a multi phenotype protocol for fine scale mapping of qtl in outbred heterogeneous stock mice l.
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A multi-phenotype protocol for fine scale mapping of QTL in outbred heterogeneous stock mice. LC Solberg , C Arboledas, P Burns, S Davidson, G Nunez, A Taylor, W Valdar , R Deacon, D Bannerman, W Cookson, D Gauguier, JNP Rawlins, R Mott, J Flint

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a multi phenotype protocol for fine scale mapping of qtl in outbred heterogeneous stock mice

A multi-phenotype protocol for fine scale mapping of QTL in outbred heterogeneous stock mice

LC Solberg, C Arboledas, P Burns, S Davidson, G Nunez, A Taylor, W Valdar, R Deacon, D Bannerman, W Cookson, D Gauguier, JNP Rawlins, R Mott, J Flint

University of Oxford, Wellcome Trust Centre for Human Genetics

heterogeneous stock hs mice
Heterogeneous Stock (HS) mice

AJ AKR

BALB

C3H C57 DBA CBA LP

HS

Random Breeding

>40 Generations

Each chromosome is a random mosaic of the founders

Northport HS founded by Robert Hitzemann (Demarest et al., 2001)

slide5

3-6000 molecular markers x 2000 mice =

6-12 million genotypes

Multiple Phenotypes

How can we make this project cost-effective?

multiple phenotypes
Multiple Phenotypes
  • Behavioral Anxiety
  • Open Field Test
  • Elevated Plus Maze
  • Food Neophagia
  • Fear Potentiated Startle
  • Lung Function (Asthma)
  • Plethysmograph
  • Other
  • Corticosterone (post-stress)
  • Electrolyte measurements
  • Haematology
  • Immunology
  • Mandible shape
  • Wound Healing
  • Tissue Collection
  • Metabolic Function (Diabetes)
  • Glucose Tolerance
  • Insulin Sensitivity
  • Adiposity Index
slide8
For several of these phenotypes there are:
  • Known phenotypic differences between progenitor strains of HS mice
  • Previously identified QTL using HS progenitor inbred crosses
slide15
21 Phenotypes, 90 Phenotype Elements

200 Phenotype Elements and Covariates * 2000 mice =

400,000 Data Points

3-6,000 Molecular Markers * 2000 mice =

6-12 Million Genotypes

i ntegrated g enotyping s ystem
Integrated Genotyping System
  • Subjects (pedigrees)
  • Phenotypes (multivariate, covariates)
  • Markers (SNPs, microsatellites)
  • Genotypes (multiple observations, editing)

(see poster)

future work
Future Work
  • Genotyping
    • 3-6,000 SNPs and microsatellites
    • sub-centimorgan spacing across entire genome
  • Statistical Analysis
    • Dynamic programming using ancestral haplotypes (HAPPY)
    • Statistical modeling in R
  • Gene Identification
conclusions
Conclusions
  • Genetic heterogeneity of HS mice make them ideal for fine mapping QTL
  • We are able to collect data accurately for multiple phenotypes from a large number of HS mice
  • We have developed a database to store all phenotypic and genotypic information
  • Data collected from this study will be used to search for genes involved in all phenotypes measured
slide24

The mouse is an ideal animal model

• Genetically well-defined strains

• Control of environmental factors

• Validated mouse models of human quantitative traits

• Inexpensive to test

• Similarity with the human genome

slide25

How do we measure anxiety in mice?

• Phenotypic correlation between open field activity and defecation defines emotionality

Low Ambulation + High defecation =

Anxious Mouse

Open field arena

• Emotionality in rodents is a good measure for susceptibility to human anxiety (Green and Hodges, 1991; Ramos and Mormede, 1998)

slide26

Fine-resolution mapping using HS

Each chromosome is a random mosaic of the founders

bioinformatics analysis
Bioinformatics: Analysis
  • HAPPY (http://www.well.ox.ac.uk/happy)
  • for each mouse, calculates the probability of descent from each HS founder at each locus by dynamic programming
  • test for QTL = test for differences between HS founder effects
  • HAPPY now integrated into R:
      • dynamic-programming in C to compute probabilities
      • full range of R analyses available (multivariate,logistic regression etc)
need for a database
Need for a Database

In TOTAL:

21 Phenotypes, 87 Phenotype elements

174,000 Data Points