Pathophysiological, Genetic and Gene Expression Features of a Novel Rodent Model of the Cardio-Metabolic Syndrome

Wallis, Robert H.; Collins, Stephan C.; Kaisaki, Pamela J.; Argoud, Karène; Wilder, Steven P.; Wallace, Karin J.; Ria, Massimiliano; Ktorza, Alain; Rorsman, Patrik; Bihoreau, Marie-Thérèse; Guyader, Dominique

doi:10.1371/journal.pone.0002962

Cited by 25 publications

(28 citation statements)

References 31 publications

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“…A chromosome 1 congenic with cardio-metabolic syndrome was constructed from BN and diabetic GotoKakizaki (GK) rats, but the donor region is proximal to the ZUC.BN-Chr1 congenic (23). Sex differences in UAE have been investigated in a congenic where SHR rats provide the donor chromosome 6 on the MWF rat background (19).…”

Section: Discussionmentioning

confidence: 99%

Leptin receptor interacts with rat chromosome 1 to regulate renal disease traits

Warden

Gularte‐Mérida

Fisler

et al. 2012

Physiological Genomics

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Linkage mapping in a backcross of {Brown Norway [BN/Crl (BN)] × ZUC-Lepr (faSte) (ZUC)} × ZUC identified a male-specific quantitative trait locus (QTL) for urinary albumin excretion (UAE) on rat chromosome 1. A homozygous ZUC.BN-(D1Rat42-D1Rat90)/Ste congenic was produced containing BN donor alleles from 135 to 276 Mb from chromosome 1 on the ZUC background. We observed threefold higher urinary albumin-to-creatinine ratios (ACR) in 15-wk-old Zucker background strain males than in same sex and age congenic animals when both strains are also homozygous for the ZUC leptin receptor fatty mutation (Lepr (faSte)) (P < 0.0001). We then linkage mapped within the donor region without confounded effects from other chromosomes. Phenotypes were collected in 248 F2 male rats in a population made by crossing parents heterozygous for both the BN donor region and ZUC Lepr (faSte). Significant interactions were observed between the Lepr genotype and chromosome 1 QTL for six renal traits: urine volume, UAE at 10 and 15 wk, ACR, right kidney weight, and plasma urea nitrogen. A few traits, such as UAE and ACR, exhibit a second peak at the distal end of the chromosome. Hydronephrosis exhibited one or two QTLs contingent on adjustment for body weight. The results now demonstrate at least two sets of coincident traits with different correlations to kidney function.

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Section: Discussionmentioning

confidence: 99%

Leptin receptor interacts with rat chromosome 1 to regulate renal disease traits

Warden

Gularte‐Mérida

Fisler

et al. 2012

Physiological Genomics

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“…A colony of GK/Ox rats bred at Biomedical Service Unit, University of Oxford, since 1995 from a GK/Par stock and BN rats obtained from a commercial supplier (Charles River Laboratories, Margate, UK) were used to produce a series of 20 BN.GK and GK.BN congenic strains using a genetic marker-assisted breeding strategy (Wallis et al 2008). BN.GK congenics were designed to contain GK single genomic blocks introgressed onto the genetic background of the BN strain, whereas the reciprocal GK.BN congenics contained BN genomic blocks transferred onto a GK genetic background (Figure 1, Supplemental Material, Table S1).…”

Section: Methodsmentioning

confidence: 99%

“…This process resulted in the isolation of the GK strain enriched for naturally occurring Wistar polymorphisms that contribute to diabetes and associated phenotypes, which we previously mapped by QTL analysis of pathophysiological phenotypes in F2 crosses between GK rats and Brown–Norway (BN) controls (Gauguier et al 1996; Argoud et al 2006). Further physiological phenotyping and multitissue transcriptome profiling in a congenic strain designed to contain a large (∼100 Mb) QTL-rich region of the GK rat in a BN background validated QTL effects and suggested that congenics can be efficiently used to dissect out cis - and trans -mediated regulation of gene transcription (Wallis et al 2008). …”

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confidence: 99%

Transcriptome Profiling in Rat Inbred Strains and Experimental Cross Reveals Discrepant Genetic Architecture of Genome-Wide Gene Expression

