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Genetic architecture of behaviour

Genetic architecture of behaviour. Genetic architecture of behaviour. How many QTL? What is the average effect size of a QTL? How do the QTL act? What is the molecular basis of QTL action?. OFA App.- John & Gene. OFA/OFD bar graph. (From DeFries, Gervais and Thomas, 1978). OFA line graph.

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Genetic architecture of behaviour

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  1. Genetic architecture of behaviour

  2. Genetic architecture of behaviour • How many QTL? • What is the average effect size of a QTL? • How do the QTL act? • What is the molecular basis of QTL action?

  3. OFA App.- John & Gene

  4. OFA/OFD bar graph (From DeFries, Gervais and Thomas, 1978).

  5. OFA line graph ) (From DeFries, Gervais and Thomas, 1978).

  6. Inbred Strain Cross

  7. Intercross experiment DeFries H1 X DeFries L1 815 animals DeFries H2 X DeFries L2 821 animals TOTAL: 1,636

  8. Loci that influence variation in Open Field Activity

  9. How many QTL?

  10. Power to detect a locus

  11. Undetectable QTL

  12. QTL estimator

  13. What is the effect size of the QTL?

  14. Average Effect Size of QTL detected in studies of rodent behaviour

  15. Average Effect Size

  16. Genetic action • How important are epistatic effects?

  17. Interaction B1 B2 A1 A2 Phenotype 100 100

  18. Interaction B1 B2 A1 A2 Interaction Phenotype 100 + 100 = 300

  19. Epistasis: definition F-All: Y = b0 + b1NA1 + b2NB1 + b3(NA1)(NB1) F-Part: Y = b0 + b1NA1 + b2NB1 NA1 is the "gene dosage" for the A1 allele in each genotype etc F-Int2,Fulldf2 = ((F-AllFss – F-PartFss)/F-AllRss)(F-Alldf1-F-Partdf1)/F-Aldf2))

  20. Circadian Rhythm Interaction QTL

  21. Interaction analysis • All pairs of markers tested for interaction on 23 phenotypes • total of 86,043 analyses

  22. Interaction analysis • All pairs of markers tested for interaction on 23 phenotypes • total of 86,043 analyses • 4,048 results gave a -LogP of > 6.7 (significance level for the likelihood under the full regression model (F-all))

  23. Interaction analysis • All pairs of markers tested for interaction on 23 phenotypes • total of 86,043 analyses • 4,048 results gave a -LogP of > 6.7 (significance level for the likelihood under the full regression model (F-all)) • 0.05 threshold is –LogP 4.9

  24. Interaction terms less than P-value 0.001 (LogP > 3)

  25. Lung Cancer Susceptibility

  26. Genetic architecture • Up to 12 QTL • Effect sizes < 10% • No evidence for interaction

  27. What is the molecular basis of the QTL?

  28. QTL mapping of arthritis susceptibility in rats

  29. Positional cloning of the QTL

  30. Reasons for success • Large effect size: ~25% of phenotypic variance • Recognizable mutation

  31. Increasing Generations F0 F1 F2 F3 F4

  32. Two Strains

  33. Eight Strains

  34. Genetically Heterogeneous Mice A/J AKR Balb C3H C57 DBA IS RIII HS Random Breeding HS generations >50

  35. High Resolution

  36. Physical Map 143 147 145 B3galt2 Cfh Uch15 Rgs2 Rgs18 Ssa2 Rgs13 Rgs1 Glrx2 141 149

  37. Coding sequence variants

  38. Coding sequence variants • None

  39. Relation between Sequence Variants and Genetic Effect

  40. Strain Sequences Must Be Consistent with QTL Action QTL A C57 BALB AKR

  41. Relation between Sequence Variants and Genetic Effect QTL Marker 1 Marker 2 No effect observable Observable effect

  42. Strain pattern of sequence differences

  43. Sequence variation

  44. Strain Distribution

  45. B3galt2 Uch15 Rgs2 Rgs18 Ssa2 Rgs13 Rgs1

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