A growth QTL (Pbwg1) region of mouse chromosome 2 contains closely linked loci affecting growth and body composition

Ishikawa, Akira; Kim, Eun‐Hee; Bolor, Hasbaira; Mollah, Md. Bazlur R.; Namikawa, Takao

doi:10.1007/s00335-007-9009-5

Cited by 23 publications

(48 citation statements)

References 32 publications

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“…The 95% confidence interval (CI) for each QTL was determined with a 1.5-LOD drop from the QTL peak (32). The mode of inheritance of alleles at the QTL detected was determined by two statistical tests using Map Manager QTX20b (13). First, one of additive, dominance, and recessive regression models was contrasted with a no-QTL model.…”

Section: Methodsmentioning

confidence: 99%

Identification of a major locus for islet inflammation and fibrosis in the spontaneously diabetic Torii rat

Fuse

Yokoi

Shinohara³

et al. 2008

Physiological Genomics

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of inflammation and fibrosis in the pancreatic islets in diabetes is largely unknown. Spontaneously diabetic Torii (SDT) rats exhibit inflammation and fibrosis in and around the islets during the development of the disease. We investigated genetic factors for diabetes, islet inflammation, and fibrosis in the SDT rat. We produced F1 and F2 rats by intercross between SDT and F344 rats, examined the onset of diabetes, glucose tolerance, and histology of the pancreas, and performed genetic analysis of these traits. We then established a congenic strain carrying the SDT allele at the strongest diabetogenic locus on the F344 genetic background and characterized glucose tolerance and histology of the pancreas. F1 rats showed glucose intolerance and inflammatory changes mainly in the islets. Genetic analysis of diabetes identified a major locus on chromosome 3, designated Dmsdt1, at which a dominantly acting SDT allele was involved. Quantitative trait locus (QTL) analysis of glucose tolerance revealed, in addition to Dmsdt1 [logarithm of odds (LOD) 5.3 near D3Mit12], three other loci, designated Dmsdt2 (LOD 4.2 at D8Rat46), Dmsdt3 (LOD 3.8 near D13Arb5), and Dmsdt4 (LOD 5.8 at D14Arb18). Analysis of a congenic strain for Dmsdt1 indicates that the dominantly acting SDT allele induces islet inflammation and fibrosis. Thus we have found a major locus on chromosome 3 for islet inflammation and fibrosis in the SDT rat. Identification of the genes responsible should provide insight into the pathogenesis of diabetes. congenic analysis; diabetes; genetic factor; glucose tolerance; quantitative trait locus DIABETES MELLITUS IS a multifactorial disease involving interaction of genetic and environmental factors. Spontaneous animal models of diabetes are widely used in research and have provided valuable information on the nature of the disease. Inflammation and fibrosis in pancreatic islets have been described in human type 2 diabetes (4) and in spontaneous animal models of type 2 diabetes, including the Goto-Kakizaki (GK) rat (12), the Zucker diabetic fatty rat (33), and the Otsuka Long-Evans Tokushima fatty (OLETF) rat (16). A role of inflammation and fibrosis in the pathogenesis of type 2 diabetes has been suggested (17), but the mechanism and genetic factors remain to be elucidated. Genetic, pathophysiological, and histological analyses using animal models should provide useful information for understanding the molecular mechanism of the inflammatory process in the development of the disease.The spontaneously diabetic Torii (SDT) rat was established from an outbred colony of Sprague-Dawley rats in 1997 as a nonobese diabetic animal model (37,38). Male SDT rats develop diabetes at 15 wk of age or later and show 100% incidence of diabetes by 40 wk of age. Pathological changes including microvascular congestion and hemorrhage in pancreatic islets appear from ϳ8 wk of age and are followed by inflammation and fibrosis in and around the islets. These pathological changes in the pancreas of SDT rats differ from those of typical autoi...

