A major effect QTL determined by multiple genes in epileptic EL mice

The EL mouse strain provides a polygenic model for epilepsy. Previous mappi ng experiments between EL and nonepileptic ABP mice identified, and a conge nic strain confirmed, a quantitative trait locus (QTL), E12, which lowered the threshold to seizures induced by gentle I rythmic tossing. To narrow th e map interval further we used a nested strategy to analyze a series of rec ombinants derived From the congenic strain. The recombinant strains reveale d a complex pattern of inheritance, with at least two independent regions o f Chromosome 2 necessary for rhythmic tossing seizures and additional regio ns associated with unusual gender effects. Similar results obtained using a completely independent paradigm, pentylenetetrazole-induced tonic-clonic s eizures, exclude the possibility that the genetic complexity was a unique p roperty of the testing assay. Thus, although conventional QTL mapping effor ts detected and appeared to confirm a trait locus with effects large enough for fine-structure mapping, subsequent dissection revealed multiple loci. Although at least one of these loci was mapped to a 1-cM interval, its indi vidual effect is small, perhaps approaching the practical limits for furthe r study. Our results in the EL mouse may be prophetic for similar assaults on other polygenic, composite neurological behaviors which vary among inbre d strains, begging the consideration of alternative strategies toward gene identification in these models.