Ultrafine mapping of SNPs from mouse strains C57BL/6J, DBA/2J, and C57BLKS/J for loci contributing to diabetes and atherosclerosis susceptibility.
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.
Davis
Richard C
RC
Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, 47-123 CHS, Los Angeles, CA 90095-1679, USA. davisr@ucla.edu
Schadt
Eric E
EE
Cervino
Alessandra C L
AC
Péterfy
Miklós
M
Lusis
Aldons J
AJ
D000818:Animals; D001161:Arteriosclerosis / Q000235:genetics*; D002874:Chromosome Mapping; D003920:Diabetes Mellitus / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics*; D008811:Mice, Inbred DBA / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics; D054411:Receptors, Leptin
D011956:Receptors, Cell Surface; D054411:Receptors, Leptin