2016 Radiation Research - Topical review on animal models of radiogenic cancers

Mouse models of radiation induced cancer, focusing on inbred strains and highly recombinant mouse models of genetic diversity

Transcript

1. Animal Models of Radiogenic Cancer Michael Weil Colorado State University Topical Review 62nd Annual Radia3on Research Society Mee3ng, Oct. 2016 Elijah Edmondson Colorado State University NCI Fredrick
2. BALB/c 1. Inbred Strains 2. Mouse Resources 3. Heterogeneous Stocks
3. BALB/c 1. Inbred Strains 2. Mouse Resources 3. Heterogeneous Stocks
4. 1. Inbred Strains 2. Mouse Resources 3. Heterogeneous Stocks
5. 1. Inbred Strains 2. Mouse Resources 3. Heterogeneous Stocks
6. Phenotypic Variability 1. Inbred Strains 2. Mouse Resources 3. Heterogeneous Stocks
7. Phenotypic Variability 1. Inbred Strains 2. Mouse Resources 3. Heterogeneous Stocks
8. 1. Inbred Strains 2. Mouse Resources 3. Heterogeneous Stocks C57BL/6 • Most commonly used strain worldwide phenome.jax.org/
9. 1. Inbred Strains 2. Mouse Resources 3. Heterogeneous Stocks C57BL/6 • Most commonly used strain worldwide • Male B6 mice can swim for an average of 591 minutes phenome.jax.org/
10. phenome.jax.org/ 1. Inbred Strains 2. Mouse Resources 3. Heterogeneous Stocks C57BL/6 • Most commonly used strain worldwide • B6 mice voluntarily drink more alcohol than other strains *females > males • Male B6 mice can swim for an average of 591 minutes
11. 1. Inbred Strains 2. Mouse Resources 3. Heterogeneous Stocks • Free bioinformatics resource • Collaborative effort • Standardized assays • Baseline phenotype data • Studies on the effects of different drugs, diets, diseases, and aging • Gene expression studies • > 40 inbred strains characterized phenome.jax.org/
12. Mouse genome informatics 1. Inbred Strains 2. Mouse Resources 3. Heterogeneous Stocks informatics.jax.org/ Free, online bioinformatics resource
13. Improved knowledge of human / mouse synteny 1. Inbred Strains 2. Mouse Resources 3. Heterogeneous Stocks
14. - high tumor incidence following radiation - low spontaneous incidence for tumor of interest Inbred strains as models for radiogenic cancers
15. ~25% <<1% ~7% CBA C3H RFM C57BL/6 F1 Acute Myeloid Leukemia (AML) Sensitive and Resistant Strains Spontaneous AML <<1% Acute Myeloid Leukemia (AML) Sensitive and Resistant Strains *About 95% of murine radiation-induced AMLs have chromosome 2 deletions ~3 Gy ~3 Gy ~3 Gy
16. Most murine radiation-induced AML involve biallelic inactivation of the PU.1 gene, with one allele being lost through a radiation-induced chromosomal deletion.
17. Is the inbred mouse the best model for a genetically diverse human population? = ? C57BL/6 1. Inbred Strains 2. Mouse Resources 3. Heterogeneous Stocks
18. Advantages to inbred mice: • strains produce lower phenotypic variance • thus fewer mice are needed to detect statistical differences Disadvantages to inbred mice: • strain-specific responses may obscure the variability we expect in a genetically diverse population such as humans Radiation carcinogenesis studies using inbred mice 1. Inbred Strains 2. Mouse Resources 3. Heterogeneous Stocks
19. Forward Genetics 2. Determine gene(s) Reverse Genetics 2. Determine phenotype(s) 1. Alter a gene 1. Define a phenotype
20. •Each marker is informative •Lower mapping resolution •Less phenotypic diversity • High mapping resolution (<3 Mb) • Abundant phenotypic diversity • Large numbers needed • Functional follow-up is challenging in HS *DO more balanced than HS (multiple funnels used) and allow the ability to utilize CC to test candidate genes Mouse models of genetic diversity Woods LC, 2013. Physical Genomics. QTL Mapping in outbred populations: successes and challenges.
21. • discovering new phenotypes with extreme variations • identifying genes underlying complex traits Mouse models of genetic diversity 1. Inbred Strains 2. Mouse Resources 3. Heterogeneous Stocks
22. “Reverse Engineered” outbred mice with highly recombinant genomes and balanced allele frequencies 1. Inbred Strains 2. Mouse Resources 3. Heterogeneous Stocks
23. MegaMUGA (illumina SNP Array) 1. Inbred Strains 2. Mouse Resources 3. Heterogeneous Stocks
24. Each mouse is a genetically unique mosaic of the 8 parental strains. *All of these strains have been completely sequenced. Mouse 20
25. Results 2. Precise phenotyping 3. SNP genotyping and bioinformatics 1. Mouse irradiations 1. Inbred Strains 2. Mouse Resources 3. Heterogeneous Stocks
26. Murine Radiation-induced AML: QTL Peak on Chromosome 2 1. Inbred Strains 2. Mouse Resources 3. Heterogeneous Stocks
27. PU.1 QTL Murine Radiation-induced AML: Chromosome 2 1. Inbred Strains 2. Mouse Resources 3. Heterogeneous Stocks
28. deletion deletion vs. Murine Radiation-induced AML: Chromosome 2 1. Inbred Strains 2. Mouse Resources 3. Heterogeneous Stocks