Published online before print February 12, 2009, doi: 10.1161/CIRCGENETICS.108.809509
Original Articles |
Genome-Wide Identification of Allelic Expression in Hypertensive Rats
From the Institute of Molecular Medicine (R.I.D., C.A.H., R.J.B., E.B., M.F., P.A.D.) and Human Genetics Center (M.L.G., E.B.), University of Texas Health Science Center, Houston, Tex.
Correspondence to Peter A. Doris, PhD, Institute of Molecular Medicine, University of Texas Health Science Center, 2121 Holcombe Blvd, Houston, TX 77030. E-mail peter.a.doris{at}uth.tmc.edu
Received July 23, 2008; accepted January 26, 2009.
Background— Identification of genes involved in complex cardiovascular disease traits has proven challenging. Inbred animal models can facilitate genetic studies of disease traits. The spontaneously hypertensive rat (SHR) is an inbred model of hypertension that exists in several closely related but genetically distinct lines.
Methods and Results— We used renal gene-expression profiling across 3 distinct SHR lines to identify genes that show different expression in SHR than in the genetically related normotensive control strain, Wistar-Kyoto. To ensure robust discovery of genes showing SHR-specific expression differences, we considered only those genes in which differential expression is replicated in multiple animals of each of multiple hypertensive rat lines at multiple time points during the ontogeny of hypertension. Mutation analysis was performed on the identified genes to uncover allelic variation. We identified those genes in which all SHR lines share a single allele of the gene when normotensive controls (Wistar-Kyoto) have fixed the alternative allele. We then identified which of the differentially expressed genes show expression that is controlled by the alleleic variation present in and around the gene. Allelic expression was demonstrated by observing the effect on gene expression of alleles inherited in the freely segregating F2 progeny of a cross between SHR and Wistar-Kyoto animals.
Conclusions— The result of these studies is the identification of several genes (Ptprj, Ela1, Dapk-2, and Gstt2) in which each of 4 SHR lines examined have fixed the same allele and in which each of 2 Wistar-Kyoto lines have a contrasting allele for which the inherited allele influences the level of gene expression. We further show that alleles of these genes lie in extensive haplotype blocks that have been inherited identical by descent in the hypertensive lines.
Key Words: genetic hypertension • spontaneously hypertensive rat • gene expression • kidney • candidate genes • gene array • haplotype
CLINICAL PERSPECTIVE
The online-only Data Supplement is available at http://circgenetics.ahajournals.org/cgi/content/full/CIRCGENETICS.108.809509/DC1.
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