Replacement of α1-Na-K-ATPase of Dahl rats by Milan rats lowers blood pressure but does not affect its activity

2001 ◽  
Vol 7 (2) ◽  
pp. 171-177 ◽  
Author(s):  
SERGEI N. ORLOV ◽  
JULIE DUTIL ◽  
PAVEL HAMET ◽  
ALAN Y. DENG
Keyword(s):  
Blood Pressure ◽  
Quantitative Trait Locus ◽  
Atpase Activity ◽  
Quantitative Trait ◽  
Chromosome Region ◽  
Homologous Region ◽  
Congenic Strains ◽  
Baseline Activity ◽  
Trait Locus

Both linkage and use of congenic strains have shown that a chromosome region near the gene for the Na-K-ATPase α1-subunit ( Atp1a1) contained a quantitative trait locus (QTL) for blood pressure (BP). Currently, two congenic strains, designated S.M5 and S.M6, were made by replacing a segment of the Dahl salt-sensitive SS/Jr (S) rat by the homologous region of the Milan normotensive rat (MNS). In S.M5, the gene for Atp1a1 is from the MNS strain; whereas in S.M6, Atp1a1 is from the S strain. The baseline activity of the α1-Na-K-ATPase and its stoichiometry were evaluated by an assay of ouabain-sensitive inwardly and outwardly directed 86Rb and 22Na fluxes in erythrocytes. The two congenic strains showed a similar BP, but both had a BP lower than that of S rats ( P < 0.0001). Neither the α1-Na-K-ATPase activity nor its stoichiometry was affected by the substitution of the Atp1a1 alleles of S by those of MNS. Thus the BP-lowering effects observed in S.M5 and S.M6 could not be attributed to the α1-Na-K-ATPase activity or its stoichiometry. Atp1a1 is not supported as a candidate to be a BP QTL.

Complete and overlapping congenics proving the existence of a quantitative trait locus for blood pressure on Dahl rat chromosome 17

2005 ◽  
Vol 21 (1) ◽  
pp. 112-116 ◽  
Author(s):  
Myrian Grondin ◽  
Vasiliki Eliopoulos ◽  
Raphaelle Lambert ◽  
Yishu Deng ◽  
Anita Ariyarajah ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Quantitative Trait Locus ◽  
Quantitative Trait ◽  
Congenic Strain ◽  
Chromosome 17 ◽  
Congenic Strains ◽  
Genome Wide ◽  
A Genome ◽  
Trait Locus ◽  
Negative Controls

Linkage studies suggested that a quantitative trait locus (QTL) for blood pressure (BP) was present in a region on chromosome 17 (Chr 17) of Dahl salt-sensitive (DSS) rats. A subsequent congenic strain targeting this QTL, however, could not confirm it. These conflicting results called into question the validity of localization of a QTL by linkage followed by the use of a congenic strain made with an incomplete chromosome coverage. To resolve this issue, we constructed five new congenic strains, designated C17S.L1 to C17S.L5, that completely spanned the ±2 LOD confidence interval supposedly containing the QTL. Each congenic strain was made by replacing a segment of the DSS rat by that of the normotensive Lewis (LEW) rat. The only section to be LL homozygous is the region on Chr 17 specified in a congenic strain, as evidenced by a total genome scan. The results showed that BPs of C17S.L1 and C17S.L2 were lower ( P < 0.04) than that of DSS rats. In contrast, BPs of C17S.L3, C17S.L4, and C17S.L5 were not different ( P > 0.6) from that of DSS rats. Consequently, a BP QTL must be located in an interval of ∼15 cM shared between C17S.L1 and C17S.L2 and unique to them both, as opposed to C17S.L3, C17S.L4, and C17S.L5. The present study illustrates the importance of thorough chromosome coverage, the necessity for a genome-wide screening, and the use of “negative” controls in physically mapping a QTL by congenic strains.

scholarly journals Defining a rat blood pressure quantitative trait locus to a <81.8 kb congenic segment: comprehensive sequencing and renal transcriptome analysis

2010 ◽  
Vol 42A (2) ◽  
pp. 153-161 ◽  
Author(s):  
K. Gopalakrishnan ◽  
J. Saikumar ◽  
C. G. Peters ◽  
S. Kumarasamy ◽  
P. Farms ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Quantitative Trait Locus ◽  
Transcriptome Analysis ◽  
Quantitative Trait ◽  
Congenic Strain ◽  
Association Studies ◽  
Chromosome 9 ◽  
Genome Wide Association Studies ◽  
Congenic Strains ◽  
Trait Locus

