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Genome-wide Studies: Linkage Analysis

Genome-wide Studies: Linkage Analysis. Eric Jorgenson. What type of plant is this?. Mendel’s Peas. 7 Characteristics. 3:1 Ratio. 9:3:3:1 Ratio. Law of Independent Assortment. Each allele pair segregates independently during gamete formation Only true when there is no Linkage

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Genome-wide Studies: Linkage Analysis

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  1. Genome-wide Studies:Linkage Analysis Eric Jorgenson

  2. What type of plant is this?

  3. Mendel’s Peas

  4. 7 Characteristics

  5. 3:1 Ratio

  6. 9:3:3:1 Ratio

  7. Law of Independent Assortment Each allele pair segregates independently during gamete formation Only true when there is no Linkage Linkage occurs when genes are located close together on the same chromosome

  8. Bimodal Distribution of PTC

  9. 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

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

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

  12. Mutation and Meiosis

  13. Recessive trait

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

  15. 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)

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

  17. 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

  18. 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

  19. 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

  20. 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

  21. 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

  22. 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

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

  24. 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

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

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

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

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

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

  30. 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

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

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

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

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

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

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

  37. 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

  38. Resources for linkage analysis • Linkage analysis programs use IBD: • http://linkage.rockefeller.edu/ • Background • Key concepts in genetic epidemiology, Burton, Tobin, and Hopper, Lancet 2005 • Genetic Linkage Studies, Teare and Barrett, Lancet 2005

  39. Multipoint Linkage Analysis • Uses information from multiple markers to estimate the LOD score • Compares trait to a genetic marker map (300-400 microsatellite markers) • Allows for the identification of the maximum LOD score

  40. PTC Linkage Analysis

  41. PTC Linkage Analysis

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

  43. 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

  44. Linkage Disequilibrium A a a a A a a a b b b b B b B b

  45. Linkage Disequilibrium A a b b

  46. 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

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

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

  49. Linkage Disequilibrium Mapping Genetic Markers Genes

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

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