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D H Moralejo

Publications and source records attributed to D H Moralejo.

At least 19 recordsLinked to original sources
PubMed2001

Identification of epistatic interactions involved in non-insulin-dependent diabetes mellitus in the Otsuka Long-Evans Tokushima Fatty rat.

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model for obese-type non-insulin-dependent diabetes mellitus (NIDDM) in humans. Our present investigation was designed to identify epistatic interactions influencing NIDDM by performing least squares analysis of variance of all pairs of informative markers in 160 F2 progenies bred from an intercross of OLETF and Fischer-344 rats. We identified four interactions between Nidd15/of (chromosome 7) and Nidd16/of (chromosome 14), Nidd15/of and Nidd17/of (chromosome 15), Nidd16/of and Nidd18/of (chromosome 15), and Nidd16/of and Nidd19/of (chromosome 17), which account for a total of approximately 40% of the genetic variation of entire glucose levels after glucose challenge in the F2. The Nidd16/of locus, which is involved in three of four digenic interactions, and the Nidd19/of are likely to correspond to Nidd2/of and Nidd14/of, NIDDM loci previously identified in the F2 by single-QTL model and multiple-QTL model, respectively, while Nidd15/of, Nidd17/of and Nidd18/of loci reflect novel NIDDM loci. An aberrant increase of the entire glucose level due to synergism occurs in the double OLETF homozygote genotype of Nidd15/of and Nidd16/of, and of Nidd16/of and Nidd19/of, as well as in the OLETF homozygote genotypes of Nidd15/of and Nidd16/of, respectively, combined with the heterozygote genotypes of Nidd17/of and Nidd18/of. These findings demonstrate that inter-allelic interactions are likely to be an important component of NIDDM susceptibility.

Animals↗
PubMed2000

Genetic evidence for obesity loci involved in the regulation of body fat distribution in obese type 2 diabetes rat, OLETF.

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model for obese type 2 diabetes in human. Obesity is essential for the onset of type 2 diabetes in this rat. Our present investigation was designed to identify quantitative trait loci (QTLs) contributing to obesity by performing a whole-genome search using 214 F(2) intercross progeny between OLETF and F344 rats. We have identified six QTLs responsible for adiposity indices of fat pads on rat chromosomes 2 (Obs1 for mesenteric fat), 4 (Obs2 for retroperitoneal fat), 8 (Obs3 for mesenteric fat), 9 (Obs4 for retroperitoneal fat), and 14 (Obs5 and Obs6 for retroperitoneal fat), demonstrating that the adiposity indices of individual fat pads were under the control of different genes. As expected, the OLETF allele corresponds to increased adiposity indices for all QTLs, except for Obs3, in which the F344 allele leads to an increase in the index.

Adipose Tissue↗
PubMed2000

Increased polyploid incidence is associated with abnormal copper accumulation in the liver of LEC mutant rat.

Long-Evans Cinnamon (LEC) rats are deleted at the p-type copper transport ATPase gene (Atp7b), so that they exhibit abnormal hepatic copper concentration. In this study, it was confirmed that LEC rat liver possesses a feature of increase in polyploid. Furthermore, a segregation analysis using backcrosses between LEC and F344 normal rats showed that the increased polyploid incidence is strongly associated with excessive copper content in their liver. These results should demonstrate that copper cytotoxicity leads to the impairment of mitotic progression, resulting in the increase of polyploid in the liver of LEC rats.

Animals↗
PubMed1999

Mapping and characterization of quantitative trait loci for non-insulin-dependent diabetes mellitus with an improved genetic map in the Otsuka Long-Evans Tokushima fatty rat.

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model for obese-type, non-insulin-dependent diabetes mellitus (NIDDM) in humans. We have previously reported four quantitative trait loci (QTLs) responsible for NIDDM on Chromosomes (Chrs) 7, 14, 8, and 11 (Nidd1-4/of for Non-insulin-dependent diabetes1-4/oletf) by a whole-genome search in 160 F2 progenies obtained by mating the OLETF and the Fischer-344 (F344) rats. Our present investigation was designed to identify and characterize novel QTLs affecting NIDDM by performing a genome-wide linkage analysis of genes for glucose levels and body weight and analysis for gene-to-gene and gene-to-body-weight interactions on an improved genetic map with a set of 382 informative markers in the 160 F2 progenies. We have identified seven novel QTLs on rat Chrs 1 (Nidd5 and 6/of), 5 (Nidd7/of), 9 (Nidd8/of), 12 (Nidd9/of), 14 (Nidd10/of) and 16 (Nidd11/of) which, together with the Nidd1-4/of, account for a total of approximately 60% and approximately 75% of the genetic variance of the fasting and postprandial glucose levels, respectively, in the F2. While the OLETF allele corresponds with increased glucose levels as expected for the novel QTLs except Nidd8 and 9/of, the Nidd8 and 9/of exhibit heterosis: heterozygotes showing significantly higher glucose levels than OLETF or F344 homozygotes. There are epistatic interactions between Nidd1 and 10/of and between Nidd2 and 8/of. Additionally, our results indicated that the Nidd6 and 11/of could also contribute to an increase of body weight, and that the other five QTLs could show no linkage with body weight, but Nidd8,9, and 10/of have an interaction with body weight.

