Crosses of NOD Mice With the Related NON Strain: A Polygenic Model for IDDM

Abstract

Chromosome locations of non-major histocompatibility complex (MHC) genes contributing to insulin-dependent diabetes mellitus (IDDM) in mice have been determined by outcrossing NOD mice to other inbred strains congenic for the NOD MHC haplotype (H2g7). At least nine non-MHC IDDM susceptibility genes (Idd) were previously identified at first backcross (BC1) after outcross of NOD to C57BL/10.H2g7 congenic mice (B10.H2g7). We investigated whether the same set of Idd loci segregated with IDDM susceptibility after outcross of NOD to NON.H2g7 congenic mice. Since the outcrosses to NON.H2g7 and B10.H2g7 were performed in the same vivarium, direct comparisons were made of the chromosomal locations and relative strengths of Idd alleles in diabetic progeny from the two different outcrosses. In comparison with the NOD x B10.H2g7 outcross, the NOD x NON.H2g7 outcross produced significantly higher IDDM frequencies in F1, F2, and BC1 generations. The high F2 diabetes frequency allowed evaluation of the effects of homozygous expression of both the susceptibility and the resistance allele at Idd loci. This analysis demonstrated that no single non-MHC Idd locus was essential for the onset of diabetes in this cross. After outcross to NON.H2g7, Idd4 (chromosome [Chr] 11), Idd5 (Chr 1), and Idd8 (Chr 14) did not segregate with IDDM in either the BC1 or the F2 generation. Diabetogenic 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, detectable only in the F2 cross, were encoded by Chr 4 (Idd9) and two newly mapped loci on Chr 13 (Idd14) and 5 (Idd15). A third dominant trait 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 extent of homozygosity for NOD background genes. This study shows that the diabetogenic phenotype can be achieved through the actions of variable combinations of MHC-unlinked genes and a diabetogenic MHC haplotype.

Identification of a new non‐major histocompatibility complex genetic locus on chromosome 2 that controls disease severity in collagen‐induced arthritis in rats

“…In fact, animal models of autoimmunity have already provided important information about chromosomal localization of susceptibility loci (1,16,(48)(49)(50)(51)(52)(53)(54)(55)(56), some of which have also been subsequently confirmed in human diseases such as systemic lupus erythematosus (43), multiple sclerosis (44,45) and type 1 diabetes (46).…”

“…The remaining 5.7 cM of Cia7 seems to be homologous to a region on mouse chromosome 3 and human chromosome 3q21-25 (36)(37)(38)(39)(40)(41) and include the candidate genes IL-7, protein kinase C A, corticotropinreleasing hormonc, and IL-2. Loci controlling insulitis and autoimmune diabetes in mice have been mapped to this region of mouse chromosome 3 (53)(54)(55)(56). A rat mammary carcinoma suppressor gene ( M a -1 ) without a yet known human homolog has also been mapped to a region approximately 10 cM centromeric from C'ia7 and could also be a candidate gene (59).…”

“…Based on homology mapping data (36)(37)(38)(39)(40)(41), several murine and human susceptibility loci have been identified within the 2 LOD score support interval (44 cM) of this candidate locus. These include mouse chromosome 3-associated Idd3 (53)(54)(55)(56), Iddl0 (53,54,56), and Iddl7 (56), loci associated with murine autoimmune type 1 diabetes, Eae3 (48,49), associated with murine EAE, and a human chromosome 1 locus (lp13) linked to multiple sclerosis and Crohn's disease (63). Candidate genes in this region include IL-12 (p35), Cd2, IL-6 receptor, Fcy receptor TB, Cd5.3, Nras, nerve growth factor B, vascular cell adhesion molecule 1, and collagen l l a l .…”

Production of congenic mouse strains carrying NOD-derived diabetogenic genetic intervals: An approach for the genetic dissection of complex traits

“…Chrs 1, 3, and 17 were also found in our backcross analysis to contain genes that impact on insulitis susceptibility, while intervals on Chrs 6 and 11 did not (Cheng et al submitted). Correlations between intervals on Chrs 1, 3, and 17 and insulitis or periinsulitis have also been reported for other crosses (Garchon et al 1991(Garchon et al , 1994Ghosh et al 1993;McAleer et al 1995;Wicker et al 1992).…”

“…From mapping studies with the NOD mouse and various diabetes-resistant strains of mice, 15 genome intervals associated with IDD susceptibility have been identified (Prochazka et al 1987;Todd et al 1991;Ghosh et al, 1993;Cornall et al 1991;Garchon et al 1991;Wicker et al 1994;Rodrigues et al 1994;Serreze et al 1994;Morahan et al 1994;Cheng 1993;McAleer et al 1995). Only one interval, that containing H-2 ~7 on …”