Ultrafine Mapping of SNPs From Mouse Strains C57BL/6J, DBA/2J, and C57BLKS/J for Loci Contributing to Diabetes and Atherosclerosis Susceptibility
- Richard C. Davis1,
- Eric E. Schadt2,
- Alessandra C.L. Cervino2,
- Miklós Péterfy13 and
- Aldons J. Lusis14
- 1Departments of Medicine and Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California
- 2Rosetta Inpharmatics, Merck and Company, Seattle, Washington
- 3Veterans Administration, Greater Los Angeles Healthcare System, Los Angeles, California
- 4Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, California
- Address correspondence and reprint requests to Richard C. Davis, Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California at Los Angeles, 47-123 CHS, Los Angeles, CA 90095-1679. E-mail: davisr{at}ucla.edu
Abstract
The inbred mouse strain C57BLKS/J (BKS) carrying a mutation of the leptin receptor lepr−/− (BKS-db) is a classic mouse model of type 2 diabetes. While BKS was originally presumed to be a substrain of C57BL/6J (B6), it has become apparent that its genome contains introgressed regions from a DBA/2 (DBA)-like strain and perhaps other unidentified sources. It has been hypothesized that the strikingly enhanced diabetes susceptibility of BKS-db compared with B6-db is conferred by this introgressed DNA. Using high-density single nucleotide polymorphisms, we have mapped the DBA and other contaminating DNA regions present in BKS. Thus, ∼70% of its genome appears to derive from B6, with ∼20% from DBA and another 9% from an unidentified donor. Comparison with 56 diverse inbred strains suggests that this donor may be a less common inbred strain or an outbred or wild strain. Using expression data from a B6 × DBA cross, we identified differentially regulated genes between these two strains. Those cis-regulated genes located on DBA-like blocks in BKS constitute primary candidates for genes contributing to diabetes susceptibility in the BKS-db strain. To further prioritize these candidates, we identified those cis-acting expression quantitative trait loci whose expression significantly correlates with diabetes-related phenotypes.
Footnotes
-
Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org.
-
- Accepted January 18, 2005.
- Received November 1, 2004.
- DIABETES
