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What are SNPs ? Single Nucleotide Polymorphism

“ From Genetics t o Pharmacogenomics ”. What are SNPs ? Single Nucleotide Polymorphism. SNP Genetics. What are SNPs ?. ACGTTTG G ATAC. ACGTTTG T ATAC. TGCAAAC C TATG. TGCAAAC A TATG. Single nucleotide polymorphisms consist of a single change in the DNA code

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What are SNPs ? Single Nucleotide Polymorphism

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  1. “FromGeneticstoPharmacogenomics ” What are SNPs ? Single Nucleotide Polymorphism SNP Genetics

  2. What are SNPs ? ACGTTTGGATAC ACGTTTGTATAC TGCAAACCTATG TGCAAACATATG • Single nucleotide polymorphisms consist of a single • change in the DNA code • SNPs occur with various allele frequencies. Those in • the 20-40% range are useful for genetic mapping. • Those at frequencies between 1% and 20% may be • used with candidate gene approaches. Usually bi-allelic. • Changes at 〈1% are called variants

  3. What are the effects of SNPs ?

  4. How many SNPs are there ? • It is estimated that the human genome contains between • 3 million and 6 million SNPs spaced irregularly at • intervals of 500 to 1,000 bases. • The SNP Consortium estimates that as many as 300,000 • SNPs may be needed to fuel studies. • 100.000 or more SNPs may be required for complex • disease gene discovery

  5. Applications • SNP Discovery • SNP Validation • - Fine Mapping • SNP Screening • - Testing

  6. SNP Discovery • SNP Discovery refers to the initial identification of new • SNPs. • The established method is electrophoresis(DNA sequencing) • with subsequent data analysis. Some indirect Discovery • techniques (e.g., dHPLC, SSCP) only indicate that a SNP • (or other mutation) exists. • DNA sequencing of multiple individuals is used to determine • the point and type of polymorphism. • Low throughput, based on established DNA sequencing • analyses or collected data (also based on electrophoretic data)

  7. SNP Validation • SNP Validation refers to genetic validation, the process • of ensuring that the SNP is not due to sequencing error • and that it is not extremely rear. This should not be • confused with assay, target or regulatory validation. • Confirmation of SNPs found in Discovery • Larger numbers of individual samples to get statistical • data on occurrence in the population

  8. SNP Screening • SNP Screening refers to researchers running thousands of • genotypes (may SNPs or many individuals or both) • Thousands to hundreds of thousands of samples per day • Two different screening strategies • - Many SNPs in a few individuals • - A few SNPs in many individuals • Different strategies will require different tools • Important in determining markers for complex genetic states

  9. SNP analysis costs are dependent on volume • Costs per assay are dependent upon the number of SNPs • being analyzed and the number of individuals. • Running cost • - one SNP in 100 individuals∼range $5∼$8/assay • - one SNP in 1,000 individuals∼range $3∼$5/assay. • - 1000 SNPs in 1000 individuals∼range $1.5~$3.00/assay. • - All these costs include the cost of the PCR step. • Future high through-put costs/assay will be driven toward • pennies per SNP.

  10. What is a DNA Array ? • A collection of nucleic acid probes which are • attached to a surface in a predetermined grid • This grid is exposed to targets from a biological • sample and the complementary pairs are detected • ("hybridization") • The complementary pairs are scored by software

  11. What Good are DNA Arrays ? • Arrays • - nucleotide changes anywhere in a genome • - identity of and amount of unique mRNAs • - re-sequencing • Ideal for Screening large# SNPs: • Present formats not really a high throughput format • but by their massive parallelism they enable certain • types of analyses, e.g. global expression profiling or • genome wide SNP screening

  12. DNA Arrays Are Valuable • Arrays allow massively parallel analysis for certain • applications this parallelism is enabling...i.e., global • expression profiling • For certain applications there may be labor savings..i.e., • comparative sequencing • But...the present formats are not yet high throughput • technology Platform Extensions for SNP Screening in • Pharmaceuticals

  13. Researcher determinants • Infrastructure: • - Lab. Instrument, labor & expertise • Investment: • - Start-up cost & running cost • Jobs: • - How big sample size ? • - How many SNPs ? • Best Choice • - Out-sourcing ?

  14. Technology Platform Extension for SNP Screening High Array # of SNPs Mass Spec. RFLP TaqMan SBE Low Low # of Individuals High

  15. Addendum

  16. TSC I : The SNP Consortium • Pharmaceutical Partners: • AstraZeneca, Bayer, Bristol-Myers Squibb Co., • GlaxoWellcome PLC, Hoffmann-LaRoche, Hoechst • Marion Roussei, (now merged with RPR to form • Aventis), Merck, Pfizer lnc, Searle, SmithKline • Beecham PLC. • Academic Partners: • The Whitehead lnstitute at MIT, Wellcome Trust at • the Sanger Center,Stanford

  17. TSC II : The SNP Consortium • At least $45 million ($3 million per pharmaceutical • company, $14 million form Wellcome Trust) • Reduction from %150 million in large part to the • efforts of Celera and NHGRI to sequence entire • genome.

  18. What is happening now ? • Japanese SNP Project: • $ 5 Million over next two years to map 100K to 150K • SNPs. Probably concentrated at one site (U. Tokyo's • Human Genome Center) • Funded by Science & Technology Agency, Ministry of • Health & Welfare and private sector.

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