A genetic linkage map of the rat derived from recombinant inbred strains

Pravenec, Michal; Guyader, Dominique; Schott, Jean‐Jacques; Buard, Jérǒme; Křen, Vladimı́r; Bı́lá, V; Szpirer, Claude; Szpirer, Josiane; Wang, J M; Huang, Hongdong; Lezin, Elizabeth St.; Spence, M. Anne; Flodman, Pamela; Printz, Morton P.; Lathrop, G.M.; Vergnaud, Gilles; Kurtz, Theodore W.

doi:10.1007/s003359900031

Cited by 105 publications

(31 citation statements)

References 44 publications

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“…11 The BXH/ HXB genotype database was assembled using a compendium of ~1100 markers. 12,13 Linkage and correlation analyses were performed for plasma cysteine and homocysteine levels, parameters of glucose and lipid metabolism, and for transcript abundance of renal Folr1. The GeneNetwork software tests for single locus associations by regression analysis and generates likelihood ratio statistics to assess the statistical significance of potential associations.…”

Section: Genetic Analysismentioning

confidence: 99%

Genetic Variation in Renal Expression of Folate Receptor 1 ( Folr1 ) Gene Predisposes Spontaneously Hypertensive Rats to Metabolic Syndrome

et al. 2016

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Metabolic syndrome is a cluster of clinical disturbances (abdominal obesity, hypertension, dyslipidemia, and impaired glucose tolerance/insulin resistance) associated with an increased risk for diabetes mellitus and cardiovascular disease. Mild hyperhomocysteinemia, a common finding in patients with arteriosclerosis, has been described as a possible component of metabolic syndrome.1,2 Because folates and B vitamins modulate metabolism of homocysteine and of other sulfur amino acids (eg, cysteine, methionine, and cystathionine), mild hyperhomocysteinemia may be mediated by nutritional or genetically determined deficiencies of these vitamins. There is a growing body of epidemiological and clinical evidence for an important role of folate deficiency in human metabolic disturbances and hypertension. [3][4][5] We have shown previously that nutritional folate deficiency leads to development of features of the metabolic syndrome in the spontaneously hypertensive rat (SHR), 6 a widely studied model of essential hypertension associated with increased risk for insulin resistance and dyslipidemia. In this study, in the BXH/HXB recombinant inbred (RI) strains derived from the SHR strain and the normotensive Brown Norway (BN) strain, 7 we used a combination of linkage and correlational analyses of physiological traits and gene expression levels to investigate genetic factors influencing folate and sulfur amino acid metabolism and risk for multiple features of the metabolic syndrome. Methods AnimalsSHR/OlaIpcv rats (referred to as the SHR strain), BN-Lx/Cub rats (referred to as the BN strain), BXH/HXB RI strains 7 derived from the SHR and BN progenitor strains, SHR.BN-D1Mit3/Igf2 congenic Abstract-Metabolism of homocysteine and other sulfur amino acids is closely associated with metabolism of folates. In this study, we analyzed the possible role of folates and sulfur amino acids in the development of features of the metabolic syndrome in the BXH/HXB recombinant inbred strains derived from the spontaneously hypertensive rat (SHR) and Brown Norway progenitors. We mapped a quantitative trait locus for cysteine concentrations to a region of chromosome 1 that contains a cis-acting expression quantitative trait locus regulating mRNA levels of folate receptor 1 (Folr1) in the kidney. Sequence analysis revealed a deletion variant in the Folr1 promoter region of the SHR. Transfection studies demonstrated that the SHR-promoter region of Folr1 is less effective in driving luciferase reporter gene expression than the Brown Norway promoter region of Folr1. Results in the SHR.BN-chr.1 congenic strain confirmed that the SHR variant in Folr1 cosegregates with markedly reduced renal expression of Folr1 and renal folate reabsorption, decreased serum levels of folate, increased serum levels of cysteine and homocysteine, increased adiposity, ectopic fat accumulation in liver and muscle, reduced muscle insulin sensitivity, and increased blood pressure. Transgenic rescue experiments performed by expressing a Folr1 transgene in the SHR ameliorated ...

