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Gene by environment effects Slide 2 Slide 3 Elevated Plus Maze (anxiety) Slide 4 Slide 5 Slide 6 Slide 7 Slide 8 Slide 9 Slide 10 Modelling E, G and GxE H 1 : phenotype ~ covariate H 2 : phenotype ~ covariate + LocusX H 3 : phenotype ~ covariate + LocusX + covariate:LocusX H 0 : phenotype ~ 1 Slide 11 PRACTICAL: Inclusion of gender effects in a genome scan To start: 1. Copy the folder faculty\valdar\FridayAnimalModelsPractical to your own directory. 2. Start R 3. File -> Change Dir and change directory to your FridayAnimalModelsPractical directory 4. Open Firefox, then File -> Open File, and open gxe.R in the FridayAnimalModelsPractical directory Slide 12 H 0 : phenotype ~ sex H 1 : phenotype ~ sex + marker Slide 13 scan.markers(Phenotype ~ Sex + MARKER, h0 = Phenotype ~ Sex,... etc) H 0 : phenotype ~ sex H 1 : phenotype ~ sex + marker Slide 14 scan.markers(Phenotype ~ Sex + MARKER, h0 = Phenotype ~ Sex,... etc) H 0 : phenotype ~ sex H 1 : phenotype ~ sex + marker Slide 15 scan.markers(Phenotype ~ Sex + MARKER, h0 = Phenotype ~ Sex,... etc) H 0 : phenotype ~ sex H 1 : phenotype ~ sex + marker Slide 16 head(ped.gender0) anova(lm(Phenotype ~ Sex + m1 + Sex:m1, data=ped.gender0)) head(ped.gender1) anova(lm(Phenotype ~ Sex + m1 + Sex:m1, data=ped.gender1) Slide 17 New approaches Advanced intercross lines Genetically heterogeneous stocks Slide 18 F2 Intercross x Avg. Distance Between Recombinations F1 F2 F2 intercross ~30 cM Slide 19 Advanced intercross lines (AILs) F0 F1 F2 F3 F4 Slide 20 Chromosome scan for F12 position along whole chromosome (Mb) goodness of fit (logP) 0 100cM significance threshold QTL Typical chromosome Slide 21 PRACTICAL: AILs To start: 1. Open Firefox, then File -> Open File, and open ail_and_ghosts.R in the FridayAnimalModelsPractical directory Slide 22 Genetically Heterogeneous Mice Slide 23 F2 Intercross x Avg. Distance Between Recombinations F1 F2 F2 intercross ~30 cM Slide 24 Pseudo-random mating for 50 generations Heterogeneous Stock F2 Intercross x Avg. Distance Between Recombinations: F1 F2 HS ~2 cM F2 intercross ~30 cM Slide 25 Pseudo-random mating for 50 generations Heterogeneous Stock F2 Intercross x Avg. Distance Between Recombinations: F1 F2 HS ~2 cM F2 intercross ~30 cM Slide 26 Genome scans with single marker association Slide 27 High resolution mapping Slide 28 Relation Between Marker and Genetic Effect Observable effect QTL Marker 1 Slide 29 Relation Between Marker and Genetic Effect Observable effect QTL Marker 2 Marker 1 Slide 30 Relation Between Marker and Genetic Effect No effect observable Observable effect QTL Marker 2 Marker 1 Slide 31 Hidden Chromosome Structure Observed chromosome structure Multipoint method (HAPPY) calculates the probability that an allele descends from a founder using multiple markers Slide 32 Haplotype reconstruction using HAPPY chromosome genotypes haplotype proportions predicted by HAPPY Slide 33 HAPPY model for additive effects Slide 34 Genome scans with single marker association Slide 35 Genome scans with HAPPY Slide 36 Results for our HS Slide 37 Many peaks mean red cell volume Slide 38 Slide 39 How to select peaks: a simulated example Slide 40 Simulate 7 x 5% QTLs (ie, 35% genetic effect) + 20% shared environment effect + 45% noise = 100% variance Slide 41 Simulated example: 1D scan Slide 42 Peaks from 1D scan phenotype ~ covariates + ? Slide 43 1D scan: condition on 1 peak phenotype ~ covariates + peak 1 + ? Slide 44 1D scan: condition on 2 peaks phenotype ~ covariates + peak 1 + peak 2 + ? Slide 45 1D scan: condition on 3 peaks