NOD x 129.H2^g7 Backcross Delineates 129S1/SvImJ-Derived Genomic Regions Modulating Type 1 Diabetes (T1D) Development In Mice

Abstract

Objective- Introduction into NOD mice of genes targeted in 129/Sv embryonic stem (ES) cells, introduces linked genes that may modulate Type 1 diabetes (T1D). Our objective was to identify 129S1/SvJ non-MHC regions contributing T1D resistance or susceptibility in backcross to NOD/LtJ.

Research design and methods- Following congenic transfer of the NOD H2^g7 haplotype onto 129S1/Sv, 310 females were produced by NOD x (NOD x 129.H2^g7)F1 backcross (N2). A genome scan for QTL affecting clinical diabetes, age of diabetes onset, and insulitis severity was performed using subphenotype characteristics to improve power and resolution for detection of diabetes susceptibility loci.

Results- 36/310 (11.6%) N2 females developed T1D between 14-40 weeks. Significant evidence of linkage for only a single previously reported Idd complex locus (Idd10/17/18, Chr 3) was indicated for clinical diabetes. The quantitative traits of insulitis either alone or combined with age at T1D onset were significantly linked to known Idd regions on Chr 1 (Idd5 region), 4 (Idd9 region), Chr 8 (Idd22), Chr 11 (Idd4.3), and proximal Chr 17 (Idd16 region). Significant 129S1/Sv resistance contributions were identified on Chr 1, 15 (2 loci), and 19, with suggestive evidence for additional novel 129/Sv resistance QTL on Chr 5 and 17 and susceptibility on Chr 2.

Conclusions- The 129S1/SvJ genome harbors collections of both known and potentially novel non-MHC Idd loci. Investigators targeting 129/Sv genes mapping within chromosomal regions reported herein or elsewhere in the genome need to exclude potential contributions from linked Idd loci by generating a NOD.129 control strain expressing the non-targeted allele.