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SMXA-5 mice are a high-fat diet-induced type 2 diabetes animal model established fromnon-diabetic SM/J and A/J mice. By using F2 intercross mice between SMXA-5 and SM/Jmice under feeding with a high-fat diet, we previously mapped a major diabetogenic QTL(T2dm2sa) on chromosome 2. We then produced the congenic strain (SM.A-T2dm2sa (R0),20.8-163.0 Mb) and demonstrated that the A/J allele of T2dm2sa deteriorated glucose toleranceand increased body weight and body mass index in the congenic strain compared to SM/J mice.We also showed that the combination of T2dm2sa and other diabetogenic loci was needed todevelop the high-fat diet-induced type 2 diabetes. In this study, to narrow the potential genomicregion containing the gene(s) responsible for T2dm2sa, we constructed R1 and R2 congenicstrains. Both R1 (69.5-163.0 Mb) and R2 (20.8-128.2 Mb) congenic mice exhibited increasesin body weight and abdominal fat weight and decreases in glucose tolerance compared to SM/Jmice. The R1 and R2 congenic analyses strongly suggested that the responsible genes existedin the overlapping genomic interval (69.5-128.2 Mb) between R1 and R2. In addition, studiesusing the newly established R1A congenic strain showed that the narrowed genomic region(69.5-75.3 Mb) affected not only obesity but also glucose tolerance. To search for candidategenes within the R1A genomic region, we performed exome sequencing analysis between SM/Jand A/J mice and extracted 4 genes (Itga6, Zak, Gpr155, and Mtx2) with non-synonymouscoding SNPs. The 3 SNPs in the Itga6, Zak, and Mtx2 genes were common variants(polymorphisms) and the SNP in Gpr155 was a relatively rare variant. These four genes couldbe candidate genes for type 2 diabetes caused by gene-gene interactions. This study indicatedthat one of the genes responsible for high-fat diet-induced diabetes exists in the 5.8 Mbgenomic interval on mouse chromosome 2. Prof. Horio Group Project |