Evidence from multiple linkage and genome-wide association studies suggest that human chromosome 2 (HSA2) contains alleles that influence blood pressure (BP). Homologous to a large segment of HSA2 is rat chromosome 9 (RNO9), to which a BP quantitative trait locus (QTL) was previously mapped. The objective of the current study was to further resolve this BP QTL. Eleven congenic strains with introgressed segments spanning <81.8 kb to <1.33 Mb were developed by introgressing genomic segments of RNO9 from the Dahl salt-resistant (R) rat onto the genome of the Dahl salt-sensitive (S) rat and tested for BP. The congenic strain with the shortest introgressed segment spanning <81.8 kb significantly lowered BP of the hypertensive S rat by 25 mmHg and significantly increased its mean survival by 45 days. In contrast, two other congenic strains had increased BP compared with the S. We focused on the <81.8 kb congenic strain, which represents the shortest genomic segment to which a BP QTL has been mapped to date in any species. Sequencing of this entire region in both S and R rats detected 563 variants. The region did not contain any known or predicted rat protein coding genes. Furthermore, a whole genome renal transcriptome analysis between S and the <81.8 kb S.R congenic strain revealed alterations in several critical genes implicated in renal homeostasis. Taken together, our results provide the basis for future studies to examine the relationship between the candidate variants within the QTL region and the renal differentially expressed genes as potential causal mechanisms for BP regulation.

scholarly journals Localization of a blood pressure QTL on rat chromosome 1 using Dahl rat congenic strains

1999 ◽  
Vol 1 (3) ◽  
pp. 119-125 ◽  
Author(s):  
YASSER SAAD ◽  
MICHAEL R. GARRETT ◽  
SOON JIN LEE ◽  
HOWARD DENE ◽  
JOHN P. RAPP
Keyword(s):  
Blood Pressure ◽  
Quantitative Trait Locus ◽  
Quantitative Trait ◽  
Congenic Strain ◽  
Chromosome 1 ◽  
Congenic Strains ◽  
Salt Hypertension ◽  
Trait Locus

Saad, Yasser, Michael R. Garrett, Soon Jin Lee, Howard Dene, and John P. Rapp. Localization of a blood pressure QTL on rat chromosome 1 using Dahl rat congenic strains. Physiol. Genomics 1: 119–125, 1999.—We previously reported that markers on rat chromosome 1 are genetically linked to blood pressure in an F2 population derived from Dahl salt hypertension-sensitive (S) and Lewis (LEW) rats. Because there was evidence for more than one blood pressure quantitative trait locus (QTL) on chromosome 1, an initial congenic strain introgressing a large 118-centimorgan (cM) segment of LEW chromosome 1 into the S background had been constructed. This initial congenic strain had a reduced blood pressure compared with S rats, proving the existence of a blood pressure QTL, but not giving a good localization of the QTL. In the present work a series of five overlapping congenic substrains were produced from the original congenic strain in order to localize a blood pressure QTL to a 25-cM region near the center of chromosome 1. The congenic substrains also ruled out the Sa locus as a blood pressure QTL in the S vs. LEW comparison because the Sa locus was contained in a congenic substrain that did not alter blood pressure.

A quantitative trait locus for aortic smooth muscle cell number acting independently of blood pressure: implicating the angiotensin receptor AT1B gene as a candidate

2005 ◽  
Vol 21 (3) ◽  
pp. 362-369 ◽  
Author(s):  
Julie Dutil ◽  
Vasiliki Eliopoulos ◽  
Éve-Lyne Marchand ◽  
Alison M. Devlin ◽  
Johanne Tremblay ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Quantitative Trait Locus ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Quantitative Trait ◽  
Cell Number ◽  
Aortic Smooth Muscle Cell ◽  
Aortic Smooth Muscle ◽  
Congenic Strains ◽  
Trait Locus

