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

The EL mouse strain provides a polygenic model for epilepsy. Previous mapping experiments between EL and nonepileptic ABP mice identified, and a congenic strain confirmed, a quantitative trait locus (QTL), El2, which lowered the threshold to seizures induced by gentle rhythmic tossing. To narrow the map interval further we used a nested strategy to analyze a series of recombinants derived from the congenic strain. The recombinant strains revealed a complex pattern of inheritance, with at least two independent regions of Chromosome 2 necessary for rhythmic tossing seizures and additional regions associated with unusual gender effects. Similar results obtained using a completely independent paradigm, pentylenetetrazole-induced tonic-clonic seizures, exclude the possibility that the genetic complexity was a unique property of the testing assay. Thus, although conventional QTL mapping efforts 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 individual effect is small, perhaps approaching the practical limits for further study. Our results in the EL mouse may be prophetic for similar assaults on other polygenic, composite neurological behaviors which vary among inbred strains, begging the consideration of alternative strategies toward gene identification in these models.