The Mouse Model System for Targeted Trimming of Disease Susceptibility Loci

SUMMARY The identification of genes responsible for a particular trait or disease, as well as genes that affect phenotypical presentation of the primary mutation (gene modifiers) is one of the major goals of biomedical science. This usually involves mapping the susceptibility locus first, followed by pinpointing the causative gene. Susceptibility loci are commonly identified through association studies in humans, and backcrossing and comparison of recombinant strains in mice. Such loci are usually quite large, spanning several mega base pairs and containing multiple genes, often with no obvious relevance to the phenotype in question. Furthermore, genes for non-coding RNAs, as well as intergenic regulatory elements, often unknown, can influence expression of genes far away from the susceptibility locus, making their identification even more challenging. Overall, the identification of the causative gene within susceptibility locus and therefore, the development of new therapeutics based on the disease mechanism may become a rather remote possibility. We propose to streamline this task by targeted trimming of susceptibility loci through homologous recombination induced at specified locations. Implementation of this approach will require generating two new mouse lines that will be subsequently crossed to reconstitute all required components. This will provide a reliable, time- and cost- efficient route to mapping causative mutations, allowing mechanistic studies of the disease.