New seizure frequency QTL and the complex genetics of epilepsy in EL mice.

EL/Suz (EL) mice experience recurrent seizures that are similar to common partial complex epilepsy in humans. In the mice, seizures occur naturally at 90-100 days of age, but can be induced in younger mice and analyzed as a semi-quantitative trait after gentle rhythmic stimulation. A previous genetic mapping study of EL backcrosses to the strains ABP/LeJ or DBA/2J showed two quantitative trait loci (QTL) with large effects on seizure frequency (El1, Chr 9; El2, Chr 2) and implied the existence of other QTL with lesser effects. To further the understanding of EL-derived seizure alleles, we examined intercross progeny of EL and the strains ABP/LeJ and DDY/Jcl, and also a backcross of (EL x DDY)F1 hybrids to DDY. A new large-effect seizure frequency QTL was found (El5, Chr 14), a more minor QTL confirmed (El3, Chr 10), and two additional QTL proposed (El4, Chr 9; El6, Chr 11). The serotonin receptor gene, Htr2a, maps near and is a candidate for El5, and linkages of other serotonin receptor genes to seizure frequency QTL are noted. In addition, a strong gender effect was revealed, and epistasis was found between Chr 9 and Chr 14 markers. Despite this progress, however, our results revealed a more complex determinism of epilepsy in EL mice than previously described. In particular, no single El locus or pair was essential for frequent seizures, as QTL with large effects, such as El5, El2, and El1, were highly dependent on genetic context. Our studies highlight the importance of gene interaction in some complex mammalian traits defined by natural variation.