Dissecting Epistatic QTL for Blood Pressure in Rats: Congenic Strains versus Heterogeneous Stocks, a Reality Check.

Advances in molecular genetics have provided well-defined physical genetic maps and large numbers of genetic markers for both model organisms and humans. It is now possible to gain a fundamental understanding of the genetic architecture underlying quantitative traits, of which blood pressure (BP) is an important example. This review emphasizes analytical techniques and results obtained using the Dahl salt-sensitive (S) rat as a model of hypertension by presenting results in detail for three specific chromosomal regions harboring genetic elements of increasing complexity controlling BP.

Theoretical model for gene-gene, gene-environment, and gene-sex interactions based on congenic-strain analysis of blood pressure in Dahl salt-sensitive rats.

There is a significant literature describing quantitative trait loci (QTL) controlling blood pressure (BP) in the Dahl salt-sensitive (S) rat. In studies to identify the genes underlying BP QTL it has been common practice to place chromosomal segments from low BP strains on the genetic background of the S rat and then reduce the congenic segments by substitution mapping. The present work suggests a model to simulate genetic interactions found using such congenic strains.

A mutation in the start codon of γ-crystallin D leads to nuclear cataracts in the Dahl SS/Jr-Ctr strain.

Cataracts are a major cause of blindness. The most common forms of cataracts are age- and UV-related and develop mostly in the elderly, while congenital cataracts appear at birth or in early childhood. The Dahl salt-sensitive (SS/Jr) rat is an extensively used model of salt-sensitive hypertension that exhibits concomitant renal disease.

Use of contiguous congenic strains in analyzing compound QTLs.

Genetic analysis of polygenic traits in rats and mice has been very useful for finding the approximate chromosomal locations of the genes causing quantitative phenotypic variation, so-called quantitative trait loci (QTL). Further localization of the causative genes and their ultimate identification has, however, proven to be slow and frustrating. A major technique for gene identification in such models utilizes series of congenic strains with progressively smaller chromosomal segments introgressed from one inbred strain into another inbred strain.

Positional identification of variants of Adamts16 linked to inherited hypertension.

A previously reported blood pressure (BP) quantitative trait locus on rat Chromosome 1 was isolated in a short congenic segment spanning 804.6 kb. The 804.

Characterization of blood pressure and renal function in chromosome 5 congenic strains of Dahl S rats.

The present study examined whether transfer of overlapping regions of chromosome 5 that include (4A+) or exclude the cytochrome P-450 (CYP) 4A genes from the Lewis rat alters the renal production of 20-hydroxyeicosatetraenoic acid (20-HETE) and/or the development of hypertension in congenic strains of Dahl salt-sensitive (S) rats. The expression of CYP4A protein and the production of 20-HETE in the renal outer medulla was greater in the 4A+ congenic strain than the levels seen in S rats or in overlapping control congenic strains that exclude the CYP4A region. Mean arterial pressure (MAP) rose from 122 +/- 2 to 190 +/- 7 mmHg in S rats and from 119 +/- 2 and 123 +/- 2 to 189 +/- 7 and 187 +/- 3 mmHg in the two control congenic strains fed an 8.

Transcriptional profiling with a blood pressure QTL interval-specific oligonucleotide array.

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).

Locating a blood pressure quantitative trait locus within 117 kb on the rat genome: substitution mapping and renal expression analysis.

Previously, a blood pressure (BP) quantitative trait locus (QTL) on rat chromosome 9 (RNO9) was localized to a <2.4 cM interval using congenic strains generated by introgressing segments of RNO9 from the Dahl salt-resistant (R) rat into the background of the Dahl salt-sensitive (S) rat. Renal gene expression using Affymetrix gene chips was profiled on S and a congenic strain spanning the 2.

Substitution mapping of a blood pressure quantitative trait locus to a 2.73 Mb region on rat chromosome 1.

Objective: To improve the localization of a blood pressure quantitative trait locus (BP QTL) on rat chromosome (RNO) 1.

Methods: Congenic substrains were derived from the progenitor congenic strains S.LEW(D1Mco4X1) and S.

Time-course genetic analysis of albuminuria in Dahl salt-sensitive rats on low-salt diet.

The Dahl salt-sensitive hypertensive (S) rat develops albuminuria early in life even on a low-salt diet. In contrast, the spontaneously hypertensive rat (SHR) is highly resistant to developing albuminuria despite elevated BP. An F(1) hybrid of S and SHR showed a low urinary albumin excretion (UAE) and low urinary protein excretion (UPE) similar to SHR, i.

Defining the blood pressure QTL on chromosome 7 in Dahl rats by a 177-kb congenic segment containing Cyp11b1.

Previously we reported that there is a blood pressure quantitative trait locus (QTL) on rat Chromosome (Chr) 7 seen when comparing Dahl salt-sensitive (S) rats and Dahl salt-resistant (R) rats. Evidence was also presented that this QTL was due to genetic variants in the adrenal steroidogenic enzyme 11beta-hydroxylase ( Cyp11b1). A series of congenic strains supported this contention.

Localization of a blood pressure QTL to a 2.4-cM interval on rat chromosome 9 using congenic strains.

A blood pressure (BP) quantitative trait locus (QTL) was previously found on rat chromosome 9 using Dahl salt-sensitive (S) and Dahl salt-resistant (R) rats. A congenic strain, S.R(chr9), constructed by introgressing an R chromosomal segment into the S background, previously proved the existence of a BP QTL in a large 34.

Identification of blood pressure quantitative trait loci that differentiate two hypertensive strains.

Objective: To describe genetic loci that differentiate blood pressures in two genetically hypertensive strains, the Dahl salt-sensitive (S) rat and the Albino Surgery (AS) rat.

Methods: A genome scan was performed using 222 genetic markers on an F2 population derived from two hypertensive strains, S and AS. The F2 rats were fed 8% NaCl for 5 weeks before blood pressure measurements were taken.

Two closely linked interactive blood pressure QTL on rat chromosome 5 defined using congenic Dahl rats.

Previously we reported the construction of a congenic strain, S.LEW, spanning a large region of rat chromosome 5. The Lewis (LEW) strain was the donor, and the Dahl salt-sensitive (S) strain was the recipient.

Multiple blood pressure QTL on rat Chromosome 2 defined by congenic Dahl rats.

Linkage analysis previously demonstrated a blood pressure quantitative trait locus (QTL) on rat Chromosome 2 (Chr 2) in crosses utilizing Dahl salt-sensitive (S) rats. The present work dissects this QTL by using congenic strains in which segments of Chr 2 from Wistar Kyoto rats (WKY) are placed on the S genetic background. Two distinct QTLs were found where one QTL was anticipated.