Consistency between sty and nsp arrays Genotype error rate estimates Generation of data files for further analyses

Genotype Error Rate Estimation: 

Genotype Error Rate Estimation

PLINK: 

PLINK Data management Summary statistics Population stratification Association analysis IBD estimation

Outline: 

Outline HKU Genome Rsearch Centre International HapMap Project Development of Software Tools Genome-Wide Association Studies

Genome-wide association studies at HKU: 

Genome-wide association studies at HKU Ongoing Hirschsprung’s Disease Intervertebral Disk Degenerative About to start Osteoporosis Hepatitis B Schizophrenia Being planned Colorectal Cancer Ischaemic Stroke

Summary: 

Summary The HKU Genome Research Centre aims to become a regional centre for genome research Establishment of core technology platforms Participation in the International HapMap Project Development of statistical methods and software tools Initiation of genome-wide association studies of several common diseases Establishment of international collaborations

Opportunities for collaboration: 

Opportunities for collaboration Sharing of samples International Consortia Sharing of facilities Increased efficiency Sharing of expertise Exchange visits, workshops, joint supervision of students