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Section: Methodsmentioning

confidence: 99%

Identification of a major locus for islet inflammation and fibrosis in the spontaneously diabetic Torii rat

Fuse

Yokoi

Shinohara³

et al. 2008

Physiological Genomics

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“…Our previous congenic analysis using B6.Cg-Pbwg1 [6] and another QTL study using the CAST/Ei inbred strain originating from wild M. m. castaneus trapped in Thailand [11] reported that the Cas allele increases body weight and weight gain at early ages. Thus, this may be the first study using castaneus mice that has revealed a QTL with an increasing effect on growth at later ages.…”

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“…Mice were sacrificed under ether anesthesia at 10 weeks of age. As described previously [6], total body length and tail length were measured and head-body length and body mass index (g/cm 2 ) were calculated. Six internal organs (heart, lung, spleen, liver, and both kidneys and testes) were weighed.…”

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confidence: 99%

“…Genomic dNA was extracted from ear clips by standard methods. Genotyping of microsatellite markers was performed as described previously [6]. Phenotypic trait data for B6.Cg-Pbwg12 and C57BL/6J mice were analyzed using a linear model of the statistical discovery software JMP version 7.02 (SAS Institute, Cary, NC).…”

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“…The B6.Cg-Pbwg12 congenic strain developed in this study will be a good animal resource for understanding the molecular and genetic mechanisms of epistasis, especially an epistatic interaction between QTLs with and without main effects. We are now planning to investigate phenotypic effects of all nine possible genotypic combinations in approximately 1,000 F 2 mice from an intercross between the B6.CgPbwg12 congenic strain for chromosome 12 and the B6.Cg-Pbwg1 congenic strain previously developed for chromosome 2 [6].…”

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Development and Characterization of a Congenic Strain Carrying Pbwg12, a Growth QTL on Mouse Chromosome 12

Ishikawa

2010

Exp. Anim.

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Abstract:In previous genome-wide QTL studies, Pbwg12 on mouse chromosome 12 was discovered in a gene pool of wild Mus musculus castaneus mice. Pbwg12 does not have a main effect but has an epistatic interaction effect on body weight after birth. In this study, we developed a congenic strain, named B6.Cg-Pbwg12, with an approximately 59-Mb wildderived genomic region harboring Pbwg12, by recurrent backcrossing to C57BL/6J. A phenotypic comparison between B6.Cg-Pbwg12 and C57BL/6J revealed that Pbwg12 does not have any main effects on body weight at 1-10 weeks of age but has a main effect on body weight gain at 6-10 weeks. A new QTL with a male-specific effect on kidney weight was discovered within the introgressed region.

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Intersubspecific subcongenic mouse strain analysis reveals closely linked QTLs with opposite effects on body weight

Mollah

Ishikawa

2011

Mamm Genome

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A previous genome-wide QTL study revealed many QTLs affecting postnatal body weight and growth in an intersubspecific backcross mouse population between the C57BL/6J (B6) strain and wild Mus musculus castaneus mice captured in the Philippines. Subsequently, several closely linked QTLs for body composition traits were revealed in an F(2) intercross population between B6 and B6.Cg-Pbwg1, a congenic strain on the B6 genetic background carrying the growth QTL Pbwg1 on proximal chromosome 2. However, no QTL affecting body weight has been duplicated in the F(2) population, except for mapping an overdominant QTL that causes heterosis of body weight. In this study, we developed 17 intersubspecific subcongenic strains with overlapping and nonoverlapping castaneus regions from the B6.Cg-Pbwg1 congenic strain in order to search for and genetically dissect QTLs affecting body weight into distinct closely linked loci. Phenotypic comparisons of several developed subcongenic strains with the B6 strain revealed that two closely linked but distinct QTLs that regulate body weight, named Pbwg1.11 and Pbwg1.12, are located on an 8.9-Mb region between D2Mit270 and D2Mit472 and on the next 3.6-Mb region between D2Mit205 and D2Mit182, respectively. Further analyses using F(2) segregating populations obtained from intercrosses between B6 and each of the two selected subcongenic strains confirmed the presence of these two body weight QTLs. Pbwg1.11 had an additive effect on body weight at 6, 10, and 13 weeks of age, and its castaneus allele decreased it. In contrast, the castaneus allele at Pbwg1.12 acted in a dominant fashion and surprisingly increased body weight at 6, 10, and 13 weeks of age despite the body weight of wild castaneus mice being 60% of that of B6 mice. These findings illustrate the complex genetic nature of body weight regulation and support the importance of subcongenic mouse analysis to dissect closely linked loci.

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A growth QTL (Pbwg1) region of mouse chromosome 2 contains closely linked loci affecting growth and body composition

Cited by 23 publications

References 32 publications

Identification of a major locus for islet inflammation and fibrosis in the spontaneously diabetic Torii rat

Identification of a major locus for islet inflammation and fibrosis in the spontaneously diabetic Torii rat

Development and Characterization of a Congenic Strain Carrying Pbwg12, a Growth QTL on Mouse Chromosome 12

Intersubspecific subcongenic mouse strain analysis reveals closely linked QTLs with opposite effects on body weight

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