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

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

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

7. Inbred Strain Cross

8. Intercross experiment
DeFries H1 X DeFries L animals
DeFries H2 X DeFries L animals
TOTAL: 1,636

9. Loci that influence variation in Open Field Activity

10. How many QTL?

11. Power to detect a locus

12. Undetectable QTL

13. QTL estimator

14. What is the effect size of the QTL?

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

16. Average Effect Size

17. Genetic action
How important are epistatic effects?

18. Interaction A1 A2 B1 B2
Phenotype

19. Interaction A1 A2 B1 B2
Interaction
Phenotype =

20. Epistasis: definition
F-All: Y = b0 + b 1NA1 + b 2NB1 + b 3(NA1)(NB1)
F-Part: Y = b0 + b 1NA1 + b 2NB1
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))

21. Circadian Rhythm Interaction QTL

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

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))

24. 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

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

26. Lung Cancer Susceptibility

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

28. What is the molecular basis of the QTL?

29. QTL mapping of arthritis susceptibility in rats

30. Positional cloning of the QTL

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

34. Increasing GenerationsF0 F1 F2 F3 F4

35. Two Strains

36. Eight Strains

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

38. High Resolution

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

41. Coding sequence variants

42. Coding sequence variants
None

43. Relation between Sequence Variants and Genetic Effect

44. Strain Sequences Must Be Consistent with QTL Action
BALB
AKR

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

46. Strain pattern of sequence differences

47. Sequence variation

48. Strain Distribution

50. Rgs1
Rgs13
Rgs18
Uch15
Rgs2
B3galt2
Ssa2

51. Genes
Rgs2
Rgs13
Rgs1
Rgs18

52. Regulators of G Protein signalling
So what are RGS proteins? They are regulators of G protein signalling, that is to say they
they regulate the formation of the heterotrimeric G protein that interacts with many cell surface receptors, including receptors for many neurotransmitters in the CNS. Therefore RGS proteins are potential candidates for contributing to variation in the behaviours we have been investigating
How can we demonstrate that variation in the RGS2 gene is responsible for the QTL? Well one simple thing we can do is to exclude the gene, and this is

53. RGS2 Knock-out shows enhanced fear response

54. Markers s 1
m-1 m
m+1 M
Strains t