Interval mapping and congenic strains for a blood pressure QTL on rat Chromosome 13

Zhang, Q. Y.; Dene, Howard; Deng, Alan Y.; Garrett, Michael R.; Jacob, Howard J.; Rapp, John P.

doi:10.1007/s003359900528

Cited by 52 publications

(51 citation statements)

References 33 publications

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“…Previous attempts [34][35][36][37][38][39][40][41][42] at isolating blood pressure QTLs in congenic strains have mostly, apart from a few exceptions, 34 -35 involved transferring the region in a single direction. In the majority of cases, this has been from the normotensive strain into the hypertensive strain, on the assumption that demonstrating a decrease in blood pressure would be easier than an increase.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 1998

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Abstract-Linkage analyses in experimental crosses of hypertensive and normotensive rats have strongly suggested the presence of a quantitative trait locus (QTL) influencing blood pressure on rat chromosome 1, at or near the Sa gene. To confirm the presence of such a locus and move toward identification of the causative gene, we have developed, through targeted breeding over 10 generations using an Sa gene polymorphism to select breeders at each generation, 2 congenic strains, 1 containing a segment of spontaneously hypertensive rat (SHR) chromosome 1 in a Wistar-Kyoto rat (WKY) genetic background (WKY.SHR-Sa), and the other a segment of WKY chromosome 1 in an SHR background (SHR.WKY-Sa). WKY.SHR-Sa contains at least Ϸ26 cM of SHR chromosome 1, between markers mD7mit206 and D1Mit2 (and including the SHR allele of the Sa gene), and SHR.WKY-Sa carries at least Ϸ15 cM of WKY chromosome 1, between mD7mit206 and D1Wox34 (and including the WKY allele of the Sa gene). Blood pressure of WKY.SHR-Sa rats measured at 16, 20, and 25 weeks of age was significantly higher than that of WKY, whereas blood pressure of SHR.WKY-Sa rats was significantly lower than that of SHR. At 25 weeks, the mean differences in systolic and diastolic blood pressure between WKY.SHR-Sa and WKY were ϩ11.5 mm Hg (Pϭ0.001) and ϩ11.6 mm Hg mm Hg (PϽ0.001), respectively. The corresponding differences between SHR.WKy-Sa and SHR were Ϫ11.3 mm Hg (Pϭ0.002) and Ϫ9.1 mm Hg (Pϭ0.005), respectively. The differences represent about one fifth of the blood pressure difference between SHR and WKY. Renal Sa mRNA levels in the congenic strains reflected their Sa allele with a high level in WKY.SHR-Sa and a low level in SHR.WKY-Sa, consistent with previous data suggesting that the level of Sa expression is primarily determined by cis-acting elements in or near the Sa gene. Our results show that we have successfully isolated a major rat chromosome 1 blood pressure QTL located in the vicinity of the Sa gene in reciprocal congenic strains derived from SHR and WKY. The strains can now be used to further define the region containing the QTL and also to characterize intermediary mechanisms through which the QTL influences blood pressure. In addition, comparison of the regions introgressed in our congenic strains with the location of the peak LOD score for chromosome 1 blood pressure QTL in second filial generation progeny derived from our SHRϫWKY cross suggests that there may be at least 1 further QTL influencing blood pressure on this rat chromosome. (Hypertension. 1998;32:639-646.)

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Section: Discussionmentioning

confidence: 99%

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

et al. 1998

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“…On the other hand, DiPaolo et al 25 found that transfer of a larger region from Dahl R rats lowered blood pressure by 25 mm Hg and had no effect on PRA in congenic SS rats. More recently, Zhang et al 26 localized this antihypertensive gene to the interval between Syt 2 and D13 Mit108, which excluded the renin gene. In the present study, transferring the entire chromosome 13 from the BN/Mcw into the Dahl S genetic background increased PRA.…”

Section: Chromosome 13 and The Ss/mcw Ratmentioning

confidence: 99%

Brown Norway Chromosome 13 Confers Protection From High Salt to Consomic Dahl S Rat

