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Genome-wide Studies: Linkage Analysis

Genome-wide Studies: Linkage Analysis. Eric Jorgenson. Bimodal Distribution of PTC. Types of Genetic Studies. Family Studies Compare trait values across family members Linkage Analysis Compare trait values with inheritance patterns Association Compare trait values against genetic variants.

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Genome-wide Studies: Linkage Analysis

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  1. Genome-wide Studies:Linkage Analysis Eric Jorgenson

  2. Bimodal Distribution of PTC

  3. Types of Genetic Studies • Family Studies • Compare trait values across family members • Linkage Analysis • Compare trait values with inheritance patterns • Association • Compare trait values against genetic variants

  4. Family Studies • Familial Relationships • Twins • Siblings • Parents/offspring • Phenotype information • Affected/Unaffected (Prostate Cancer) • Quantitative measure (Blood Pressure) • No Genotype information required

  5. Why do Family Studies? • Is the trait genetic? • What is the mode of transmission? • Dominant • Recessive • Additive • Polygenic (Multiple genes involved)

  6. Mutation and Meiosis

  7. Recessive trait

  8. First PTC Family Study L. H. Snyder Science 1931

  9. Adding Genotype Data • Linkage Analysis study • 300-400 genetic markers spaced evenly across the genome (in genetic length) • Candidate Gene study • 1 or more genetic variants in a gene • Can also look at multiple genes • Genome-wide Association Study • 500,000-2,000,000 genetic markers spaced evenly across the genome (using linkage disequilibrium)

  10. Linkage Analysis • Narrow down position of disease gene • No biological knowledge needed • Genetic markers (not disease gene) • Recombination

  11. Recombination a A a a b B b b A a a a A a a a b b b b B b B b

  12. Recombination a A a a b B b b R NR NR R A a a a A a a a b b b b B b B b

  13. Independent Assortment a A a a b B b b 25% 25% 25% 25% A a a a A a a a b b b b B b B b

  14. No recombination a A a a b B b b 0% 50% 50% 0% A a a a A a a a b b b b B b B b

  15. Recombination Fraction a A a a b B b b 61 420 442 77 A a a a A a a a b b b b B b B b

  16. Recombination Fraction Recombination Fraction q = Recombinants / Total = 61 + 77 / 61 + 77 + 442 + 420 = 138 / 1000 = 13.8% 61 420 442 77 A a a a A a a a b b b b B b B b

  17. Linkage • Recombination fraction q < 50% • Two traits: PTC and KELL blood group • Two genetic markers • One trait and one genetic marker Linkage Analysis

  18. a a A A Phase known b B B b a A a a b B b b A a a a A a a b b b b B b B

  19. Dominant Trait D d d d 1 2 3 3 D d D d d d 1 3 2 3 2 3

  20. Linkage Analysis • LOD score based on recombination • LOD (q) = log (q)R (1 - q)NR ____________________ (q = 1/2) R + NR

  21. Linkage Analysis 1 2 3 3 R NR NR 1 3 2 3 2 3

  22. LOD score LOD (q) = log (q)1 (1 - q)2 ____________________ (q = 1/2) 1 + 2 = 0.07 for q = 1/3

  23. Calculate a LOD score for q = .25 D d d d 1 2 3 3 D d D d d d d d 1 3 1 3 2 3 1 3

  24. What if we don’t know phase? • We calculate the LOD score for each phase • Divide by 2

  25. Phase Unknown LOD (q) = ½ log (q)1 (1 - q)2 ____________________ (q = 1/2) 1 + 2 + ½ log (q)1 (1 - q)2 ____________________ (q = 1/2) 1+ 2 = -0.02 for q = 0.44

  26. IBD • Identity by descent • Allele Sharing methods • Often used for affected sib pairs

  27. Identity By Descent a A a A 25% 25% 25% 25% A A a A A a a a

  28. Identity By Descent Sibling 1 A A Alleles shared IBD 2 1 1 0 A A a A A a a a

  29. Identity By Descent Sibling 1 A A 2 1 1 0 A A a A A a a a

  30. Identity By Descent Parent 1 a A Alleles shared IBD 1 1 1 1 A A a A A a a a

  31. Identity By Descent Parent 1 a A 2 1 1 0 A A a A A a a a

  32. Identity By Descent • IBD can be used for linkage analysis • Expect 50% alleles shared between siblings • Look for IBD > 50% for concordant pairs • Look for IBD < 50% for discordant pairs

  33. Identity By Descent • Linkage analysis programs use IBD: • http://linkage.rockefeller.edu/ • Take Saunak Sen’s class (EPI 219) in the spring if you want to learn about statistical methods in genetic epidemiology in greater detail

  34. PTC Linkage Analysis

  35. PTC Linkage Analysis

  36. Fine Mapping Linkage markers Genes Kim et al. Science 2003

  37. Linkage Disequilibrium a A a a b B b b A a a a A a a a b b b b B b B b

  38. Linkage Disequilibrium A a a a A a a a b b b b B b B b

  39. Linkage Disequilibrium A a b b

  40. Linkage Disequilibrium A a a a b b b b A a A a a a a a b b b b b b b b

  41. Linkage Disequilibrium a A a A A a B b b b b b Time

  42. Genomewide Linkage Analysis Genetic Markers q = 10% on average Genes

  43. Linkage Disequilibrium Mapping Genetic Markers Genes

  44. PTC Linkage Disequilibrium Mapping Kim et al. Science 2003

  45. TAS2R38 Receptor Structure Kim et al. J Dent Res 2004

  46. 3 SNPs in the TAS2R38 Gene P A V Taster Non-taster A V I

  47. TAS2R38 Diplotype and PTC Score Kim et al. Science 2003

  48. Confirm Mode of Inheritance L. H. Snyder Science 1931

  49. Confirm Mode of Inheritance • Strong recessive model association p < 10-33 • Replication using a recessive model in an independent sample p < 10-32

  50. Explain Linkage Signal

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