Experiment
Previously identified QTL Szs11 (seizure susceptibility 11) on mouse Chromosome 5 was confirmed and refined using congenic line analysis. A congenic line (B6.D2-Szs11) carrying the Szs11 locus derived from DBA/2J (seizure susceptible) on a C57BL/6J (seizure resistant) genetic background was constructed. The DBA/2J donor region spans markers D5Mit75 (20 cM) and D5Mit403 (61 cM). A reciprocal congenic line was constructed with a larger C57BL/6J donor segment, extending from D5Mit345 (centromere) to D5Mit403 (56 cM). Animals were tested daily to achieve maximal electroshock seizure threshold (MEST) beginning at 8-9 weeks of age.
Szs11 explained approximately 10% of the variance in congenic animals. Seizure resistance is conferred by C57BL/6J alleles at Szs11. As expected, D2.B6-Szs11 congenic animals displayed significantly higher MEST values compared to DBA/2J control animals. Conversely, B6.D2-Szs11 male congenic animals displayed lower MEST values (seizure susceptibility) compared to C57BL/6J control males. Seizure susceptibility did not differ significantly between B6.D2-Szs11 and C57BL/6J females.
Obvious candidate genes mapping to the Szs11 interval include Gabra2 (40 cM), Gabra4, Gabrb1, and Gabrg1 (40 cM). However, SNP analysis did not reveal polymorphism in gene sequences between C57BL/6J and DBA/2J. Differential gene expression analysis was not performed so it is unknown if the level of mRNA transcript differs between C57BL/6J and DBA/2J. Additional candidate genes for Szs11 are Slc34a2 (31 cM), Cckar (34 cM), Txk (40 cM), Chrna9 (41 cM), Cnga1 (41 cM), Gnrhr (44 cM), and Adrbk2 (60 cM).
Analysis Tools