CROSSES OF NOD MICE WITH THE RELATED NON STRAIN - A POLYGENIC MODEL FOR IDDM

Chromosome locations of non-major histocompatibility complex (MHC) gen es contributing to insulin-dependent diabetes mellitus (IDDM) in mice have been determined by outcrossing NOD mice to other inbred strains c ongenic for the NOD MHC haplotype (H2(g7)). At least nine non-MHC IDDM susceptibility genes (Idd) were previously identified at first backcr oss (BC1) after outcross of NOD to C57BL/10.H2(g7) congenic mice (B10. H2(g7)). We investigated whether the same set of Idd loci segregated w ith IDDM susceptibility after outcross of NOD to NON.H2(g7) congenic m ice, Since the outcrosses to NON.H2(g7) and B10.H2(g7) were performed in the same vivarium, direct comparisons were made of the chromosomal locations and relative strengths of Idd alleles in diabetic progeny fr om the two different outcrosses, In comparison with the NOD x B10.H2(g 7) outcross, the NOD x NON.H2(g7) outcross produced significantly high er IDDM: frequencies in Fl, F2, and BC1 generations, The high F2 diabe tes frequency allowed evaluation of the effects of homozygous expressi on of both the susceptibility and the resistance allele at Idd loci, T his analysis demonstrated that no single non-MHC Idd locus was essenti al for the onset of diabetes in this cross, After outcross to NON.H2(g 7), Idd4 (chromosome [Chr] 11), Idd5 (Chr 1), and Idd8 (Chr 14) did no t segregate with IDDM in either the BC1 or the F2 generation, Diabetog enic NOD-derived alleles at Idd2 (Chr 9), Idd3 (Chr 3), and Idd10 (Chr 3) were segregating in the BC1, An NON-derived allele contributing to susceptibility on Chr 7 (Idd7) was also detected, Dominant traits, de tectable only in the F2 cross, were encoded by Chr 4 (Idd9) and two ne wly mapped loci on Chr 13 (Idd14) and 5 (Idd15). A third dominant trai t was encoded by Chr 6 (possibly Idd6), but here, in contrast to Idd9, Idd14, and Idd15, the NON allele was diabetogenic, Stepwise logistic regression analysis of the BC1 and F2 data confirmed that the ability to identify certainty of the non-MHC Idd loci was contingent on the ex tent of homozygosity for NOD background genes, This study shows that t he diabetogenic phenotype can be achieved through the actions of varia ble combinations of MHC-unlinked genes and a diabetogenic MHC haplotyp e.