Animals↗
PubMed1999

Identification of novel non-insulin-dependent diabetes mellitus susceptibility loci in the Otsuka Long-Evans Tokushima fatty rat by MQM-mapping method.

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model for obese-type, non-insulin-dependent diabetes mellitus (NIDDM) in humans. We have previously identified 11 quantitative trait loci (QTLs) responsible for NIDDM susceptibility on Chromosomes (Chrs) 1, 5, 7, 8, 9, 11, 12, 14, and 16 (Nidd1-11/of for Non-insulin-dependent diabetes 1-11/oletf) by using the interval mapping method in 160 F(2) progenies obtained by mating the OLETF and the Fischer-344 (F344) rats. MQM-mapping, which was applied for QTL analysis based on multiple-QTL models, is reported to be more powerful than interval mapping, because in the process of mapping one QTL the genetic background, which contains the other QTLs, is controlled. Application of MQM-mapping in the F(2) intercrosses has led to a revelation of three novel QTLs on rat Chrs 5 (Nidd12/of), 7 (Nidd13/of), and 17 (Nidd14/of), in addition to Nidd1-11/of loci. The three QTLs, together with the Nidd1-11/of, account for a total of approximately 70% and approximately 85% of the genetic variance of the fasting and postprandial glucose levels, respectively, in the F(2). While the OLETF allele corresponds with increased glucose levels as expected for Nidd12 and 14/of, the Nidd13/of exhibits heterosis: heterozygotes showing significantly higher glucose levels than OLETF or F344 homozygotes. There is epistatic interaction between Nidd2 and 14/of. Additionally, our results indicated that the novel QTLs could show no linkage with body weight, but Nidd12/of has an interaction with body weight.

Animals↗
PubMed1999

Identification of possible quantitative trait loci responsible for hyperglycaemia after 70% pancreatectomy using a spontaneously diabetogenic rat.

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model for obese-type non-insulin-dependent diabetes mellitus (NIDDM) in humans. The OLETF rat exhibits sustained hyperglycaemia after partial pancreatectomy, while the normal control rat does not. This difference is thought to be genetically determined and to be caused by impairment of beta-cell regrowth, a possible event involved in the pathogenesis of NIDDM. Our investigation was designed to identify quantitative trait loci (QTL) responsible for post-pancreatectomy hyperglycaemia by performing a genome-wide scan in an F2 intercross obtained by mating the OLETF and Fischer-344 (F344) rats. We have identified three possible QTL on rat chromosomes (Chrs) 3, 14 and 19 that account for a total of approximately 75% of the genetic variance in the F2. For the QTL on Chr 14, the OLETF allele corresponds with increased glucose levels, as expected. Surprisingly, for the QTL on Chr 19, the F344 allele corresponds with increased glucose levels. The Chr 3 QTL exhibits heterosis, heterozygotes showing significantly higher glucose levels than OLETF or F344 homozygotes. We also found evidence for interaction (epistasis) between the QTL on Chrs 14 and 19.

Animals↗
PubMed1999

An efficient multiplex PCR suitable for large scale typing in linkage mapping.

The dissection of polygenic traits is made possible with the development of microsatellite markers. Linkage study of this kind involves many markers with tens of hundreds of samples. Although typing essentially contains only two steps: PCR amplification and gel electrophoresis. Such work is still heavy when a large number of samples had to be genotyped. Multiplex PCR may reduce the work, but one has to optimize the conditions from marker to marker. Here we describe a dye-compatible multiplex PCR that works under standardized condition without the need to pre-determine the combinational primer concentration and the time-consuming step to mix many samples with gel loading dye before electrophoresis. This successful protocol should greatly reduce the cost and labor for genetic study of polygenic traits.

Animals↗
PubMed1998

A major quantitative trait locus co-localizing with cholecystokinin type A receptor gene influences poor pancreatic proliferation in a spontaneously diabetogenic rat.

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model for obese-type, non-insulin-dependent diabetes mellitus (NIDDM) in humans. The OLETF rat has poor capacity for pancreatic proliferation, which may be the critical pathogenetic event in NIDDM development. Our investigation was designed to identify quantitative trait loci (QTLs) responsible for poor pancreatic proliferation by examining compensatory proliferation of the pancreatic remnant after partial pancreatectomy and performing a genome-wide scan in an F2 intercross obtained by mating the OLETF and the Fischer-344 (F344) rats. We identified a highly significant QTL on rat Chromosome 14 with a maximum lod score of 16.7, which accounts for 55% of the total variance. The QTL co-localizes with the gene encoding cholecystokinin type A receptor (CCKAR) which is likely to mediate the trophic effect of cholecystokinin on pancreas and is defective in the OLETF rat.