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Section: Genetic Analysismentioning

confidence: 99%

Genetic Variation in Renal Expression of Folate Receptor 1 ( Folr1 ) Gene Predisposes Spontaneously Hypertensive Rats to Metabolic Syndrome

et al. 2016

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“…The second was D7Mit4, closely linked to cellular oncogene myc. The gene order is D7Mit4-(2.9 cM)-myc-(10 cM)-D7Mit5 (Pravenec et al, 1996). Similarly, F344 allele at this locus favoured to form T-lymphoma (P = 0.00002).…”

Section: Discussionmentioning

confidence: 95%

“…We postulated that it was due to close correlation between T-lymphomas incidence and the length of latency. In this segment, oncogene jun is located in the order of D5Mit4-D5Mit5-jun-D5Mit7 (Pravenec et al, 1996). Jun oncogene is essential to the efficient growth of certain tumours (Angel et al, 1988).…”

Section: Discussionmentioning

confidence: 99%

Propylnitrosourea-induced T-lymphomas in LEXF RI strains of rats: genetic analysis

Shisa

Tanuma

et al. 1999

Br J Cancer

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Our recent studies have shown that types of lymphomas and leukaemias are determined by host genes in certain experimental models (Yamada et al, 1994a(Yamada et al, , 1994b. Propylnitrosourea (PNU)-induced T-lymphomas are one such example. F344 rats exhibit high susceptibility, whereas many other strains of rats develop predominantly erythro-or myeloid leukaemias (Shisa and Hiai, 1985;Shisa and Suzuki, 1991) We have assumed that a single dominant gene of F344 rats determines the susceptibility to T-lymphomas and that another independently segregating dominant gene determines the length of the latency period (Shisa and Hiai, 1985). Subsequent efforts to map such genes with crosses between F344 and LE rats, however, have met with great difficulty (Shisa et al, unpublished observation). The difficulty seems to arise partly from paucity of rat genetic marker at that time and partly because these traits are quantitative in nature and mutigenic, rather than a single gene inheritance.The recombinant inbred (RI) strains represent a set of stable inbred strains derived from F2 intercross between two parental inbred stains. The RI strains are extremely useful for the genetic analysis of complex traits (Taylor, 1978;Bailey, 1981). To analyse T-lymphoma susceptibility, we have established a new set of rat RI strains, LEXF, from matings between F344 and LE/Stm strains rats. The LEXF RI strains comprise 11 independent strains and 13 of their sublines. The strain distribution pattern (SDP) of LEXF has been extensively analysed (Shisa et al, 1997;Lu et al, 1998).In this paper, we report the PNU-induced carcinogenesis in the LEXF RI strains, and survey the host genes responsible for determination of the disease types and length of the latency period calculated using quantitative trait locus (QTL) analysis with the Map Manager QT software developed by Manly (1993). We found that numerous QTL with opposed functions are involved in determining the types of lymphomas and latency periods. To control type I and type II errors (Belknap et al, 1992(Belknap et al, , 1996, we further evaluated these putative loci in 137 backcross generation of (F344 × LE)F1 × LE rats. Significant linkage with T-lymphomagenesis was confirmed for three loci on chromosome 5, 7 and 10 and suggestive linkage, for a locus on chromosome 1. MATERIALS AND METHODS AnimalsThe LE/Stm rats were originally derived from a closed colony of Long-Evans rats at Ben May Laboratory, University of Chicago (Chicago, IL, USA) and maintained at Saitama Cancer Center Research Institute by brother-sister matings for > 50 generations. The F344 rats were derived from a pair of F344/DuCrj rats purchased from Charles River Japan, Inc. (Kanagawa, Japan) and thereafter maintained by brother-sister matings for > 23 generations. The LEXF was a set of 11 independent RI strains and 13 sublines (Shisa et al, 1997) In this study all LEXF RI strains except for LEXF 6B, a poor breeder, were used. These sublines were branched out at the 7th to 11th generations after an attempt to fix coat colour. ...

