Searching for genomic region of high-fat diet-induced type 2 diabetes in mouse chromosome 2 by analysis of congenic strains.
Searching for genomic region of high-fat diet-induced type 2 diabetes in mouse chromosome 2 by analysis of congenic strains.
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DOI：
10.1371/journal.pone.0096271
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Horio F
中科院分区：
文献类型：
--
作者：
Kobayashi M;Ohno T;Ihara K;Murai A;Kumazawa M;Hoshino H;Iwanaga K;Iwai H;Hamana Y;Ito M;Ohno K;Horio F
SMXA-5小鼠是由非糖尿病SM/J和A/J小鼠建立的高脂饮食诱导的2型糖尿病动物模型。利用SMXA-5和SM/J小鼠在高脂饲料喂养下杂交的F2代小鼠，我们先前在2号染色体上定位了一个主要的致糖尿病QTL（T2 dm 2sa）。然后，我们产生了同源品系（SM. A-T2 dm 2sa（R 0），20.8-163.0 Mb），并证明了与SM/J小鼠相比，T2 dm 2sa的A/J等位基因损害了同源品系中的葡萄糖耐量并增加了体重和体重指数。我们还发现，T2 dm 2sa和其他糖尿病基因座的组合需要发展高脂饮食诱导的2型糖尿病。在这项研究中，为了缩小包含负责T2 dm 2sa的基因的潜在基因组区域，我们构建了R1和R2同源菌株。与SM/J小鼠相比，R1（69.6-163.0 Mb）和R2（20.8-128.2 Mb）同源小鼠均表现出体重和腹部脂肪重量增加以及糖耐量受损。R1和R2的同源性分析表明，在R1和R2之间的重叠基因组区间（69.6-128.2 Mb）中存在相关基因。此外，使用新建立的R1 A同源株的研究表明，缩小的基因组区域（69.6-75.4 Mb）不仅影响肥胖，而且影响葡萄糖耐量。为了寻找R1 A基因组区域内的候选基因，我们在SM/J和A/J小鼠之间进行了外显子组测序分析，并提取了4个具有非同义编码SNP的基因（Itga 6，Zak，Gpr 155和Mtx 2）。这四个基因可能是基因间相互作用导致的2型糖尿病的候选基因。这项研究表明，负责高脂肪饮食诱导的糖尿病的基因之一存在于小鼠2号染色体上的5.8 Mb基因组间隔中。
SMXA-5 mice are a high-fat diet-induced type 2 diabetes animal model established from non-diabetic SM/J and A/J mice. By using F2 intercross mice between SMXA-5 and SM/J mice 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 impaired glucose tolerance and 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 to develop the high-fat diet-induced type 2 diabetes. In this study, to narrow the potential genomic region containing the gene(s) responsible for T2dm2sa, we constructed R1 and R2 congenic strains. Both R1 (69.6–163.0 Mb) and R2 (20.8–128.2 Mb) congenic mice exhibited increases in body weight and abdominal fat weight and impaired glucose tolerance compared to SM/J mice. The R1 and R2 congenic analyses strongly suggested that the responsible genes existed in the overlapping genomic interval (69.6–128.2 Mb) between R1 and R2. In addition, studies using the newly established R1A congenic strain showed that the narrowed genomic region (69.6–75.4 Mb) affected not only obesity but also glucose tolerance. To search for candidate genes within the R1A genomic region, we performed exome sequencing analysis between SM/J and A/J mice and extracted 4 genes (Itga6, Zak, Gpr155, and Mtx2) with non-synonymous coding SNPs. These four genes might be candidate genes for type 2 diabetes caused by gene-gene interactions. This study indicated that one of the genes responsible for high-fat diet-induced diabetes exists in the 5.8 Mb genomic interval on mouse chromosome 2.
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影响因子：
7.7
作者：
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通讯作者：
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DOI：
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