Vascular hyperplasia may be involved in the remodeling of vasculature. It was unknown whether there were genetic determinants for aortic smooth muscle cell number (SMCN) and, if so, whether they acted independently of those for blood pressure (BP). To unravel this issue, we utilized congenic strains previously constructed for BP studies. These strains were made by replacing various chromosome 2 segments of the Dahl salt-sensitive (S) rat with those of the Milan normotensive rat (MNS). We measured and compared SMCN in aortic cross-sectional areas and BPs of these strains. Consequently, a quantitative trait locus (QTL) for SMCN was localized to a chromosome region not containing a BP QTL, but harboring the locus for the angiotensin II receptor AT1B ( Agtr1b). Agtr1b became a candidate for the SMCN QTL because 1) two significant mutations were found in the coding region between S and all congenic strains possessing the MNS alleles, and 2) contractile responses to angiotensin II were significantly and selectively reduced in congenic rats harboring the MNS alleles of the SMCN QTL compared with S rats. The current investigation presents the first line of evidence that a QTL for aortic SMCN exists, and it acts independently of QTLs for BP. The relevant congenic strains developed therein potentially provide novel mammalian models for the studies of vascular remodeling disorders.

scholarly journals Successful Isolation of a Rat Chromosome 1 Blood Pressure Quantitative Trait Locus in Reciprocal Congenic Strains

Hypertension ◽  
1998 ◽  
Vol 32 (4) ◽  
pp. 639-646 ◽  
Author(s):  
Simon A. Frantz ◽  
Michael Kaiser ◽  
Sheila M. Gardiner ◽  
Dominique Gauguier ◽  
Madeleine Vincent ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Quantitative Trait Locus ◽  
Quantitative Trait ◽  
Chromosome 1 ◽  
Congenic Strains ◽  
Successful Isolation ◽  
Trait Locus

Quantitative trait locus for seizure susceptibility on mouse chromosome 5 confirmed with reciprocal congenic strains

2007 ◽  
Vol 31 (3) ◽  
pp. 458-462 ◽  
Author(s):  
Thomas N. Ferraro ◽  
George G. Smith ◽  
Candice L. Schwebel ◽  
Falk W. Lohoff ◽  
Patrick Furlong ◽  
...  
Keyword(s):  
Quantitative Trait Locus ◽  
Quantitative Trait ◽  
Genetic Background ◽  
Seizure Threshold ◽  
Maximal Electroshock ◽  
Seizure Susceptibility ◽  
Chromosome 5 ◽  
Congenic Strains ◽  
Combining Data ◽  
Trait Locus

Multiple quantitative trait locus (QTL) mapping studies designed to localize seizure susceptibility genes in C57BL/6 (B6, seizure resistant) and DBA/2 (D2, seizure susceptible) mice have detected a significant effect originating from midchromosome 5. To confirm the presence and refine the position of the chromosome 5 QTL for maximal electroshock seizure threshold (MEST), reciprocal congenic strains between B6 and D2 mice were created by a DNA marker-assisted backcross breeding strategy and studied with respect to changes in MEST. A genomic interval delimited by marker D5Mit75 (proximal to the acromere) and D5Mit403 (distal to the acromere) was introgressed for 10 generations. A set of chromosome 5 congenic strains produced by an independent laboratory was also studied. Comparison of MEST between congenic and control (parental genetic background) mice indicates that genes influencing this trait were captured in all strains. Thus, mice from strains having D2 alleles from chromosome 5 on a B6 genetic background exhibit significantly lower MEST compared with control littermates, whereas congenic mice harboring B6 chromosome 5 alleles on a D2 genetic background exhibit significantly higher MEST compared with control littermates. Combining data from all congenic strains, we conclude that the gene(s) underlying the chromosome 5 QTL for MEST resides in the interval between D5Mit108 (26 cM) and D5Mit278 (61 cM). Generation of interval-specific congenic strains from the primary congenic strains described here may be used to achieve high-resolution mapping of the chromosome 5 gene(s) that contributes to the large difference in seizure susceptibility between B6 and D2 mice.

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

2002 ◽  
Vol 8 (2) ◽  
pp. 81-86 ◽  
Author(s):  
Michael R. Garrett ◽  
John P. Rapp
Keyword(s):  
Blood Pressure ◽  
Quantitative Trait Locus ◽  
Quantitative Trait ◽  
Congenic Strain ◽  
Major Effect ◽  
Large Region ◽  
Chromosome 5 ◽  
Low Blood Pressure ◽  
Trait Locus

Previously we reported the construction of a congenic strain, S.LEW( 5 ), 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. The congenic strain included a blood pressure quantitative trait locus (QTL). In the present work, a series of nine congenic substrains were constructed from S.LEW( 5 ) which defined two closely linked blood pressure QTL in the region previously thought to contain only one. LEW low-blood-pressure alleles at both QTL were required for a major effect on blood pressure. Neither LEW allele alone had a significant effect on blood pressure. The two QTL were localized to regions 6.3 and 4.6 cM, and these were 1.0 cM apart.

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