Kaisaki

Otto

Argoud

et al. 2016

G3 Genes|Genomes|Genetics

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To test the impact of genetic heterogeneity on cis- and trans-mediated mechanisms of gene expression regulation, we profiled the transcriptome of adipose tissue in 20 inbred congenic strains derived from diabetic Goto–Kakizaki (GK) rats and Brown–Norway (BN) controls, which contain well-defined blocks (1–183 Mb) of genetic polymorphisms, and in 123 genetically heterogeneous rats of an (GK × BN)F2 offspring. Within each congenic we identified 73–1351 differentially expressed genes (DEGs), only 7.7% of which mapped within the congenic blocks, and which may be regulated in cis. The remainder localized outside the blocks, and therefore must be regulated in trans. Most trans-regulated genes exhibited approximately twofold expression changes, consistent with monoallelic expression. Altered biological pathways were replicated between congenic strains sharing blocks of genetic polymorphisms, but polymorphisms at different loci also had redundant effects on transcription of common distant genes and pathways. We mapped 2735 expression quantitative trait loci (eQTL) in the F2 cross, including 26% predominantly cis-regulated genes, which validated DEGs in congenic strains. A hotspot of >300 eQTL in a 10 cM region of chromosome 1 was enriched in DEGs in a congenic strain. However, many DEGs among GK, BN and congenic strains did not replicate as eQTL in F2 hybrids, demonstrating distinct mechanisms of gene expression when alleles segregate in an outbred population or are fixed homozygous across the entire genome or in short genomic regions. Our analysis provides conceptual advances in our understanding of the complex architecture of genome expression and pathway regulation, and suggests a prominent impact of epistasis and monoallelic expression on gene transcription.

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“…5). Recently, congenic and expression studies have shown that multiple loci within this region play a role in glycemic control (5,7,10,15,26,44). Furthermore, the homologous region in humans has been identified in several linkage studies (6,8,14,19,27,28,42,47), and three genes in this region have recently been identified in human genome wide association studies (GWAS) (Tcf7l2, HHEX and IDE) (34 -36, 38, 49).…”

Section: Discussionmentioning

confidence: 99%

Fine-mapping a locus for glucose tolerance using heterogeneous stock rats

Woods

Holl

Tschannen

et al. 2010

Physiological Genomics

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Solberg Woods LC, Holl K, Tschannen M, Valdar W. Finemapping a locus for glucose tolerance using heterogeneous stock rats. Physiol Genomics 41: 102-108, 2010. First published January 12, 2010 doi:10.1152/physiolgenomics.00178.2009.-Heterogeneous stock (HS) animals provide the ability to map quantitative trait loci at high resolution [Ͻ5 Megabase (Mb)] in a relatively short time period. In the current study, we hypothesized that the HS rat colony would be useful for fine-mapping a region on rat chromosome 1 that has previously been implicated in glucose regulation. We administered a glucose tolerance test to 515 HS rats and genotyped these animals with 69 microsatellite markers, spaced an average distance of Ͻ1 Mb apart, on a 67 Mb region of rat chromosome 1. Using regression modeling of inferred haplotypes based on a hidden Markov model reconstruction and mixed model analysis in which we accounted for the complex family structure of the HS, we identified one sharp peak within this region. Using positional bootstrapping, we determined the most likely location of this locus is from 205.04 to 207.48 Mb. This work demonstrates the utility of HS rats for finemapping complex traits and emphasizes the importance of taking into account family structure when using highly recombinant populations.type 2 diabetes; quantitative trait loci; mapping; mixed model analysis HETEROGENEOUS STOCKS (HS) are a powerful tool for rapidly fine-mapping loci involved in complex traits (41). These animals are originally derived from eight inbred founder strains and then bred for 40 -50 generations in a pattern that aims to minimize inbreeding (1, 16). The resulting colony represents a random mosaic of the founders, with the distance between recombination approaching 2 cM, enabling rapid fine-mapping of quantitative trait loci (QTLs) (31). An HS rat stock was developed in 1984 using the following eight inbred founder strains: ACI/N, BN/N, BUF/N, F344/N, M520/N, MR/N, WKY/N, WN/N (16). Multiple phenotypes have been finemapped using the HS mouse (41). To date, however, the HS rat colony has only been used to fine-map a single locus for fear-related behavior (18).We hypothesized that HS rats would be useful for finemapping a region on rat chromosome 1 that has previously been identified for several metabolic traits, including glucose tolerance, in several linkage studies in the rat (3,11,12,20,32,37,45,46). Human linkage and genome-wide association studies for type 2 diabetes have also identified the homologous human region (6,19,25). While many of the previous rat studies have used animal models of diabetes such as the Goto-Kakizaki (GK) or Otsuka Long-Evans Tokushima Fatty rat (11,12,20,32,46), this locus has also been mapped for diabetes or glucose tolerance using founders of the HS colony: Wistar Kyoto (WKY) and August Copenhagen Irish (ACI) (37,45). These studies indicate that diabetes susceptibility alleles will segregate within the HS rat colony. While the WKY rat has previously been found to exhibit hyperglycemia and glucose intoleranc...

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Pathophysiological, Genetic and Gene Expression Features of a Novel Rodent Model of the Cardio-Metabolic Syndrome

Cited by 25 publications

References 31 publications

Leptin receptor interacts with rat chromosome 1 to regulate renal disease traits

Leptin receptor interacts with rat chromosome 1 to regulate renal disease traits

Transcriptome Profiling in Rat Inbred Strains and Experimental Cross Reveals Discrepant Genetic Architecture of Genome-Wide Gene Expression

Fine-mapping a locus for glucose tolerance using heterogeneous stock rats

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