Rosetta Inpharmatics - 2004 Publications

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2004 Publications

Ultrafine Mapping of SNPs From Mouse Strains C57BL/6J, DBA/2J, and C57BLKS/J for Loci Contributing to Diabetes and Atherosclerosis Susceptibility.
Diabetes. 2005 Apr;54(4):1191-9.

Richard C. Davis¹, Eric E. Schadt², Alessandra C.L. Cervino², Miklós Péterfy¹,³, and Aldons J. Lusis1,⁴

¹Departments of Medicine and Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California
² Rosetta Inpharmatics, Merck and Company, Seattle, Washington
³ Veterans Administration, Greater Los Angeles Healthcare System, Los Angeles, California
⁴ Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, California

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, approximately 70% of its genome appears to derive from B6, with approximately 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 x 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.