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Integrative analysis of the genomic architecture of a complex kidney damage QTL in inbred hypertensive rats implies Tmem63c for translational research

ABSTRACT: Despite recent advances in genomics, the identification of genes underlying complex diseases remains challenging. Inbred rat strains offer well-established experimental models to support the identification of susceptibility genes for diseases such as kidney damage associated with elevated blood pressure or hypertension. Here, we combined quantitative trait locus (QTL) mapping in two contrasting inbred rat strains with targeted next generation sequencing (NGS), compartment-specific transcriptome sequencing (RNA-Seq), and phenotype directed follow-up translational analysis.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE102546 | GEO | 2018/08/11

REPOSITORIES: GEO

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Project description:Although the evidence for a genetic predisposition to human essential hypertension is compelling, the genetic control of blood pressure (BP) is poorly understood. The Dahl salt-sensitive (S) rat is a model for studying the genetic component of BP. Using this model we previously reported the identification of 16 different genomic regions that contain one or more BP quantitative trait loci (QTLs). The proximal region of rat chromosome 1 contains multiple BP QTLs. Of these, we have localized the BP QTL1b region to a 13.5cM (20Mb) region. Interestingly, five additional independent studies in rats and four independent studies in humans have reported genetic linkage for BP control by regions homologous to QTL1b. To view the overall renal transcriptional topography of the positional candidate genes for this QTL, we sought a comparative gene expression profiling between a congenic strain containing QTL1b and control S rats by employing: (1) a saturated QTL1b interval specific oligonucleotide array, and (2) a whole genome cDNA microarray representing 20,465 unique genes that are positioned outside the QTL. Results indicated that 19 out of the 231 positional candidate genes for this QTL are differentially expressed between the two strains tested. Surprisingly, over 1,500 genes outside of QTL1b were differentially expressed between the two rat strains. Integrating the results from the two approaches revealed at least one complex network of transcriptional control initiated by the positional candidate Nr2f2. This network appears to account for the majority of gene expression differences occurring outside of the QTL interval. Further substitution mapping is currently underway to test the validity of each of these differentially expressed positional candidate genes. These results demonstrate the importance of using a saturated oligonucleotide array for identifying and prioritizing differentially expressed positional candidate genes of a BP QTL. Keywords: : rat, hypertension, genetics, polygenic trait, microarray, gene expression

Project description:Although the evidence for a genetic predisposition to human essential hypertension is compelling, the genetic control of blood pressure (BP) is poorly understood. The Dahl salt-sensitive (S) rat is a model for studying the genetic component of BP. Using this model we previously reported the identification of 16 different genomic regions that contain one or more BP quantitative trait loci (QTLs). The proximal region of rat chromosome 1 contains multiple BP QTLs. Of these, we have localized the BP QTL1b region to a 13.5cM (20Mb) region. Interestingly, five additional independent studies in rats and four independent studies in humans have reported genetic linkage for BP control by regions homologous to QTL1b. To view the overall renal transcriptional topography of the positional candidate genes for this QTL, we sought a comparative gene expression profiling between a congenic strain containing QTL1b and control S rats by employing: (1) a saturated QTL1b interval specific oligonucleotide array, and (2) a whole genome cDNA microarray representing 20,465 unique genes that are positioned outside the QTL. Results indicated that 19 out of the 231 positional candidate genes for this QTL are differentially expressed between the two strains tested. Surprisingly, over 1,500 genes outside of QTL1b were differentially expressed between the two rat strains. Integrating the results from the two approaches revealed at least one complex network of transcriptional control initiated by the positional candidate Nr2f2. This network appears to account for the majority of gene expression differences occurring outside of the QTL interval. Further substitution mapping is currently underway to test the validity of each of these differentially expressed positional candidate genes. These results demonstrate the importance of using a saturated oligonucleotide array for identifying and prioritizing differentially expressed positional candidate genes of a BP QTL. Pairs of Cy5 and Cy3 labeled targets were co-hybridized onto either the oligonucleotide microarray or a custom TIGR rat cDNA array consisting of 26,401 probe elements representing 20,465 unique non-QTL1b genes. A âflip-dyeâ design was used as the experimental method of choice to account for potential dye-bias labeling effects. Seven âflip dyeâ normalized files are submitted for the oligonucleotide array and twelve individual hybridizations are submitted for the cDNA array.