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Next-Generation Sequencing

Next-Generation Sequencing. Eric Jorgenson Epidemiology 217 3/5/13. Outline. Overview Examples of Next Generation Sequencing Studies: Whole Genome, Exome, Families (IBD), Cancer PTC Taste Sensitivity Implications. Sequencing costs have fallen.

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Next-Generation Sequencing

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  1. Next-Generation Sequencing Eric Jorgenson Epidemiology 217 3/5/13

  2. Outline Overview Examples of Next Generation Sequencing Studies: Whole Genome, Exome, Families (IBD), Cancer PTC Taste Sensitivity Implications

  3. Sequencing costs have fallen

  4. Number of Genetic Markers for Genetic Studies Genome-wide Linkage Studies 300-400 Microsatellite Markers Genome-wide Association Studies 100,000-2,500,000 SNPs Exome Sequencing Studies 30,000,000 Basepairs Exome Array Studies >240,000 exonic variants Whole Genome Sequencing Studies 3,200,000,000 Basepairs

  5. Links to Sequencing Projects 1000 Genomes: http://browser.1000genomes.org/Homo_sapiens/Info/Index Exome Sequencing Project: https://esp.gs.washington.edu/drupal/ Exome Array Design: http://genome.sph.umich.edu/wiki/Exome_Chip_Design#Second_Generation_Arrays

  6. Variant detection through next generation sequencing Meyerson et al. NRG 2010

  7. Outline Overview Examples of Next Generation Sequencing Studies: Whole Genome, Exome, Families (IBD), Cancer PTC Taste Sensitivity Implications

  8. Sequencing of a Single Individual with Family Data Lupski et al. NEJM 2010

  9. The First 8 Human Genomes

  10. SNP Distribution in Proband

  11. Nonsynonymous SNPs in Known Disease Genes

  12. CMT Subtypes: Many Genes

  13. ANNOVAR: Using Annotation to Narrow the Search Space openbioinformatics.org/annovar

  14. Phenotypes in Unsequenced Family Members

  15. Family Pedigree

  16. Putative Causal Variant at a Conserved Amino Acid

  17. Exome Sequencing Identifies a Tibetan Adaptation Yi et al. Science 2010

  18. Sequence Data Improves Identity By Descent Resolution Su and Jorgenson 2012

  19. Family Sequencing for Rare Diseases Roach et al. Science 2010

  20. Cancer: Tumor vs. Normal Lee et al. Nature 2010

  21. Exome Sequencing in Prostate Cancer Barbieri et al. Nature Genetics 2012

  22. Exome Sequencing in Prostate Cancer Barbieri et al. Nature Genetics 2012

  23. Nonsynonymous Somatic Mutations in Neuroblastoma Molenaar et al. Nature 2012

  24. Mutation count associated with age, stage, and survival Molenaar et al. Nature 2012

  25. Outline Overview Examples of Next Generation Sequencing Studies: Whole Genome, Exome, Families (IBD), Cancer PTC Taste Sensitivity Implications

  26. Distribution of PTC Phenotype Number of Subjects PTC Score

  27. TAS2R38 Receptor Structure rs1726866 rs10246939 rs713598 Kim et al. J Dent Res 2004

  28. 3 SNPs Form 3 Haplotypes P A V Taster Non-taster A V I Rare A A V

  29. PTC Phenotype by TAS2R38 Diplotype Number of Subjects PTC Score

  30. Outliers After Adjusting for TAS2R38 Diplotype Number of Subjects PTC Score

  31. Unusual PTC Phenotypes (AVI Homozygotes in Green) 11 8 9 3 8 10 12 9 9 9

  32. Unusual PTC Phenotypes (AVI Homozygotes in Green) 11 14 10 10 9 2 4 11 11

  33. 10 Genomes, 5 Hard Drives

  34. Summary of Variation

  35. Quality Control:99.8% Concordance

  36. Variant Distribution in Utah

  37. Variant Distribution in Utah

  38. Using Relatedness 11 8 9 3 8 10 12 9 9 9

  39. Identity By Descent

  40. Identity By Descent

  41. Nonsynonymous Variants

  42. Outline Overview Examples of Next Generation Sequencing Studies: Whole Genome, Exome, Families (IBD), Cancer PTC Taste Sensitivity Implications

  43. How can whole genome sequence influence treatment? • Identify Genes with Protein Altering Mutations • Determine Variation in Specific Genes

  44. Genes with Protein Altering Variants

  45. ABO Blood Group

  46. Determination of ABO Type

  47. Huntington’s Disease Testing Almqvist AJHG 1999

  48. Links to videos and articles http://www.bloomberg.com/video/84364498/ http://www.bloomberg.com/video/84364540/ http://www.businessweek.com/videos/2012-11-06/bloomberg-reporter-gets-second-opinion-on-dna-test http://www.bloomberg.com/news/2012-01-17/search-genome-as-tennis-thrice-weekly-no-barrier-to-decoded-dna.html http://www.bloomberg.com/news/2012-02-15/harvard-mapping-my-dna-turns-scary-as-threatening-gene-emerges.html http://www.businessweek.com/news/2012-11-06/my-dna-results-spur-alzheimer-s-anxiety-at-12-000-cost#p1

  49. Appendix: Study Design Considerations in Sequencing • Families

  50. Families can reduce error rates Roach et al. Science 2010

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