Animals↗
PubMed1998

An integrated genetic map of the rat with 562 markers from different sources.

Genetic maps are the primary resources for genetic study. Genetic map construction was quite difficult in the past decade for lack of polymorphic markers. This situation has been changed since the development of microsatellite markers or simple sequence length polymorphisms (SSLPs) because they are abundant and more polymorphic. Here we report the construction of an integrated genetic map of the rat derived from two F2 intercrosses. A map of 376 markers from 160 (OLETF x F344)F2 progenies and a map of 333 markers from 71 (F344 x LEC)F2 animals are integrated by use of common set of 120 anchor markers chosen to be spaced at an average of 15 cM in the genome. The resulting integrated map with 194 newly developed rat markers from WIBR/MIT CGR, 269 Mit/Mgh markers, 94 Wox markers, and 5 markers of various origins covers the majority of 21 chromosomes of the rat with a total genetic distance of 1797 cM and an average marker spacing of 3.2 cM. The current map provides detailed information for markers from different sources and, therefore, should be helpful to the research community.

Animals↗
PubMed1998

Identification of a quantitative trait locus influencing plasma insulin levels after 70% pancreatectomy using the OLETF rat.

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model for obese-type non-insulin-dependent diabetes mellitus (NIDDM) in humans. The OLETF rat has poor capacity for proliferation of pancreatic beta-cells after partial pancreatectomy, which may be the critical pathogenetic event in NIDDM development. The poor pancreatic beta-cell proliferation in this model is characterized by reduction in beta-cell mass and decrease in insulin content in the remnant pancreas. Our investigation was designed to identify quantitative trait loci (QTLs) responsible for beta-cell mass and plasma insulin levels after partial pancreatectomy by performing a genome-wide scan in an F2 intercross obtained by mating the OLETF and the Fischer-344 (F344) rats. We have identified a suggestive QTL for the plasma insulin levels, near D20Mgh5 on rat chromosome 20, with a maximum lod score of 3.75 which accounts for 20% of the total variance, while no QTLs were detected for beta-cell mass. This chromosome 20 QTL, whose OLETF allele is associated with low plasma insulin levels through acting in an incompletely recessive manner, may affect insulin secretion itself rather than beta-cell proliferation.

Animals↗
PubMed1998

X-linked locus is responsible for non-insulin-dependent diabetes mellitus in the OLETF rat.

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat has been recently established as the best model of non-insulin-dependent diabetes mellitus (NIDDM) with mild obesity. In this study, we found that the F1 progeny produced from the crosses of OLETF and F344 rats exhibit a reciprocal cross effect on NIDDM-relevant phenotypes, fasting and postprandial glucose levels and body weight, suggesting the existence of X-linked locus affecting susceptibility to NIDDM. We thus examined the linkage between 7 X-linked microsatellite markers and NIDDM-relevant phenotypes, using 160 (OLETF x F344)F2 progeny. Suggestive evidence for a X-linked locus affecting glucose levels at 120 min after glucose administration was found in a region near X-linked marker, DXMgh4. The identified locus also showed significant effects on fasting glucose levels and body weight.

Animals↗
PubMed1998

Fetal copper uptake and a homolog (Atp7b) of the Wilson's disease gene in rats.

LEC rats are defective at the p-type copper transport ATPase gene (Atp7b) and exhibit excessive hepatic copper accumulation. However, copper concentration in fetal liver of LEC rats is lower than that of F344 normal rats. In this study, we made fetal backcrosses between LEC and F344 normal rats. At 19 days of gestation, hepatic copper concentrations of (LECXF344)F1XLEC and LECX(LECXF344)F1 fetuses were equivalent to those of F344 and LEC fetuses, respectively, irrespective of their Atp7b genotype. Furthermore, Atp7b expression was identified in the uterus and the maternal portion of placenta, but not in the fetal portion of placenta, in pregnant F344 rats. From these results, we speculate that the Atp7b product might contribute to a copper transport system from mother to fetus in the maternal portion, but not in the fetal portion of placenta.

Adenosine Triphosphatases↗
PubMed1995

The rat homologue of the Wilson's disease gene was partially deleted at the 3' end of its protein-coding region in Long-Evans Cinnamon mutant rats.

LEC mutant rats exhibit an abnormal hepatic copper accumulation, due to the defection of the rat homologue of the Wilson's disease gene. In this study, we found a definitive evidence that the rat Wilson's disease gene of LEC rats was partially deleted at the 3' end of its protein-coding region, by performing Southern blot analysis. Furthermore, in Northern blot analysis, we confirmed that expression of the rat Wilson's disease gene was deficient in the liver of LEC rats. The partial deletion of the rat Wilson's disease gene should be responsible for the deficient expression of that gene in LEC rats.

Animals↗