et al. 2001

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Abstract-Consomic rats (SS.BN13), in which chromosome 13 from normotensive inbred Brown Norway rats from a colony maintained at the Medical College of Wisconsin (BN/Mcw) was introgressed into the background of Dahl salt-sensitive (SS/Mcw) rats, also maintained in a colony at the Medical College of Wisconsin, were bred. The present studies determined the mean arterial pressure (MAP) responses to salt and renal and peripheral vascular responses to norepinephrine and angiotensin II; 24-hour protein excretion and histological analyses were used to assess renal pathology in rats that received a high salt (4% NaCl) diet for 4 weeks. MAP of rats measured daily during the fourth week averaged 170Ϯ3. Key Words: hypertension, sodium dependent Ⅲ rats Ⅲ sodium Ⅲ chromosome 13 Ⅲ blood pressure Ⅲ consomic D ahl salt-sensitive (SS) rats exhibit many of the abnormalities that occur with hypertension in African Americans, 1,2 including blood pressure salt sensitivity, 3,4 insulin resistance, 5 and hyperlipidemia. 6 They have a low renin form of hypertension 3 that is refractory to treatment with converting enzyme inhibitors 7,8 and is effectively treated with diuretics. 7,9 Moreover, these rats rapidly develop severe progressive hypertensive glomerulosclerosis that leads to end-stage renal disease, as is commonly also seen in African Americans with hypertension. 9,10 For these reasons, insights and findings of the studies in SS rats may provide valuable clues to the genetic basis of hypertension and related traits in African Americans.The explosion of genomic resources in the rat has led to remarkable advances in identifying the regions of the rat genome that contain blood pressure quantitative trait loci (QTLs), as reviewed by Hamet et al, 11 Zicha and Kunes,12 and Rapp. 13 We have recently completed a linkage analysis based on an intercross of SS and Brown Norway (BN) salt-insensitive rats in which total genome scans using 238 polymorphic markers, evenly distributed throughout the genome, were scored. All F2 rats (113 males and 99 females) were extensively phenotyped for 239 measured or derived traits. This linkage analysis indicated the existence of a broad range of traits related to pathways of functional importance in hypertension that mapped to 19 chromosomes. 14,15 The development of congenic strains has been used by a number of laboratories, including our own, to confirm and narrow QTL regions of interest. 16,17 Despite the usefulness of congenic rat models in the deconstruction of complex traits and the identification of candidate genes, this work has been hampered by the time and expense involved in producing these informative recombinant rats. Even with the use of markerassisted selection to identify the rats best suited for backcrossing in generations, 18 we have found that the process of developing an inbred congenic strain requires nearly 2 years and 5 to 7 generations of backcrosses to achieve rats that are sufficiently isogenic to make meaningful comparisons.To overcome these limitations, we have been developing ...

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“…Clearly, this is speculative at this stage, but the presence of clustered QTL is a situation frequently encountered in QTL mapping studies. [13][14][15][16] One way to prove the existence of these two putative QTL would be the construction of congenic and subcongenic strains differing in this part of the genome. 17 Another explanation for the lack of linkage with the other measures of activity may be the relatively small number of F2 progeny tested, especially from the BN Â WKY F2 cross.…”

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Further dissection of a genomic locus associated with behavioral activity in the Wistar–Kyoto hyperactive rat, an animal model of hyperkinesis

Moisan

Llamas

et al. 2003

Mol Psychiatry

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Molecular genetic studies of attention-deficit hyperactivity disorder (ADHD) are a major focus of current research since this syndrome has been shown to be highly heritable. 1 Our approach has been to search for quantitative trait loci (QTL) in a genetic animal model of hyperkinesis, the Wistar-Kyoto hyperactive (WKHA) rat, by a whole-genome scan analysis. In a previous article, we reported the detection of a major QTL associated with behavioral activity in an F2 cross between WKHA and Wistar-Kyoto (WKY) rat strains.2 Here, we extend our analysis of this cross by adding new genetic markers, now defining a 10 cM interval on rat chromosome 8 associated with ambulatory and exploratory activities. Then we present a replication of this QTL detection, at least for exploratory activity, by a new genetic mapping analysis of an activity QTL in an F2 cross between the WKHA and Brown Norway (BN) rat strains. Overall, the results provide compelling evidence for the presence of gene(s) influencing activity at this locus. The QTL interval has been refined such that the human orthologous region could be defined and tested in human populations for association with ADHD. Ultimately, the improved dissection of this genomic locus should allow the identification of the causal genes. Molecular Psychiatry (2003Psychiatry ( ) 8, 348-352. doi:10.1038 With the development of a dense genetic map of the rat genome, [3][4][5][6] we were able to test many new microsatellite markers between Wistar-Kyoto hyperactive (WKHA) and Wistar-Kyoto (WKY) rat strains. In total, we tested 142 markers between D8Mgh4 and the telomere of chromosome 8. Only five markers were found to be polymorphic, showing the particularly high level of homology in this region of the genome between the two strains. Our data set was reanalyzed for genetic linkage using these new markers using MAPMAKER program 7 and the results are presented in Figure 1. Maximum LOD score was obtained for ambulatory activity over 1 h in activity cages, LOD ¼ 15.9 with 35% of the phenotypic variance explained by this quantitative trait loci (QTL), with a rise of 7 LOD units compared to our previous report.2 The confidence interval of this QTL is now narrowed to B10 cM between D8Mit15 and ACPH markers. A similar increase was observed for the other traits related to activity including exploratory activity in an open field (LOD maximum ¼ 9.3, 21.6% of the phenotypic variance explained). However, in particular for the latter trait, one can observe two peaks in the LOD score curve. This observation can be interpreted in different ways, one of them being the presence of two linked QTLs. 7Because of the scarcity of polymorphic markers between WKHA and WKY strains, we decided to map activity QTL in a more polymorphic cross. Because the Brown Norway (BN) rat is the most distant genetically from the Wistar-derived strains, 8 we compared its behavioral activity to WKHA and WKY rats. The three parental strains were assessed for their motor activity behavior at approximately 8 and 13 weeks of age. As illu...

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Interval mapping and congenic strains for a blood pressure QTL on rat Chromosome 13

Cited by 52 publications

References 33 publications

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

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

Brown Norway Chromosome 13 Confers Protection From High Salt to Consomic Dahl S Rat

Further dissection of a genomic locus associated with behavioral activity in the Wistar–Kyoto hyperactive rat, an animal model of hyperkinesis

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