Major histocompatibility complex-linked diabetogenic gene of the nonobese diabetic mouse. Analysis of genomic DNA amplified by the polymerase chain reaction.

Inheritance of insulin-dependent diabetes mellitus (IDDM) is polygenic, and at least one of the genes conferring susceptibility to diabetes is tightly linked to the MHC. Recent studies have suggested that DQB1 of humans and I-A beta of mice are closely associated with susceptibility and resistance to IDDM. For further characterization and localization of the MHC-linked diabetogenic gene, we studied the genomic sequence of the A beta gene of the nonobese diabetic (NOD) mouse, an animal model of IDDM, in comparison with those of its sister strains, nonobese nondiabetic and cataract Shionogi (CTS) mice, and the original strain, outbred Imperial Cancer Research (ICR) mice. Genomic DNAs from these strains were amplified in vitro by the polymerase chain reaction with thermostable Taq polymerase. The amplified sequences were analyzed by restriction endonuclease digestion, hybridization with allele-specific oligonucleotide probes, and direct sequencing. The unique I-A beta sequence of NOD mice was observed in the sister strain, CTS mice, and in one mouse of the original strain, outbred ICR mice. These data together with the results of MAb typing of MHC molecules and restriction mapping of the I-A region suggest that the unique class II MHC of NOD mice is not the result of a recent mutation, but is derived from the original strain. Since class I MHC of CTS mice is different from the MHC of NOD mice at both the K and D loci, CTS mice are a naturally occurring recombinant strain with NOD type class II MHC and non-NOD type class I MHC. Thus, breeding studies in crosses of NOD with CTS mice should provide biological information on whether the unique class II MHC of NOD mice is diabetogenic.