1. ¹The Jackson Laboratory, Bar Harbor, ME, USA
2. ²Centenary Institute of Cancer Medicine and Cell Biology, Newtown, NSW, Australia

Correspondence: Dr EH Leiter, The Jackson Laboratory, 600 Main St., Bar Harbor, ME 04609, USA. E-mail: ehl@jax.org

Received 21 December 2004; Revised 6 June 2005; Accepted 7 June 2005; Published online 14 July 2005.

Abstract

While sharing the H2^g7 MHC and many other important Type I diabetes susceptibility (Idd) genes with NOD mice, the NOR strain remains disease free due to resistance alleles within the 12% portion of their genome that is of C57BLKS/J origin. Previous F2 segregation analyses indicated multiple genes within the 'Idd13' locus on Chromosome 2 provide the primary component of NOR diabetes resistance. However, it was clear other genes also contribute to NOR diabetes resistance, but were difficult to detect in the original segregation analyses because they were relatively weak compared to the strong Idd13 protection component. To identify these further genetic components of diabetes resistance, we performed a new F2 segregation analyses in which NOD mice were outcrossed to a 'genome-conditioned' NOR stock in which a large component of Idd13-mediated resistance was replaced with NOD alleles. These F2 segregation studies combined with subsequent congenic analyses confirmed the presence of additional NOR resistance genes on Chr. 1 and Chr. 4, and also potentially on Chr. 11. These findings emphasize the value for diabetes gene discovery of stratifying not only MHC loci conferring the highest relative risk but also as many as possible of the non-MHC loci presumed to contribute significantly.