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“…The efforts of Howard Jacob and many others resulted in the generation of linkage maps and other genetic resources based on crosses between the SHR and the normotensive Brown Norway (BN) rat and between other strains as well. 8,[32][33][34][35] The SHR-BN model was emphasized because the 2 progenitor strains constituted a highly polymorphic genetic system that afforded an abundance of contrasting DNA markers, as well as a variety of contrasting phenotypes relevant to hypertension and related metabolic disorders. Ultimately, to confirm the results of QTL mapping studies and establish proof of QTL identity at the molecular level, it would be necessary to develop congenic and transgenic strains of SHR.…”

Section: Developing New Tools and Strategies For Genetic Dissection Omentioning

confidence: 99%

Molecular Genetics of Experimental Hypertension and the Metabolic Syndrome

Pravenec

Kurtz²

2007

Hypertension

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Abstract-Genetic studies of human and experimental hypertension provide a means to identify key pathways that predispose individuals to increased blood pressure and associated risk factors for cardiovascular and metabolic diseases. The pathways so identified can then serve as targets for therapeutic intervention. This article discusses genetic studies in animal models of hypertension in which specific genes have been identified that regulate blood pressure and biochemical features of the metabolic syndrome. Consistent with studies in humans with monogenic disorders of blood pressure regulation, studies in rat models have demonstrated that naturally occurring genetic variation in pathways regulating sodium chloride transport can contribute to inherited variation in blood pressure. Such studies have also indicated that naturally occurring variation in genes, such as Cd36, that regulate fatty acid metabolism and ectopic accumulation of fat and fat metabolites can influence both biochemical and hemodynamic features of the metabolic syndrome and mediate the antidiabetic effects of drugs that activate the peroxisome proliferator-activated receptor-␥. Angiotensin II receptor blockers with the ability to selectively modulate activity of peroxisome proliferator-activated receptor-␥ and expression of genes in these fat metabolism pathways may represent useful prototypes for a new class of transcription modulating drugs aimed at treating patients with hypertension and the metabolic syndrome. Key Words: genetics Ⅲ rats Ⅲ inbred SHR Ⅲ metabolic syndrome X Ⅲ hypertension Ⅲ angiotensin II type 1 receptor blockers Ⅲ peroxisome proliferator-activated receptors G enes involved in the pathogenesis of complex clinical disorders including essential hypertension and the metabolic syndrome are often referred to as quantitative trait loci (QTL). Identification of QTL at the molecular level is considered to be 1 of the major challenges in modern medicine, and it is hoped that QTL discovery in animal models and in humans will reveal mechanistic pathways that can ultimately serve as new targets for therapeutic intervention. The spontaneously hypertensive rat (SHR) and the Dahl salt-sensitive rat are the most widely studied animal models of spontaneous hypertension, and their value for investigating the pharmacology and pathophysiology of hypertension and cardiovascular disease has been recognized for many years. 1-3 Until recently, however, it was unclear whether these spontaneous animal models of hypertension would prove useful for the identification of naturally occurring gene variants involved in the regulation of blood pressure (BP) or related cardiovascular and metabolic phenotypes. It was also unknown whether any such genes would prove relevant to the pathogenesis and treatment of any clinical disorders in humans.Major advances in methods for QTL mapping, together with the pioneering research of Rapp 4 and other investigators, sparked multiple efforts to map genes influencing BP-related phenotypes in Dahl rats and in the SHR. These ...

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A genetic linkage map of the rat derived from recombinant inbred strains

Cited by 105 publications

References 44 publications

Genetic Variation in Renal Expression of Folate Receptor 1 ( Folr1 ) Gene Predisposes Spontaneously Hypertensive Rats to Metabolic Syndrome

Genetic Variation in Renal Expression of Folate Receptor 1 ( Folr1 ) Gene Predisposes Spontaneously Hypertensive Rats to Metabolic Syndrome

Propylnitrosourea-induced T-lymphomas in LEXF RI strains of rats: genetic analysis

Molecular Genetics of Experimental Hypertension and the Metabolic Syndrome

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