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Gene Mapping

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  1. Gene Mapping

  2. Study Designs • Positional Cloning • Linkage Analysis • Linage Disequilibrium Mapping • Candidate Gene

  3. Differences in Family-based Studies • Family Studies • Family-based Association Studies • Linkage Analysis • Families • Phenotypes

  4. Differences in Family-based Studies • Family Studies • Phenotype • Family-based Association Studies • Phenotype • Genotype • Linkage Analysis • Phenotype • Linkage Markers • Recombination

  5. Linkage Analysis Genetic Markers Genes

  6. Linkage Disequilibrium Mapping Genetic Markers Genes

  7. Candidate Gene Genetic Markers Gene of Interest

  8. The PTC Gene Phenylthiocarbamide (PTC) Taste Sensitivity

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

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

  11. First PTC Family Study L. H. Snyder (Science 1931)

  12. Phenotype Definition • Qualitative: Paper strip • Quantitative: Blind Sorting Test

  13. Phenotype Definition • Qualitative: Paper strip • Quantitative: Blind Sorting Test r r r r r r r r r r r r r r 1 2 3 4 5 6 7 8 9 10 11 12 13 14

  14. Phenotype Definition • Qualitative: Paper strip • Quantitative: Blind Sorting Test r r r r r r r 1 2 3 4 5 6 7

  15. Phenotype Definition • Qualitative: Paper strip • Quantitative: Blind Sorting Test r 7

  16. Phenotype Definition • Qualitative: Paper strip • Quantitative: Blind Sorting Test r r r r r r 7 7 7 H2O H2O H2O

  17. Bimodal Distribution of PTC

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

  19. Recombination • First discovered in Drosophila • Two traits known to exist on the same chromosome were not always inherited together

  20. Recombination A A a a B B b b A a b B

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

  22. Back Cross a A a a b B b b A a a a A a a a b b b b B b B b

  23. 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

  24. 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

  25. 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

  26. 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

  27. 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

  28. Linkage • Recombination fraction q < 50% • Two traits • Two genetic markers • One trait and one genetic marker Linkage Analysis

  29. Harry Potter’s Pedigree Uncle Vernon Lily Potter James Potter Aunt Petunia Harry Potter Dudley Dursley

  30. Linkage Analysis of the Wizard Phenotype W Wizardry locus 1 Marker locus

  31. Linkage Analysis of the Wizard Phenotype W w 1 2

  32. Harry Potter’s Pedigree w 1 W 2 w 3 W 4 Uncle Vernon Lily Potter James Potter Aunt Petunia Harry Potter Dudley Dursley

  33. Harry Potter’s Pedigree Recombinant Nonrecombinant w 1 W 2 w 3 W 4 q = 25% Uncle Vernon Lily Potter James Potter Aunt Petunia w 5 w 6 w 2 W 4 W 2 W 4 W 7 W 8 Not informative Harry Potter Dudley Dursley w 6 w 2 W 4 W 8

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

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

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

  37. Linkage Analysis LOD (q) = log (q)1 (1 - q)2 ____________________ (q = 1/2) 1 + 2 = 0.07 for q = 1/3

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

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

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

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

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

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

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

  45. Genome-wide Linkage Analysis Genetic Markers q = 10% on average Genes

  46. The PTC linkage study • Positional Cloning study design • Blind Sorting Test • 267 individuals in 27 large families • LOD of 8.85 on 7q31 near KEL

  47. Gene Identification • 4 Mb critical region • Too small for linkage analysis • Linkage Disequilibrium mapping • Fine scale Positional Cloning

  48. LD Mapping for PTC Genetic markers Genes

  49. Linkage Disequilibrium Mapping Genetic Markers Genes

  50. Single Nucleotide Polymorphisms (SNPs) A C