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

Abstract

Insulin-dependent (Type 1) diabetes (IDD) in the NOD mouse is inherited as a complex polygenic trait making the identification of susceptibility genes difficult. Currently none of the non-MHC IDD susceptibility genes in NOD have been identified. In this paper we describe the congenic mouse approach that we are using for the dissection of complex traits, such as IDD. We produced a series of six congenic strains carrying NOD-derived diabetogenic genomic intervals, which were previously identified by linkage analysis, on a resistant background. These congenic strains were produced for the purpose of characterizing the function of each of these genes, alone and in combinations, in IDD pathogenesis and to allow fine mapping of the NOD IDD susceptibility genes. Histological examination of pancreata from 6 to 8-month-old congenic mice reveals that intervals on Chromosomes (Chrs) 1 and 17, but not 3, 6, and 11, contain NOD-derived genes that can increase the trafficking of mononuclear cells into the pancreas. Insulitis was observed only very rarely, even in older congenic mice, indicating that multiple genes are required for this phenotype. These results demonstrate the utility of this congenic approach for the study of complex genetic traits.

Genetic Reconstitution of Autoimmune Type 1 Diabetes With Two Major Susceptibility Genes in the Rat

“…To confirm the susceptibility loci and identify the responsible genes in animal models of type 1 diabetes, many congenic strains have been produced in NOD mice and BB rats. These studies have shown that most congenic strains carrying susceptibility allele(s) on nondiabetic genetic backgrounds do not develop diabetes (12)(13)(14). In addition, most congenic strains carrying resistant allele(s) on diabetes-prone genetic backgrounds suppressed the development of the disease.…”

“…To confirm the susceptibility genes in type 1 diabetes, several studies on the genetic reconstitution of the disease on nondiabetic genetic backgrounds have been performed but have been unsuccessful to date (12)(13)(14). The congenic rat strain carrying two major susceptibility alleles, the RT1 u haplotype and Lyp/Ian4l1, of the BB rat on the F344 genetic background did not exhibit diabetes or insulitis (12).…”

“…Similarly, the congenic strain carrying the Lyp/Ian4l1 allele of the BB rat on the F344 background showed the lymphopenia phenotype without insulitis and diabetes (13). In addition, the congenic strains carrying susceptibility alleles of the NOD mouse on the C57BL/6 (B6) genetic background did not develop diabetes, but insulitis was occasionally observed in some of the animals (14). In contrast, genetic reconstitution of another autoimmune disease, systemic lupus erythematosus, has successfully been performed.…”

Increased Entry into the IFN-γ Effector Pathway by CD4+ T Cells Selected by I-Ag7 on a Nonobese Diabetic Versus C57BL/6 Genetic Background

“…In this paper, we used NOD, C57BL/6, B6.G7 mice (C57BL/6-congenic mice with an introgressed NOD MHC interval; the B6.G7 mice do not develop diabetes, although they develop minor pancreatic lymphocytic infiltration; Ref. 47 …”

Modulating Protective and Pathogenic CD4+ Subsets via CD137 in Type 1 Diabetes

“…At present, at least 20 genes are thought to play a role in this complex, multigenic process (1). The strongest genetic contribution is from the major histocompatibility complex (MHC) class II molecule, I-A g7 ; however, even two copies of I-A g7 are insufficient to mediate diabetes when placed on a nonautoimmune non-MHC background (3). Therefore, although substitution of other MHC class II molecules can prevent diabetes (indicating that I-A g7 is necessary for disease), it is not both necessary and sufficient; many non-MHC Idd loci contribute critically to the disease process.…”