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Genome-wide Studies: Linkage Analysis

This overview explores the role of family studies in genetic research, focusing on prostate cancer. It delves into the significance of familial relationships, including twins, siblings, and parent-offspring dynamics, in identifying genetic traits. The piece explains the principles of linkage analysis and its applications without needing genotype information. By examining quantitative traits such as blood pressure and the modes of genetic transmission (dominant, recessive, polygenic), it highlights the intricacies of genetic epidemiology, linkage disequilibrium, and the importance of identifying disease-associated genetic markers.

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Genome-wide Studies: Linkage Analysis

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  1. Genome-wide Studies:Linkage Analysis

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

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

  4. Bimodal Distribution of PTC

  5. Mutation and Meiosis

  6. Recessive trait

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

  8. PTC Population Genetics Wooding Genetics 2006, adapted from Cavalli-Sforza 1994

  9. Genetic Epidemiology • Adding Genotype data • Candidate Gene study • Linkage Analysis study • Linkage Disequilibrium fine mapping

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

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

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

  21. a a A A b B B b a A a a b B b b Phase known

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

  23. 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

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

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

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

  27. Identity By Descent Sibling 1 A A 2 1 1 0 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 • 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

  31. PTC Linkage Analysis

  32. PTC Linkage Analysis

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

  34. 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

  35. Linkage Disequilibrium A a a a A a a a b b b b B b B b

  36. Linkage Disequilibrium A a b b

  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 B b b b b b Time

  39. Single Nucleotide Polymorphisms (SNPs) A C

  40. Linkage Disequilibrium A G C T A T C G

  41. Linkage Disequilibrium r2 = 1 D’ = 1 A G 50% C T 50% A T 0% C G 0%

  42. Linkage Disequilibrium r2 < 1 D’ = 1 A G 34% C T 33% A T 33% C G 0%

  43. Linkage Disequilibrium r2 = 0 D’ = 0 A G 25% C T 25% A T 25% C G 25%

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

  45. Linkage Disequilibrium Mapping Genetic Markers Genes

  46. Gene Identification • Substitute disease status • Peak in LD should be near disease variant • Random SNPs • 50,000 basepairs apart on average

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

  48. Candidate Gene Genetic Markers Gene of Interest

  49. PTC Candidate Genes • 150 Genes in the region • Sequenced 16 genes • 9 TAS2R bitter taste receptors • 7 OR odorant like receptors • Strongest Association in TAS2R38

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

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