Genome Research at HKU Beyond the HapMap

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Genome Research at HKUBeyond the HapMap

• Pak C. Sham
• The University of Hong Kong
• NRPGM Workshop, Jan 2007

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Outline

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

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Established in 2002 with seed funding of HK 120M
from UDF
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

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Executive Committee

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

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Oligosynthesis
DNA Sequencing Gene Scan
MassArray Genotyping
2D Gel and DiGE
MDLC
Fluorescence Polarization
Pyrosequencing
PCR Farm
Bioplex cytokine phosphoprotein assays
Quantitative PCR
Core Facilities
Mass spectrometry and Protein profiling
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Affymetrix microarray system
Pathway analysis
Pathway Assist
Bioanalyzer
Core Facilities
Gene expression profiling
Genotype data management system, linkage and
association analyses
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• 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.

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Proteomics
Colorectal cancer
Bioinformatics
Collaborative Research
Hirschsprungs disease
Lung Cancer
L-SIGN (SARS)
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UGC-funded HK 50M research program led by
Professor Kathy Cheah
Skeletal development and degeneraton from infancy
to old age
Integration of modern genomic science and
technology with clinical practice.
Candidate gene and genome-wide approaches for
identifying genes and gene networks involved in
degeneration of intervertebral discs
Mouse models for studying the genomics and
proteomics of normal and abnormal skeletal
development
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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

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

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

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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."

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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

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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 (gt 5 frequency)
• Phase I 5 kb initial density across genome (1
  million SNPs)
• Phase II 1 kb density (gt 2.5 million SNPs)
• Deep resequencing of 10 x 500 kb regions (48
  individuals 1 SNP/300 bp) ENCODE

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Genotyping Platforms

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

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Genotype Data Quality

• Blinded quality assessment exercise
• Very high overall genotyping accuracy (99.7)
• All centres contributing data of high (gt99)
  quality.

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Phase 1 HapMap Paper
International HapMap Consortium, Oct 2005
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Allele Frequencies Differences in Populations
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LD patterns in Beijing /Tokyo samples
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Tag SNP Information Capture
Curves right to left Random Selected by
pairwise tagging Selected by multi-marker
tagging
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Haplotype Diversity and Ancestral Recombination
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80 recombination occurs in 15 sequence
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The HapMap Homepage
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Empirical assessment of ancestry
CEPH/European Yoruba Han Chinese Japanese
2K SNPs
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Empirical assessment of ancestry
Entire Phase I HapMap
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Empirical assessment of ancestry
Han Chinese Japanese
10K SNPs
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Outline

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

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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 gt C with at
least one tag SNP, where C is specified by the
user.
Bioinformatics (2005)
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Tag SNP selection using both LD and functional
information
Sham et al (2006) Bioinformatics
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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

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Genotype Error Rate Estimation
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PLINK

• Data management
• Summary statistics
• Population stratification
• Association analysis
• IBD estimation

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Outline

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

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Genome-wide association studies at HKU

• Ongoing
• Hirschsprungs Disease
• Intervertebral Disk Degenerative
• About to start
• Osteoporosis
• Hepatitis B
• Schizophrenia
• Being planned
• Colorectal Cancer
• Ischaemic Stroke

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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

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Opportunities for collaboration

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