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Physiogenomic resources for rat models of heart, lung and blood disorders

Abstract

Cardiovascular disorders are influenced by genetic and environmental factors. The TIGR rodent expression web-based resource (TREX) contains over 2,200 microarray hybridizations, involving over 800 animals from 18 different rat strains. These strains comprise genetically diverse parental animals and a panel of chromosomal substitution strains derived by introgressing individual chromosomes from normotensive Brown Norway (BN/NHsdMcwi) rats into the background of Dahl salt sensitive (SS/JrHsdMcwi) rats. The profiles document gene-expression changes in both genders, four tissues (heart, lung, liver, kidney) and two environmental conditions (normoxia, hypoxia). This translates into almost 400 high-quality direct comparisons (not including replicates) and over 100,000 pairwise comparisons. As each individual chromosomal substitution strain represents on average less than a 5% change from the parental genome, consomic strains provide a useful mechanism to dissect complex traits and identify causative genes. We performed a variety of data-mining manipulations on the profiles and used complementary physiological data from the PhysGen resource to demonstrate how TREX can be used by the cardiovascular community for hypothesis generation.

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Figure 1: Correlation of gene expression with infarct size in genetically diverse parental strains.
Figure 2: Physiological indices for pulmonary vascular remodeling in SS lung after chronic hypoxia.
Figure 3: Differentially expressed genes in lungs of SS and FHH-1BN animals exposed to hypoxia.
Figure 4: Inducible complexes interacting with cis-motifs.

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Acknowledgements

This work was funded by grants to N.H.L., J.Q. and H.J.J. from the National Heart, Lung, and Blood Institute's Programs for Genomic Applications. We would like to acknowledge V. Sheffield and S.E. Old for their support.

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Correspondence to Norman H Lee.

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Supplementary information

Supplementary Fig. 1

Quality control scatter plot (PDF 32 kb)

Supplementary Table 1

Differentially regulated genes between parental strains and consomic animals. (PDF 272 kb)

Supplementary Table 2

Differentially regulated genes averaged across SS-xBN consomic panel. (PDF 249 kb)

Supplementary Table 3

Differentially regulated genes averaged across all tissues within the SS-xBN panel. (PDF 249 kb)

Supplementary Table 4

Differentially regulated genes in hypoxic versus normoxic conditions. (PDF 255 kb)

Supplementary Table 5

Hemodynamic values and infarct size. (PDF 289 kb)

Supplementary Table 6

Correlation analysis statistics. (PDF 436 kb)

Supplementary Table 7

Real-time PCR and western blot variation of microarray data. (PDF 435 kb)

Supplementary Table 8

Promoter retrieval and MEME/MAST analysis. (PDF 254 kb)

Supplementary Methods (PDF 366 kb)

Supplementary Note (PDF 100 kb)

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Malek, R., Wang, Hy., Kwitek, A. et al. Physiogenomic resources for rat models of heart, lung and blood disorders. Nat Genet 38, 234–239 (2006). https://doi.org/10.1038/ng1693

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