Searching for genomic region of high-fat diet-induced type 2 diabetes in mouse chromosome 2 by analysis of congenic strains.
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.
Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Aichi, Japan.
Misato
M
Kobayashi
Division of Experimental Animals, Center for Promotion of Medical Research and Education, Graduate School of Medicine, Nagoya University, Nagoya, Aichi, Japan.
Tamio
T
Ohno
Center for Gene Research, Nagoya University, Nagoya, Aichi, Japan.
Kunio
K
Ihara
Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Aichi, Japan.
Atsushi
A
Murai
Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Aichi, Japan.
Mayumi
M
Kumazawa
Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Aichi, Japan.
Hiromi
H
Hoshino
Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Aichi, Japan.
Koichiro
K
Iwanaga
Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Aichi, Japan.
Hiroshi
H
Iwai
Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Aichi, Japan.
Yoshiki
Y
Hamana
Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
Mikako
M
Ito
Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
Kinji
K
Ohno
Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Aichi, Japan.
Fumihiko
F
Horio
D050153:Abdominal Fat / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D033481:Chromosomes, Mammalian / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D059305:Diet, High-Fat; D004843:Epistasis, Genetic; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D039503:Integrin alpha6 / Q000235:genetics*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D020297:Mice, Congenic; D024101:Mitochondrial Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D017422:Sequence Analysis, DNA; D015430:Weight Gain
D001786:Blood Glucose; D039503:Integrin alpha6; D020930:MAP Kinase Kinase Kinases; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D043562:Receptors, G-Protein-Coupled; C551409:Gpr155 protein, mouse; C000598760:Mtx2 protein, mouse; C581706:Map3k20 protein, mouse