International Mammalian Genome Society

The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

E46 Genetic Dissection of QTLs Responsible for NIDDM and Obesity by Genome-Wide Scans in Diabetogenic OLETF Rat

Kozo Matsumoto1, T. Ogino1, K. Sugiura3, T. Miyake3, Y. Taniguchi3, S. Wei1, K. Wei1, A. Mizuno2, K. Shima2, T. Yamada1,3, H. Kose1, Y. Sasaki3. 1Institute for Animal Experimentation, 2Dept. Lab. Med., University of Tokushima School of Medicine, 3Kuramoto, Tokushima, 770-8503, Japan; 3Laboratory of Animal Breeding and Genetics, Graduate School of Agriculture, Kyoto University, Kyoto 606, Japan

Obesity is a major risk factor for a number of chronic diseases including non-insulin dependent diabetes mellitus (NIDDM), hypertension and coronary heart disease in human. The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an excellent animal model for obese-type NIDDM in human. Here, we present 3 significant QTLs and 11 suggestive QTLs for NIDDM loci (Nidd1~14/of) analyzed by Mapmaker/QTL and MQM mapping methods. A half of genes of them interact with body weight, suggesting that genes relating to obesity may be one of the major causes of the onset of NIDDM in this rat. We also show heterosis and epistatic interaction among the genes. Our present study is also designed to identify and to characterize novel QTLs affecting obesity by genome-wide scan.

We generated 160 (OLETF x F344) F2 progeny which were phenotyped at the 30-35 week-old for glucose levels and body weight, and 214 (OLETF x F344) F2 progeny which were phenotyped at the 30-35 week-old for insulin levels; body weight and pancreatic weight; weights of mesenteric fat, retroperitoneal fat, epididymal fat and subcutaneous fat; and fasting serum levels of total cholesterol (TCHO), triglyceride (TG), free fatty acid (FFA) and leptin. DNAs from tails of the F2 rats were genotyped using more than 300 in former case and 200 informative SSLPs in latter case. Linkage between the phenotypes and genotypes were carried out by MAPMAKER/QTL program and MQM mapping method.

We have identified significant QTLs for NIDDM (Nidd1, 2, and 14/of) on chromosome 7, 14, and 17, respectively; for obesity (Obs1 & Obs4) responsible for body fat on chromosome 14 and 7, respectively; and body weight (Bw1 & Bw2) on chromosome 10 and 16, respectively. Interestingly, Obs1 locus for retroperitoneal fat on long arm of chromosome 14 coincided with a suggestive QTL for triglyceride, suggesting a relationship between the Obs1 locus for retroperitoneal fat weight and a metabolism of triglyceride. The other significant QTL for hyperglycemia on short arm of chromosome 14 also co-localized with another suggestive QTL for retroperitoneal fat, indicating that the locus has pleiotropic effects on glucose levels and retroperitoneal fat weight. Our results may indicate direct relationship between loci for obesity traits and the onset of NIDDM.


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