phenotype ~ covariates + peak 1 + peak 2 + peak 3 + ? Slide 46 1D scan: condition on 4 peaks phenotype ~ covariates + peak 1 + peak 2 + peak 3 + peak 4 + ? Slide 47 1D scan: condition on 5 peaks phenotype ~ covariates + peak 1 + peak 2 + peak 3 + peak 4 + peak 5 + ? Slide 48 1D scan: condition on 6 peaks phenotype ~ covariates + peak 1 + peak 2 + peak 3 + peak 4 + peak 5 + peak 6 + ? Slide 49 1D scan: condition on 7 peaks phenotype ~ covariates + peak 1 + peak 2 + peak 3 + peak 4 + peak 5 + peak 6 + peak 7 + ? Slide 50 1D scan: condition on 8 peaks phenotype ~ covariates + peak 1 + peak 2 + peak 3 + peak 4 + peak 5 + peak 6 + peak 7 + peak 8 + ? Slide 51 1D scan: condition on 9 peaks phenotype ~ covariates + peak 1 + peak 2 + peak 3 + peak 4 + peak 5 + peak 6 + peak 7 + peak 8 + peak 9 + ? Slide 52 1D scan: condition on 10 peaks phenotype ~ covariates + peak 1 + peak 2 + peak 3 + peak 4 + peak 5 + peak 6 + peak 7 + peak 8 + peak 9 + peak 10 + ? Slide 53 1D scan: condition on 11 peaks phenotype ~ covariates + peak 1 + peak 2 + peak 3 + peak 4 + peak 5 + peak 6 + peak 7 + peak 8 + peak 9 + peak 10 + peak 11 + ? Slide 54 Peaks chosen by forward selection Slide 55 Bootstrap sampling 1 2 3 4 5 6 7 8 9 10 10 subjects Slide 56 Bootstrap sampling 1 2 3 4 5 6 7 8 9 10 1 2 2 3 5 5 6 7 7 9 10 subjects sample with replacement bootstrap sample from 10 subjects Slide 57 Slide 58 Forward selection on a bootstrap sample Slide 59 Slide 60 Slide 61 Bootstrap evidence mounts up Slide 62 In 1000 bootstraps Bootstrap Posterior Probability (BPP) Slide 63 Results Slide 64 Tea Break Slide 65 Study design 2,000 mice 15,000 diallelic markers More than 100 phenotypes each mouse subject to a battery of tests spread over weeks 5-9 of the animals life Slide 66 101 Phenotypes Anxiety (conditioned and unconditioned tasks) [24] Asthma (plethysmography) [13] Biochemistry [15] Diabetes (glucose tolerance test) [16] Haematology [15] Immunology [9] Weight/size related [8] Wound Healing [1] Slide 67 High throughput phenotyping facility Slide 68 Photo ID Slide 69 Open Field Slide 70 Anxious mouse Non anxious mouse Slide 71 Elevated Plus Maze (anxiety) Slide 72 Slide 73 Slide 74 Slide 75 Slide 76 Food hyponeophagia (reluctance to try new food) Slide 77 Home Cage activity Slide 78 Startle & Conditioning Slide 79 Plethysmograph Slide 80 Slide 81 Glucose Tolerance Test (diabetes) Slide 82 Wound healing Slide 83 Slide 84 Slide 85 Slide 86 PRACTICAL: http://gscan.well.ox.ac.uk Slide 87 END Slide 88 An individuals phenotype follows a mixture of normal distributions Slide 89 m Maternal chromosome Paternal chromosome Slide 90 m Chromosome 1 Chromosome 2 ABCDEFABCDEF Strains Slide 91 Markers m ABCDEFABCDEF Strains Slide 92 Markers m ABCDEFABCDEF Strains Slide 93 Markers m 0.5 cM Slide 94 Markers m 0.5 cM 1 cM Slide 95 Markers m 0.5 cM 1 cM Slide 96 Analysis Probabilistic Ancestral Haplotype Reconstruction (descent mapping): implemented in HAPPY http://www.well.ox.ac.uk/~rmott/happy.html Slide 97 Slide 98 M1 Q M2 m1 q m2 M1 ? m2 recombination Slide 99 M1 Q M2 m1 q m2 m1 Q M2 M1 q m2 M1 q m2 Slide 100 M1 Q M2 m1 q m2 M1 Q m2 M1 Q m2 m1 q M2 m1 Q M2 M1 q m2 M1 q m2 Slide 101 M1 Q M2 m1 q m2 M1 m2 M1 m2 m1 m2 m1 M2 M1 m2 M1 m2 Qq Qqq Q Slide 102 M1 ? m2 m1 ? m2 cM distances determine probabilities Slide 103 M1 ? m2 m1 ? m2 cM distances determine probabilities Eg, Slide 104 Interval mapping M1 M2 m1 m2 M1 m1 M2 m2 LOD score Slide 105 Interval mapping M1 M2 m1 m2 M1 m1 M2 m2 LOD score Q q Slide 106 Interval mapping M1 M2 m1 m2 M1 m1 M2 m2 LOD score Q q Slide 107 Interval mapping M1 M2 m1 m2 M1 m1 M2 m2 LOD score Q q