Experimental crosses

Inbred Strain Cross

Backcross

F2 cross F2 F1 F0 Generation

Phenotype ABAABB

Experimental crosses Inbred strain crosses Recombinant inbreds Alternatives

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

Experimental crosses Inbred strain crosses Recombinant inbreds Alternatives

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

Missing genotype problem

Key references Maximum likelihood methods Linear regression Imputation

r/qtl Broman, Sen & Churchill

Significance Thresholds

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

Thresholds Permutation test

Thresholds Permutation test SUBJECT.NAME Sex Phenotype m1 m2 m3 m4 F2$798 F F2$364 F F2$367 F F2$287 F F2$205 M

Thresholds Permutation test SUBJECT.NAME Sex Phenotype m1 m2 m3 m4 F2$798 F F2$364 F F2$367 F F2$287 F F2$205 M SUBJECT.NAME Sex Phenotype m1 m2 m3 m4 F2$798 F F2$364 F F2$367 F F2$287 F F2$205 M shuffle

Permutation tests to establish thresholds Empirical threshold values for quantitative trait mapping GA Churchill and RW Doerge Genetics, 138, 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.

The model problem

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

Alternative resources

One locus may contain many QTL

Genetically Heterogeneous Mice

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

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

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

single marker association

HAPPY method

Many peaks mean red cell volume

Linkage disequilibrium

Mouse F2 population: LD on chromosome 1

Mouse Heterogenenous Stock: LD on chromosome 11

Mapping in structured populations by resample model averaging. Valdar W, Holmes CC, Mott R, Flint J. Genetics Aug;182(4): 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 Mar;178(3):

LD on chromosome 11 in three outbred stocks

Imputation of genomes

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

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