Abstract
The mouse Ly49 and human killer cell immunoglobulin-like receptors (KIR) gene clusters encode activating and inhibitory class I MHC receptors on natural killer (NK) cells. A direct correlation between the presence of multiple activating KIR and various human autoimmune diseases including diabetes has been shown. Previous studies have implicated NK cell receptors in the development of diabetes in the non-obese diabetic (NOD) inbred mouse strain. To assess the contribution of Ly49 to NOD disease acceleration the Ly49 gene cluster of these mice was sequenced. Remarkably, the NOD Ly49 haplotype encodes the largest haplotype and the most functional activating Ly49 of any known mouse strain. These activating Ly49 include three Ly49p-related and two Ly49h-related genes. The NOD cluster contains large regions highly homologous to both C57BL/6 and 129 haplotypes, suggesting unequal crossing over as a mechanism of Ly49 haplotype evolution. Interestingly, the 129-like region has duplicated in the NOD genome. Thus, the NOD Ly49 cluster is a unique mix of elements seen in previously characterized Ly49 haplotypes resulting in a disproportionately large number of functional activating Ly49 genes. Finally, the functionality of activating Ly49 in NOD mice was confirmed in cytotoxicity assays.
| Original language | English |
|---|---|
| Pages (from-to) | 509-521 |
| Number of pages | 13 |
| Journal | Genes and Immunity |
| Volume | 9 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 2008 |
| Externally published | Yes |
Bibliographical note
Funding Information:Funds were made available to The Wellcome Trust Sanger Institute (Cambridge, UK) by The National Institute of Allergy and Infectious Diseases (NIAID), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the Juvenile Diabetes Research Foundation International (JDRF) for sequencing Idd regions in the NOD mouse. The Wellcome Trust Sanger Institute generated initial sequences from the ends of BACs from a NOD BAC library (CHORI-29; Pieter de Jong, Research Genetics), which was developed from the NOD/ShiLtJ mouse strain. An application was made to the Sanger Institute by APM and Christophe Benoist (Harvard Medical School, Boston, MA, USA) for the sequencing of the Ly49 cluster (IDD6.3). CHORI-29 BACs with end-sequence homologous to the Ly49 region of the B6 genome were shotgun subcloned and sequenced. Finished Ly49-containing BAC sequence is publicly available online (http://www.sanger.ac.uk/ Projects/M_musculus-NOD/) and through GenBank with the following accession numbers: CH29-584N12 (CU442703), CH29-511G10 (CU467659), CH29-575J15 (CU463286), CH29-171N14 (CU424478), CH29-540A18 (CU570803), CH29-4H7 (CU469450) and CH29-493D4 (CU207332).
Funding Information:
We thank Christophe Benoist for his essential aid in initiating the sequencing of the NOD Ly49 region. We also thank Dr Silvia Vidal for her help with MCMV plaque assays and reagents. We gratefully acknowledge the genome sequencing efforts of The Wellcome Trust Sanger Institute. This work was supported by an Operating Grant from the Canadian Institutes of Health Research (CIHR MOP 62841). This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This project has also been funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract no. NO1-CO-12400. SB is supported by a scholarship from the Fonds de la recherche en santé du Québec. L-HT is supported by a CIHR Cancer Training Program scholarship. APM is supported by a New Investigator Award from the CIHR.
ASJC Scopus Subject Areas
- Immunology
- Genetics
- Genetics(clinical)
