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Linkage Analysis

Linkage Analysis. Eric Jorgenson Epidemiology 217 2/26/13. Worldwide Distribution of Human Earwax SNP rs17822931. Yoshiura et al., Nature Genetics 2006. Geographic Distribution of PTC Phenotype. High. Low. Wooding Genetics 2006, adapted from Cavalli-Sforza 1994.

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Linkage Analysis

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  1. Linkage Analysis Eric Jorgenson Epidemiology 217 2/26/13

  2. Worldwide Distribution of Human Earwax SNP rs17822931 Yoshiura et al., Nature Genetics 2006

  3. Geographic Distribution of PTC Phenotype High Low Wooding Genetics 2006, adapted from Cavalli-Sforza 1994

  4. Bimodal Distribution of PTC

  5. 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

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

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

  8. Mutation and Meiosis

  9. Recessive trait

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

  11. Human Chromosomes TAS2R38

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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

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

  20. Human Linkage Analysis • RFLP Markers for Linkage (1980) • Huntington’s Disease Linkage (1983) • Cystic Fibrosis Linkage (1985) • Cystic Fibrosis Gene (1989) • Huntington’s Disease Gene (1993)

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

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

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

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

  25. LOD score LOD (q) = log (q)1 (1 - q)2 ____________________ (q = 1/2) 1 + 2

  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 Parent 1 a A Alleles shared IBD 1 1 1 1 A A a A A a a a

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

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

  31. Identity By Descent Sibling 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. Multipoint Linkage Analysis

  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. Linkage Disequilibrium Mapping Genetic Markers Genes

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

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

  45. 3 SNPs in the TAS2R38 Gene P A V P A I P V V P V I A A V A A I A V V A V I

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

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

  48. Explain Linkage Signal

  49. Geographic Distribution of PTC Phenotype Wooding Genetics 2006, adapted from Cavalli-Sforza 1994

  50. Geographic Distribution of PTC Haplotypes Kim et al. Science 2003

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