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Experimental crosses

Experimental crosses

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Experimental crosses

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  1. Experimental crosses

  2. Inbred Strain Cross

  3. Backcross

  4. F2 cross Generation F0 F1 F2

  5. 1400 1200 1000 800 Phenotype 600 400 200 0 0.5 AA AB BB

  6. Experimental crosses • Inbred strain crosses • Recombinant inbreds • Alternatives

  7. F0 Parental Generation F1 Generation F2 Generation Interbreeding for approximately 20 generations to produce recombinant inbreds 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

  11. Key references • Maximum likelihood methods • Linear regression • Imputation

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

  13. Significance Thresholds

  14. Significance Thresholds Lander, E. Kruglyak, L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage resultsNature Genetics. 11, 241-7, 1995

  15. Thresholds • Permutation test

  16. 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

  17. 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 shuffle 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

  18. 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.

  19. The model problem

  20. The model problem • Linked QTL corrupt the position estimates • Unlinked QTL decreases the power of QTL detection

  21. Alternative resources

  22. One locus may contain many QTL

  23. Genetically Heterogeneous Mice

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

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

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

  27. single marker association

  28. single marker association HAPPY method

  29. Many peaks mean red cell volume

  30. Linkage disequilibrium

  31. Mouse F2 population: LD on chromosome 1

  32. Mouse Heterogenenous Stock: LD on chromosome 11

  33. 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.

  34. LD on chromosome 11 in three outbred stocks

  35. LD on chromosome 11 in three outbred stocks

  36. Imputation of genomes

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

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