USE OF RECOMBINANT CONGENIC AND CONGENIC STRAINS OF NOD MICE TO IDENTIFY A NEW INSULIN-DEPENDENT DIABETES RESISTANCE GENE

Insulin-dependent diabetes mellitus (IDDM) in NOD/Lt mice represents a complex polygenic disease. NOR/Lt is a recombinant congenic strain (R CS) in which limited regions of the NOD/Lt genome have been replaced b y genome from the C57BL/KsJ strain. NOR mice are insulitis resistant a nd diabetes free despite genetic identity with NOD at numerous chromos omal regions containing previously described insulin-dependent diabete s (Idd) genes, including the strongly diabetogenic H2(g7) major histoc ompatibility complex (MHC) haplotype. The present study revealed BKs-d erived genome on segments of chromosomes (Chr) 1, 2, 4, 5, 7, 11, 12, and 18, approximating 11.6% of the total NOR genome analyzed. (NOD x N OR)F-2 segregation analysis was employed to identify chromosomal regio ns in NOR containing Idd resistance alleles. IDDM developed in 33% (10 /30) of F-1 females, and 29.3% (36/123) of F-2 females aged to 1 yr. A previously unrecognized diabetes resistance locus (designated Idd13(r ) strongly protective in homozygous state was identified on NOR Chr 2 in linkage with the Il1 alpha structural gene. The existence of this l ocus was confirmed by construction of a NOD stock congenic for NOR-der ived markers on Chr 2. Our analysis shows the utility of RCS and conge nic stocks for the identification and isolation of non-MHC genes with strong antidiabetogenic functions.