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Genomics

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

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Genomics

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  1. 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

  2. Why Sequence the Bovine Genome? • 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 • 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) • NIH pays half of the sequencing!

  3. BOVINE GENOME SEQUENCING • 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 • Sequencing for genetic variation -> SNPs • ~ 40 million sequence reads • ~ US$1.27 each (20% of current commercial rate!) • Assembly of 6X provides ~ 80% sequence coverage • Total costs: ~US$51M, where NHGRI pays ~50% (~US$25M) • Sequencing at Baylor College of Medicine (Houston, Texas) • Start Dec 2003 and complete within 18 months • Provide tools for functional genomics!!! Hereford Holstein, Norwegian Cattle, Jersey, Angus, Limousin, Brahman

  4. Functional genomics Genome sequencing

  5. Technologies in functional genomics • Gene expression • DNA-microarrays • Genetic variation • Single Nucleotide Polymorphisms (SNPs)

  6. CONTROL TREATED DNA-microarrays cDNA cDNA 1 1 2 2 3 1 2 2 3 1 3 3 Mix and hybridize Spot ARRAY (Gene) 2 3 1 1 2 3 Detection

  7. Genomic response: • Breed • Age • Nutrition • Environment • Disease DNA-microarrays • Gene expression • Meat quality

  8. SNPs Single Nucleotide Polymorphisms DNA • Frequent • Well distributed • Stable • Functional? • High-throughput genotyping

  9. Genetic variation: 0.3 % (~10 mill SNPs)

  10. 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 millionpublic-private 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 tocommon illnesses such as asthma, cancer, diabetes and heart disease. Expected to take three years to complete….. SNPs haplotypes/haplotype tags

  11. Study genome function: • Biological samples • Phenotypes • Pedigree • Control environment/nutrition • Genotypes • Gene expression data • Proteome data • Biological knowledge • ….. Biobank BIOINFORMATICS!!!

  12. www.cigene.no Agricultural University of Norway Norwegian School of Veterinary Science Institute of Aquaculture Research University of Oslo University of Bergen Norwegian Computing CentreNorwegian Radium Hospital Norwegian University of Science and Technology National platform for detection, typing and interpretation of SNPs

  13. 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

  14. 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)

  15. Norwegian Biobank Cattle • Norway was the first country to establish a nation-wide health card recording system in cattle • 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) • Also intensive recording of milk, beef and reproduction traits • 90% of all cows have been registered since 1978 -> ~ 4 mill cows • Complete listing of pedigree structure -> ~ 7,5 mill individuals • Progeny testing of 250-300 daughters per sire • Paternity testing of bulls • Systematic storage of semen from all bulls since 1982 DNA • Choose among ~280.000 cows/bulls for in vivo experiments

  16. 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!!! Sequencing effort Phase 1 Phase 2 Other projects Validation of SNPs Genotype biobank SNP-detection Gene expression Proteomics

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