Potential Problems with Transgenic Mouse Lines in Pharmacokinetics and Toxicology
Problem | Solution |
---|---|
Genetic background modifies phenotype | • Backcross to defined genetic background, with matched wild-type controls |
• Generate multiple independent lines | |
High background “noise” due to overlapping substrate specificities between, or structural homology within, gene families | • Delete endogenous interfering genes (may be technically difficult if several spread throughout the genome) |
Species differences in gene regulation | • Express transgene under endogenous promoter |
Integration position affects genotype | • Generate multiple independent lines |
Gene deletion is embryonic lethal or causes significant welfare problems | • Use conditional deletion (i.e., Cre/LoxP) |
Residual activity remains after gene targeting (i.e., truncated protein acts as dominant negative) | • Delete gene completely |