P.10.22 Powerful mouse resource for determining modifier genes for neuromuscular diseases

Determining modifier genes is extremely important for understanding differences in both normal and disease phenotypes, and for designing potential therapeutic avenues for disease. Finding modifier genes in humans is difficult, especially controlling for environmental factors. Therefore researchers have harnessed animal models for such studies, with proven success. The Collaborative Cross (CC) is a revolutionary genetic resource comprised of a reference population of hundreds of mouse lines descended from eight genetically and phenotypically diverse founder strains. This resource facilitates high resolution mapping of genes for traits of interest. We aim to identify quantitative trait loci (QTL) containing genes that in the future might be exploited as disease modifiers for neuromuscular disorders. We studied CC strains generated in Western Australia, measuring a range of traits, including gene expression levels from skeletal muscle, and in vivo phenotypes such as voluntary running wheel performance. These studies revealed great variation across strains. As we have previously shown that cardiac actin expression can modulate skeletal muscle actin disease, we also produced progeny from multiple CC strains that were deficient in skeletal muscle actin. Some of these strains survived significantly longer than the usual maximum lifespan of 9 days. From all these studies, measurements from a relatively low number of strains have allowed mapping of QTL, confirming the power of The CC, and setting a foundation for identification of important modifier genes for skeletal muscle disease.