Mapping by genetic interaction: high-resolution congenic mapping of the type 1 diabetes loci Idd10 and Idd18 in the NOD mouse.

As many of the linked chromosome regions that predispose to type 1 diabetes in the NOD mouse have been dissected, it has become apparent that the initially observed effect is in fact attributable to several loci. One such cluster of loci on distal chromosome 3, originally described as Idd10, is now known to comprise three separate loci, Idd10, Idd17, and Idd18. Although these loci have a significant combined effect on diabetes development, their individual effects are barely detectable when diabetes is used as a read-out, which makes fine-mapping them by use of a conventional congenic approach impractical. In this study, we demonstrate that it is possible to map loci, with modest effects, to regions small enough for systematic gene identification by capitalizing on the fact that the combined loci provide more profound, measurable protection. We have mapped the Idd10 and Idd18 loci to 1.3- and 2.0-cM intervals, respectively, by holding the Idd3 allele constant. In addition, we have excluded Csf1 and Nras as candidates for both loci.