Genetic localization of interacting modifiers affecting severity in a murine model of polycystic kidney disease.

Genetic analysis of mouse disease models provides a means to investigate how modifying loci cause variation in phenotypic expression. We have shown that polycystic kidney disease (PKD) progression in the juvenile cystic kidney (jck) mutation can be influenced by an epistatic interaction between alleles of different strain backgrounds and we localized one of these loci to chromosome 1. Using a chromosome 1 congenic strain, we improved the genetic analysis and mapped the interacting locus to proximal chromosome 4, with a highly significant lod association of 5.5. Re-analysis of the original F(2) cross reveals that in this cohort, while the lod association of the chromosome 4 locus alone is not significant, its effect is apparent when analyzed in combination with the chromosome 1 locus. This result suggests that correlation of paired genotype data with phenotype data will be an effective means to detect epistatic interactions contributing to complex traits, and that these associations can be tested using appropriate congenic lines.