MMRRC National Consortium Supported by NCRR-NIH Mutant Mouse Research Modeling Human Disease & Health NCRR May 11,2010
Organization MMRRC National Consortium Supported by NCRR-NIH National network of breeding/distribution facilities for mouse models University of California at Davis Kent Lloyd University of Missouri John Critser University of North Carolina at Chapel Hill Terry Magnuson The Jackson Laboratory Leah Rae Donahue Informatics, Coordination & Service Center The Jackson Laboratory Michael Sasner
Mission Import, Archive, Distribute Transgenic/mutant mouse models Mouse ES cell lines 2,245 mutant/transgenic mouse models 29,617 ES lines MMRRC National Consortium Supported by NCRR-NIH
Translational Research Goal Integrate emerging technologies in phenotyping & genomic analyses with clinical resources Outcome Develop & provide tailored therapies, early detection/prevention MMRRC National Consortium Supported by NCRR-NIH
Systems Genetics & Predictive Biology in Mouse = C57BL/6J
Systems Genetics & Predictive Biology in Mouse = C57BL/6J Genomic variability
Systems Genetics & Predictive Biology in Mouse X X Collaborative Cross Breast cancer predisposition mouse models Identification of susceptibility regions in mouse Highly robust sequencing and genomic analysis Mouse Phase I Unit Novel drug screens Risk prediction Population screening Prevention Back to the mouse for creation of Genetically Engineered Mouse Models Endogenous Preclinical Models incorporating genomic variation Apply genomic technology Describe new breast cancer predisposition models in humans Identification of analogous human gene in patients Application to Population New breast cancer predisposition gene(s) in mouse
THE COLLABORATIVE CROSS A New Platform for Systems Genetics International Collaboration
The Collaborative Cross Is a large panel of recombinant inbred (RI) mouse lines that models human genomic diversity. The CC platform has been designed to have: - Genome wide variation - Randomization - Reproducibility - Power The ultimate goal is to support the development of systems genetics and predictive biology in mammals.
In 2004 Selection of the founders for the CC F A= A/J B= C57BL/6J C= 129S1/SvImJ D= NOD/LtJ E= NZO/HILtJ F= CAST/EiJ G= PWK/PhJ H= WSB/EiJ B D E A G C H Photo courtesy of Brynn Voy
A/J C57BL6 129S1 NOD NZO PWK CAST WSB Parentals G1 G2 G2:F1 G2:F2 G2:F3 G2:F20
Genome wide diversity A/J C57BL6/J 129S1/SvIm NOD/Lt NZO/HlLt PWK/PhJ CAST/EiJ WSB/EiJ Captures 90% of the variation present in the mouse The variation is randomly distributed across the genome (there are no blind spots) Yang et al. 2007 Nature Genetics 39, 1100 Roberts et al. 2007 Mammalian Genome 18, 473
Randomization A/J C57BL6 129S1 NOD NZO PWK CAST WSB
Reproducibility X
Power
What can you use the CC for? Correlate genetic with phenotypic variation Effect of GxE interaction on phenotypic trait - Diet - Drug - Age - Housing conditions Identify CC lines that are new (or better) models for a particular disease trait Predictive biology -Integrate data across different biological assays on the same genome as well as on different genomes - Correlating phenotypic variability with genomic variation
Ted Garland, UCR
Average Distance (Kilometers) Average Running Distances: Days 11 and 12 of Wheel Access 20 precc 129s1/SvlmJ A/J 18 C57Bl6/J Cast/EiJ NOD/LtJ NZO/HILtJ PWK/PhJ WSB/EiJ 16 14 12 10 8 6 4 2 0
Genotype and Genome CC lines genotyped using the Mouse Diversity Array (Pardo Manuel de Villena and Churchill) 20X high-throughput Illumina sequencing 17 lines COMPLETED www.sanger.ac.uk/mod elorgs/mousegenomes/ Full sequence imputation for each CC-RI line (correlate phenotype with genomic variation) Reference lines to be cryopreserved at MMRRC & reference population genotyped to monitor drift
Databases and Tools CC breeding database, designed to: - Track each mouse from each fully inbred CC line - Randomize mice within experiments - Combine and analyze mice between experiments Genotyping Tools and Databases - Cel File Processing: online tool for managing Affymetrix CEL files - Vinos: A "Probe-set"-centric low-level Cel-file interface - SNP Data Retrieval and Filtering - Strain Sequence Identity Interval Viewer - DNA methylation tool Phenotypes and Mapping (clinical datawarehouse) - Custom phenotypic databases - Refinement of mapping tools developed for the PreCC
UNC: - Ongoing CC lines: 303 - Genotyped with MusDiv array: >250 (1 is not true CC) Israel: - Ongoing CC lines: 220 - Genotyped with MusDiv array: 42 (5 are not true CC) Perth: - Ongoing CC lines: 170 - Genotyped with MusDiv array: 6 (1 is not true CC)
Systems Genetics & Predictive Biology in Mouse X X Collaborative Cross Breast cancer predisposition mouse models Identification of susceptibility region in mouse Highly robust sequencing and genomic analysis Create specific GEMs New breast cancer predisposition gene in mouse Preclinical endogenous models
Mouse Phase I Unit-Preclinical Models Endogenous Mouse Models across genomic variation Chuck Perou - UNC
X X Systems Genetics Preclinical endogenous models Translational Research (genomic variation) MMRRC National Consortium Supported by NCRR-NIH Biomedical Research Community CTSA s: Columbia, Duke, UC Davis, UNC Chapel Hill, U. Michigan, Washington U., Yale