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Genomics
• Mapping and sequencing genomes
– Why and how ?
• Functional genomics
– Basic understanding of genome function
– Study how genes affect economically important traits
Sigbjørn Lien
Centre for Integrative Genetics / Department of Animal and Aquacultural Sciences
Agricultural University of Norway
Why Sequence the Bovine Genome?
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National Human Genome Research Institute (NHGRI) ranks cow as
high priority:
– Physical map well advanced
– Need 3rd equidistant mammal from rodents and humans
– Preferably an animal model
• Comparative genomics
– Genome dynamics  NIH pays half of the sequencing!
– Human health
• Need a RUMINANT genome
– Detailed gene order and organisation
– Detailed structure of gene and control regions
• Step change in progress/cost of QTL/gene discovery (up to 10X)
BOVINE GENOME SEQUENCING
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6-8X coverage
 1.5-2.5X coverage ordered path of BAC clones + BAC end sequences
 4-5X (2 kb), 1-2X (10 kb) and 0.4X (50 kb) coverage shotgun library sequencing
Hereford
 Sequencing for genetic variation -> SNPs Holstein, Norwegian Cattle, Jersey, Angus, Limousin, Brahman
 ~ 40 million sequence reads
 ~ US$1.27 each (20% of current commercial rate!)
 Assembly of 6X provides ~ 80% sequence coverage
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Total costs: ~US$51M, where NHGRI pays ~50% (~US$25M)
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Sequencing at Baylor College of Medicine (Houston, Texas)
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Start Dec 2003 and complete within 18 months
• Provide tools for functional genomics!!!
Functional genomics
Genome sequencing
Technologies in functional genomics
• Gene expression
– DNA-microarrays
• Genetic variation
– Single Nucleotide Polymorphisms (SNPs)
CONTROL
DNA-microarrays
TREATED
cDNA
cDNA
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Mix and hybridize
Spot
(Gene)
ARRAY
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Genomic response:
• Breed
• Age
• Nutrition
• Environment
• Disease
DNA-microarrays
• Gene expression
• Meat quality
SNPs
DNA
Single Nucleotide Polymorphisms
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Frequent
Well distributed
Stable
Functional?
High-throughput genotyping
Genetic variation: 0.3 %
(~10 mill SNPs)
International Consortium Launches Genetic
Variation Mapping Project
HapMap Will Help Identify Genetic Contributions to Common Diseases
WASHINGTON, October 29, 2002.
An international research consortium today launched an approximately $100 million publicprivate effort to create the next generation map of the human genome. Called the International
HapMap Project, this new venture is aimed at speeding the discovery of genes related to
common illnesses such as asthma, cancer, diabetes and heart disease.
Expected to take three years to complete…..
SNPs
haplotypes/haplotype tags
Study genome function:
BIOINFORMATICS!!!
 Biological samples
 Phenotypes
Biobank
 Pedigree
 Control environment/nutrition
 Genotypes
 Gene expression data
 Proteome data
 Biological knowledge
 …..
www.cigene.no
Agricultural University of Norway
Norwegian School of Veterinary Science
Institute of Aquaculture Research
University of Oslo
University of Bergen
Norwegian Computing Centre
Norwegian Radium Hospital
Norwegian University of Science and Technology
National platform for detection, typing and interpretation of SNPs
A. Establish and maintain a national core facility providing:
 (i) a high-throughput SNP-typing service of human, animal, plant
and microbial materials.
 (ii) key competence concerning identification and methodological
integration of experimental and theoretical approaches for making
a causal connection between genomic and phenotypic data on
complex traits in fish, mammals, plants and micro-organisms.
B. Use this core facility within livestock and marine functional
genomics to promote a deep mechanistic understanding of
commercially important traits
National platform for detection, typing and interpretation of SNPs
High-througput technology - CIGENE
DNA/RNA-extraction
BioRobot M48
PCR
MJR-tetrads
Workstation 2
Multimek96 (Beckman)
Workstation 1
BiomekFX (Beckman)
DATABASE
LIMS
Normalization of DNA
Victor3 (PerkinElmer)
MassARRAY (Sequenom)
Sequencing & SNPlex (ABI3730)
Norwegian Biobank Cattle
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Norway was the first country to establish a nation-wide health card recording
system in cattle
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Each cow has an individual health card, drugs and antibiotics can only be
prescribed by vets -> very reliable recording
10 traits ...........46 traits...........64 traits
(1975)
(1978)
(1989)
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Also intensive recording of milk, beef and reproduction traits
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90% of all cows have been registered since 1978 -> ~ 4 mill cows
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Complete listing of pedigree structure -> ~ 7,5 mill individuals
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Progeny testing of 250-300 daughters per sire
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Paternity testing of bulls
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Systematic storage of semen from all bulls since 1982  DNA
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Choose among ~280.000 cows/bulls for in vivo experiments
Norway’s participation in the
sequencing consortium
FOCUS ON OUR STRENGTHS:
 Unique biobank material
 Competence and technology to “BRIDGE THE
GENOTYPE-PHENOTYPE GAP”
 Sequencing for genetic variation!!!
Phase 1
Sequencing effort
Phase 2
SNP-detection
Other projects
Validation of
SNPs
Genotype
biobank
Gene expression
Proteomics