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. 2019 Jul 15;12(7):dmm038539.
doi: 10.1242/dmm.038539.

Conserved properties of genetic architecture of renal and fat transcriptomes in rat models of insulin resistance

Georg W Otto  1 , Pamela J Kaisaki  2 , Francois Brial  3 , Aurélie Le Lay  3 , Jean-Baptiste Cazier  4 , Richard Mott  5 , Dominique Gauguier  6   3   7
Affiliations

Conserved properties of genetic architecture of renal and fat transcriptomes in rat models of insulin resistance

Georg W Otto et al. Dis Model Mech. .

Abstract

To define renal molecular mechanisms that are affected by permanent hyperglycaemia and might promote phenotypes relevant to diabetic nephropathy, we carried out linkage analysis of genome-wide gene transcription in the kidneys of F2 offspring from the Goto-Kakizaki (GK) rat model of type 2 diabetes and normoglycaemic Brown Norway (BN) rats. We mapped 2526 statistically significant expression quantitative trait loci (eQTLs) in the cross. More than 40% of eQTLs mapped in the close vicinity of the linked transcripts, underlying possible cis-regulatory mechanisms of gene expression. We identified eQTL hotspots on chromosomes 5 and 9 regulating the expression of 80-165 genes, sex or cross direction effects, and enriched metabolic and immunological processes by segregating GK alleles. Comparative analysis with adipose tissue eQTLs in the same cross showed that 496 eQTLs, in addition to the top enriched biological pathways, are conserved in the two tissues. Extensive similarities in eQTLs mapped in the GK rat and in the spontaneously hypertensive rat (SHR) suggest a common aetiology of disease phenotypes common to the two strains, including insulin resistance, which is a prominent pathophysiological feature in both GK rats and SHRs. Our data shed light on shared and tissue-specific molecular mechanisms that might underlie aetiological aspects of insulin resistance in the context of spontaneously occurring hyperglycaemia and hypertension.

Keywords: Diabetes mellitus; Goto-Kakizaki rat; SNP; Spontaneously hypertensive rat; Systems genetics; Transcriptome; eQTL.

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Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

Figures

Fig. 1.
Fig. 1.
Breeding design applied to map expression quantitative trait loci (eQTL) in the Goto-Kakizaki (GK) rat strain. (A,B) Reciprocal genetic crosses between male and female GK and Brown Norway (BN) rats used to produce individual (GK×BN) F2 rats are illustrated (A) and compared with the breeding scheme designed to derive recombinant inbred strains (RI-S) from spontaneously hypertensive rats (SHRs) and BN rats (B).
Fig. 2.
Fig. 2.
Distribution LOD scores for renal expression quantitative trait loci (eQTL) mapped in the GK×BN F2 cross. LOD scores are plotted against the proportion of eQTLs detected with all Illumina oligonucleotides (blue line) and those containing DNA variation between GK and BN strains (red line).
Fig. 3.
Fig. 3.
Kidney expression quantitative trait loci (eQTL) architecture in GK×BN F2 hybrids. (A) Genetic positions of statistically significant eQTLs (FDR P-value <0.05) are plotted against the LOD scores. (B) Local and distant eQTLs are illustrated by plotting genetic positions of statistically significant eQTLs and the genomic position of the linked transcripts. (C) Distribution of LOD scores for significant eQTLs is shown. (D) Genome mapping of pairs of eQTL and linked transcripts localized in the same chromosomes was used to determine relationships between the statistical significance of genetic linkage and genomic distances between transcripts and genetic markers. (E) Mapping data from pairs of transcripts and eQTLs localized to different chromosomes illustrate distant (trans) effects of genetic loci on gene transcription and eQTL hotspots (arrows). (F-I) Chromosomal distribution and genome-wide trans-mediated regulation of cross direction effect (CDE) (F,G) and sex-specific (H,I) eQTLs are shown. Chromosomes are colour coded on the circle to illustrate the effects of eQTLs mapped to the same chromosomes on the expression of distant genes. Arrows indicate genomic regions of eQTL enrichment. Details of eQTLs are given in Tables S1 and S2.
Fig. 4.
Fig. 4.
Comparative analyses of kidney and adipose tissue expression quantitative trait loci (eQTLs) mapped in the GK×BN F2 cross. (A,B) The effect of GK alleles at the eQTLs [expression ratio (ER)] on gene expression (A) and eQTL statistical significance (LOD score) (B) in kidney and adipose tissue were plotted to illustrate the strong conservation of eQTLs detected in both tissues. Full details of statistically significant eQTLs, illustrating shared and tissue-specific genetic regulation of gene expression, are given in Table S4.
Fig. 5.
Fig. 5.
Tissue-specific contribution of expression quantitative trait loci (eQTLs) genes to pathways enriched in both kidney and adipose tissue. (A,B) The expression ratio (ER) of eQTLs genes contributing to significant enrichment of phagosome (A) and metabolic pathways (B) in kidney and white adipose tissue are plotted to illustrate tissue-specific and conserved effects of segregating GK alleles in the GK×BN F2 cross on eQTL gene transcription regulation. Full details of statistically significant eQTLs, illustrating shared and tissue-specific genetic regulation of gene expression, are given in Table S4.
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