Mapping Data

Experiment

• Experiment
  TEXT-QTL
• Chromosome
  7
• Reference
  J:131557 Serreze DV, et al., Through Regulation of TCR Expression Levels, an Idd7 Region Gene(s) Interactively Contributes to the Impaired Thymic Deletion of Autoreactive Diabetogenic CD8+ T Cells in Nonobese Diabetic Mice. J Immunol. 2008 Mar 1;180(5):3250-9
• ID
  MGI:3783680

Genes

Gene	Assay Type
Idd7	visible phenotype
D7Mit346	PCR

Notes

• Experiment
  Linkage analysis was performed to identify non-MHC genetic loci involved in the deletion of autoreactive CD8+ T-cells. NOD/ShiLtDvs mice carrying the H2^g7 allele display loss of ability to select against autoreactive CD8+ T-cells, which contributes to development of type 1 diabetes mellitus. C57BL/6J animals congenic for a NOD-derived portion of chromosome 17 (D17Mit21-D17Mit10) containing H2^g7 do not display this phenotype.
  
  A population of 295 (NOD/ShiLtDvs x B6.NOD-H2^g7)F2 animals transgenic for T-cell receptor (TCR) genes Tg(TcraAI4)1Dvs and Tg(TcrbAI4)1Dvs were created. Animals were phenotyped at 5- to 6-weeks of age for the number of CD4+CD8+ T-cells co-expressing AI4 TCR transgenes. The highest and lowest expressing CD4+CD8+ F2 animals wereselected for initial genotyping of 132 SNP markers spaced ~20 cM apart.
  
  Highly significant linkage to loss of deletion of AI4 TCR-expressing T-cells mapped to 15 cM (30.2 Mb) on mouse Chromosome 7 (LOD=8.06). The QTL interval spans approximately 6 cM -23 cM (21.2 Mb - 43.3 Mb). This locus explains 10.47% of the variance and co-localizes with the previously identified diabetes susceptibility locus Idd7 (4 cM). NOD/ShiLtDvs-derived alleles at Idd7 confer decreased intrathymic AI4 T-cell selection.
  
  Theassociation of Idd7 with inhibition of AI4 TCR-expression T-cell deletion was confirmed in a AI4 transgene-expressing congenic line carrying C57BL/6J-derived chromosome 17 DNA from Gpi (11 cM; 33.9 Mb) to D7Mit346 (34 cM; 58.6 Mb) encompassing the Idd7 region on a NOD genetic background. The NOD.B6-(Gpi-D7Mit346) Tg(TcraAI4)1Dvs Tg(TcrbAI4)1Dvs animals congenic displays significantly higher double-positive thymocyte numbers compared to NOD/ShiLtDvs- Tg(TcraAI4)1Dvs Tg(TcrbAI4)1Dvs animals and B6.NOD-H2^g7 Tg(TcraAI4)1Dvs Tg(TcrbAI4)1Dvs animals, indicating the C57BL/6J-derived allele of Idd7 promotes normal deletion of autoreactive T-cells. The Idd7 locus also appears to regulate expression of the Tg(TcraAI4)1Dvs transgene as AI4 TCR alpha-chain expression is significantly decreased in NOD-Tg(TcraAI4)1Dvs Tg(TcrbAI4)1Dvs animals compared to NOD.B6-(Gpi-D7Mit346) Tg(TcraAI4)1Dvs Tg(TcrbAI4)1Dvs and B6.NOD-H2^g7 Tg(TcraAI4)1Dvs Tg(TcrbAI4)1Dvs animals.
  
  Suggestive loci associated with inhibition of CD4+CD8+ T-cell deletion mapped to 77.5 cM (148.7 Mb) on chromosome 4 (LOD=1.55), 39 cM (85.4 Mb) on chromosome 12 (LOD=2.77), 36 cM (60 Mb) on chromosome 13 (LOD=2.14), and 38 cM (67 Mb) on chromosome 17 (LOD=1.38). The chromosome 4 locus overlaps with previously identified diabetes susceptibility QTLs Idd9 and Idd11, while the chromosome 13 locus overlaps with Idd14.