1 / 61

Linkage Analysis

Linkage Analysis. Eric Jorgenson EPI 217 1/25/11. More taste strips. One long One short. 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

kita
Download Presentation

Linkage Analysis

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Linkage Analysis Eric Jorgenson EPI 217 1/25/11

  2. More taste strips • One long • One short

  3. Bimodal Distribution of PTC

  4. 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

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

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

  7. Mutation and Meiosis

  8. Recessive trait

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

  10. Human Chromosomes

  11. Human Genetic Map (1977) McKusick and Ruddle Science 1977

  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 • Note that textbook has n-r (=NR) in numerator and n in denominator.

  23. Dominant Trait D d d d 1 2 3 3 D d D d d d 2 3 2 3 1 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 = 0.07 for q = 1/3

  26. D d d d Phase Known 1 1 2 2 D d d d 1 2 3 3 D d D d d d 2 3 2 3 1 3

  27. ? ? ? ? Phase Unknown ? ? ? ? ? ? D d d d 1 2 3 3 D d D d d d 2 3 2 3 1 3

  28. Phase Unknown 1 2 3 3 ? ? ? 1 3 2 3 2 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 Parent 1 a A Alleles shared IBD 1 1 1 1 A A a A A a a a

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

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

  36. Identity By Descent Sibling 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. PTC Linkage Analysis

  39. PTC Linkage Analysis

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

  41. 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

  42. Linkage Disequilibrium A a a a A a a a b b b b B b B b

  43. Linkage Disequilibrium A a b b

  44. 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

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

  46. Linkage Disequilibrium Mapping Genetic Markers Genes

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

  48. Single Nucleotide Polymorphism (SNP)

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

  50. 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

More Related