1. Experimental crosses

2. Inbred Strain Cross

3. Backcross

4. F2 cross F2 F1 F0 Generation

5. 0 200 400 600 800 1000 1200 1400 0.5 Phenotype ABAABB

6. Experimental crosses Inbred strain crosses Recombinant inbreds Alternatives

7. Recombinant Inbreds F 0 Parental Generation F 1 Generation F 2 Generation Interbreeding for approximately 20 generations to produce recombinant inbreds

8. Experimental crosses Inbred strain crosses Recombinant inbreds Alternatives

9. Three problems in QTL analysis Missing genotype problem Significance thresholds Model selection problem

10. Missing genotype problem

13. Key references Maximum likelihood methods Linear regression Imputation

14. r/qtl http://www.rqtl.org/ Broman, Sen & Churchill

15. Significance Thresholds

16. Lander, E. Kruglyak, L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results Nature Genetics. 11, 241- 7, 1995

17. Thresholds Permutation test

18. Thresholds Permutation test SUBJECT.NAME Sex Phenotype m1 m2 m3 m4 F2$798 F -0.738004 -1 1 1 -1 F2$364 F 0.413330 0 0 0 0 F2$367 F 1.417480 -1 1 1 -1 F2$287 F 0.811208 1 -1 -1 1 F2$205 M 1.198270 0 0 0 0

19. Thresholds Permutation test SUBJECT.NAME Sex Phenotype m1 m2 m3 m4 F2$798 F -0.738004 -1 1 1 -1 F2$364 F 0.413330 0 0 0 0 F2$367 F 1.417480 -1 1 1 -1 F2$287 F 0.811208 1 -1 -1 1 F2$205 M 1.198270 0 0 0 0 SUBJECT.NAME Sex Phenotype m1 m2 m3 m4 F2$798 F 0.413330 -1 1 1 -1 F2$364 F 1.417480 0 0 0 0 F2$367 F 1.198270 -1 1 1 -1 F2$287 F -0.738004 1 -1 -1 1 F2$205 M 0.811208 0 0 0 0 shuffle

20. Permutation tests to establish thresholds Empirical threshold values for quantitative trait mapping GA Churchill and RW Doerge Genetics, 138, 963-971 1994 An empirical method is described, based on the concept of a permutation test, for estimating threshold values that are tailored to the experimental data at hand.

21. The model problem

22. Linked QTL corrupt the position estimates Unlinked QTL decreases the power of QTL detection

23. Alternative resources

27. One locus may contain many QTL

29. Genetically Heterogeneous Mice

30. Pseudo-random mating for 50 generations Heterogeneous Stock F2 Intercross x Avg. Distance Between Recombinations: F1 F2 HS ~2 cM F2 intercross ~30 cM

31. Pseudo-random mating for 50 generations Heterogeneous Stock F2 Intercross x Avg. Distance Between Recombinations: F1 F2 HS ~2 cM F2 intercross ~30 cM

32. Hidden Chromosome Structure Observed chromosome structure Multipoint method (HAPPY) calculates the probability that an allele descends from a founder using multiple markers

33. single marker association

34. HAPPY method

35. Many peaks mean red cell volume

36. Linkage disequilibrium

37. Mouse F2 population: LD on chromosome 1

38. Mouse Heterogenenous Stock: LD on chromosome 11

39. Mapping in structured populations by resample model averaging. Valdar W, Holmes CC, Mott R, Flint J. Genetics. 2009 Aug;182(4):1263-77. Efficient control of population structure in model organism association mapping. Kang HM, Zaitlen NA, Wade CM, Kirby A, Heckerman D, Daly MJ, Eskin E. Genetics. 2008 Mar;178(3):1709-23.

41. LD on chromosome 11 in three outbred stocks

46. Imputation of genomes

47. Sleep Vocalization Dissection 16 weeks 21 weeks Hypoxia Echo/ECG Basal Activity Startle PPI Fear Conditioning Swim test Elevated Plus Maze Open Field Test Neophagia Crl:CFW(SW) DNA Brain Blood Spleen Limbs Tail fibroblasts Ears Liver Adrenals Lungs Heart x 2000 Phenotyping pipeline

48. FACS: CD4/CD8 ratio H2-Ea Scarb1 Biochemistry: Total Cholesterol