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LOW Genetically Determined Risk of HIGH

Epilepsy in Environments 2 & 3

LOW Genetically Determined Risk of HIGH

Epilepsy in Environments 2 & 3

FIGURE 1 A model of genome-environment interaction in mouse epilepsy models. All mice, whether described as mutant or wild-type, can be considered to have some genetically determined risk of epilepsy in any given environment. Because epilepsy is defined as recurrent, spontaneous seizures, this risk of epilepsy is directly correlated with the animal's genetic resistance to seizure triggers in that environment. This model assumes that all seizures have some proximal trigger, either endogenous or exogenous (the precise nature of which is unimportant for the model). Genetic resistance to seizure triggers should be stable at any point during its life as long as the animal's genome remains unchanged. A: The range of seizure triggers in environment 1 has a maximum and minimum level, and any individual mouse or mouse strain (e.g., A, B, or C) whose genetic resistance is stronger than the maximum seizure trigger level will never exhibit seizures in that environment. Any mouse (e.g., D, E, or F) with a genetic resistance within the seizure trigger range of environment 1 will eventually have one or more seizures. B: Seizure trigger levels are not constant within their range in a given environment. Whereas the genetic resistances of mouse strains D-F are all within the seizure trigger range for environment 1, seizure frequency can vary depending on temporal fluctuations in actual seizure trigger levels. C: The range of seizure triggers can vary among different environments. Thus, a mouse may be normal in one environment but experience seizures if moved to another. This model provides a useful framework for interpreting the genotype-phenotype relationship for mouse epilepsy models.

environments. Mice from strain B also have a relatively high intrinsic seizure resistance (~4.0) but would be expected to have occasional seizures in environment 2. The other strains (C-F) show corresponding environment-dependent shifts in seizure and epilepsy risk.

Now consider a scenario in which a researcher selects strain A mice for creating a gene knockout, with the intention of creating a model of epilepsy. After mutating the Xyz gene in strain A, no seizure phenotype is observed. Is this result strong evidence that gene Xyz is not involved in epilepsy? No, the targeted mutation in Xyz might have actually lowered the intrinsic resistance of strain A, but a relatively moderate environmental seizure trigger range "prevented" the appearance of spontaneous seizures. Introduction of the Xyz-mutated strain A mouse into a different environment might expose the latent seizure phenotype and thus the potential role of gene Xyz in epilepsy. The exposure of gene-modified and control animals to electrical or chemical convulsants to examine changes in latent hyper-excitability phenotypes is theoretically equivalent to moving animals to an environment with a higher average sum seizure trigger level. Creation of the Xyz gene knockout using strain B or C originally, rather than strain A, would have accomplished a similar goal. In summary, a genetic epilepsy phenotype cannot be evaluated in terms of only a single gene of interest but should be viewed instead as a dynamic interaction of gene, genome, and environment.

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