Congenic mapping and candidate sequencing of susceptibility genes for type 1 diabetes in the NOD mouse

Inheritance of type I diabetes is polygenic with a major susceptibility gene located in the major histocompatibility complex (MHC). In addition to MHC-linked susceptibility, a number of susceptibility genes have been mapped outside the MHC in both humans and animal models. In order to localize and identify susceptibility genes for type I diabetes, we have developed a series of congenic strains in which either susceptibility intervals from the NOD mouse, a mouse model of type I diabetes, were introgressed onto control background genes or protective intervals from control strains were introgressed onto NOD background genes. NOD.CTS-H-2 congenic mice, which possess recombinant MHC with NOD alleles at class 11 A and E genes, which are candidates for Idd1, revealed that Idd1 consists of multiple components, one in class 11 (Idd1) and the other adjacent to, but distinct from, Idd1 (Idd16). Phenotypes of NOD.IIS-Idd3 congenic mice, which share the same alleles at both Il2 and Il21 as the NOD mouse, were indistinguishable from the NOD parental strain, indicating that both 112 and 1121 are candidates for Idd3. In contrast, NOD.IIS-Idd10 congenic mice, which share the same alleles at Fcgr1, a previous candidate for Idd10, as the NOD mouse, were protected from type 1 diabetes, suggesting that Fcgr1 may not be responsible for the Idd10 effect. These data suggest that the use of strain colony closely related to a disease model to find the same candidate mutation on different haplotypes and make congenic strains with this recombinant chromosome, termed ancestral haplotype congenic mapping, is an effective strategy for fine mapping and identification of genes responsible for complex traits.