Positional Cloning of Diabetes Genes

Several mouse strains are diabetic already at the juvenile age or develop diabetes mellitus during their life. Before these strains become diabetic, they often show several or all features of the metabolic syndrome, which is very similar to the etiology of diabetes in humans. Under the assumption that natural mutations are responsible for the development of diabetes in those mouse strains, they are valuable resources for the identification of diabetes genes and modifiers. Usually, several steps are necessary to detect the causative genes in the genome. These include the initial identification of the genomic regions contributing to the disease which is typically done by linkage mapping in an F₂ intercross or backcross population, fine mapping of the identified chromosomal interval to narrow down the target region carrying the causative genetic variation and subsequent functional and genetic characterization of the target gene or a small subset of genes. Here, we give a general overview on genetic models and the strategy for identifying diabetes genes and provide a specific protocol for the mapping and fine mapping of chromosomal regions carrying diabetes genes.