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Alan Y Deng - One of the best experts on this subject based on the ideXlab platform.

  • epistasis not numbers regulates functions of clustered Dahl Rat quantitative trait loci applicable to human hypertension
    Hypertension, 2005
    Co-Authors: Sophie Charron, Raphaelle Lambert, Vasiliki Eliopoulos, Chenda Duong, Annie Menard, Alan Y Deng
    Abstract:

    Quantitative trait loci (QTLs) for blood pressure (BP) were found on chromosome 10 of Dahl salt-sensitive Rats and are potentially important to human essential hypertension. But their identities and how they influence BP together were not known. Presently, we first fine mapped existing QTLs, C10QTL1, C10QTL2, and C10QTL3, by constructing congenic strains. In the process, a new QTL, C10QTL4, was identified. Because the intervals harboring C10QTL1 and C10QTL4 contain a maximum of 16 and 10 possible genes, respectively, a limited number of specific gene targets has been identified to be QTLs residing in human homologous regions on chromosome 17. Moreover, because none of these candidates encodes a gene known to influence BP, the 2 QTLs will represent novel genes for BP regulations. Second, we used congenic strains with QTL combinations to analyze the interactions between the QTLs. Consequently, a double combination of C10QTL4 and C10QTL1 possessed the same BP as each of the 2 QTLs alone. BP of a triple combination of C10QTL4, C10QTL1, and C10QTL3 was not different from BP of the C10QTL4 and C10QTL1 double combination. These results demonstRate that C10QTL4, C10QTL1, and C10QTL3 are epistatic to one another in their BP effects. In contrast, when adding C10QTL2 into the triple formation of the 3 QTLs above to create a quadruple QTL combination, BP increased proportionately, indicating that C10QTL2 acts independently of C10QTL4, C10QTL1, and C10QTL3. The epistatic and additive interactions uncovered in the animal model will help elucidate similar interactions playing a role in human essential hypertension.

  • multiple quantitative trait loci for blood pressure interacting epistatically and additively on Dahl Rat chromosome 2
    Hypertension, 2005
    Co-Authors: Julie Dutil, Vasiliki Eliopoulos, Johanne Tremblay, Pavel Hamet, Sophie Charron, Alan Y Deng
    Abstract:

    Our previous work demonstRated 2 quantitative trait loci (QTLs), C2QTL1 and C2QTL2, for blood pressure (BP) located on chromosome (Chr) 2 of Dahl salt-sensitive (DSS) Rats. However, for a lack of markers, the 2 congenic strains delineating C2QTL1 and C2QTL2 could not be sepaRated. The position of the C2QTL1 was only inferred by comparing 2 congenic strains, one having and another lacking a BP effect. Furthermore, it was not known how adjacent QTLs would interact with one another on Chr 2. In the current investigation, first, a critical chromosome marker was developed to sepaRate 2 C2QTLs. Second, a congenic substrain was created to cover a chromosome fragment thought to harbor C2QTL1. Finally, a series of congenic strains was produced to systematically and comprehensively cover the entire Chr 2 segment containing C2QTL2 and other regions previously untested. Consequently, a total of 3 QTLs were discovered, with C2QTL3 located between C2QTL1 and C2QTL2. C2QTL1, C2QTL2, and C2QTL3 reside in chromosome segments of 5.7 centiMorgan (cM), 3.5 cM, and 1.5 cM, respectively. C2QTL1 interacted epistatically with either C2QTL2 or C2QTL3, whereas C2QTL2 and C2QTL3 showed additive effects to each other. These results suggest that BP QTLs closely linked in a segment interact epistatically and additively to one another on Chr 2.

  • complete and overlapping congenics proving the existence of a quantitative trait locus for blood pressure on Dahl Rat chromosome 17
    Physiological Genomics, 2005
    Co-Authors: Myrian Grondin, Julie Dutil, Raphaelle Lambert, Vasiliki Eliopoulos, Sophie Charron, Anita Ariyarajah, Yishu Deng, Myriam Moujahidine, Alan Y Deng
    Abstract:

    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 0.6) 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.

  • dissecting quantitative trait loci into opposite blood pressure effects on Dahl Rat chromosome 8 by congenic strains
    Journal of Hypertension, 2004
    Co-Authors: Anita Ariyarajah, Ana Palijan, Julie Dutil, Kalyani Prithiviraj, Yishu Deng, Alan Y Deng
    Abstract:

    Objective Our previous linkage analyses showed that there was likely a quantitative trait locus (QTL) for blood pressure (BP) on chromosome 8 (Chr 8) in the strain comparison between the Dahl salt-sensitive (S) and the Lewis (LEW) Rats. The current work is to delineate the chromosome interval harboring this QTL by using congenic strains with different chromosome substitutions. Methods Two congenic strains were produced by replacing different segments of the S Rats with the homologous segments of the LEW Rats. A genome-wide marker screening was utilized to acceleRate this process. The two strains geneRated are designated as C8S.L1 and C8S.L2, respectively. BPs of the Rats were measured by telemetry. Results C8S.L1 showed a BP lower than that of S Rats. In contrast, C8S.L2 did not have chromosome overlaps with C8S.L1, but unexpectedly, exhibited a BP-raising effect, higher than that of S Rats. Conclusion There are at least two QTLs present in a section of Chr 8 that possess opposite BP effects. The current congenic work reveals not only the presence of QTLs, but the complexity of QTLs on BP. The novel congenic strain with hypertension more severe than S provides a new model for studies in elucidating physiological mechanisms controlling BP.

  • comprehensive congenic coverage revealing multiple blood pressure quantitative trait loci on Dahl Rat chromosome 10
    Hypertension, 2003
    Co-Authors: Ana Palijan, Julie Dutil, Raphaelle Lambert, Zsuzsa Sivo, Alan Y Deng
    Abstract:

    Chromosome mapping based on congenic strains can restrict quantitative trait loci (QTLs) for blood pressure (BP) into small intervals that are otherwise indistinguishable in linkage analysis. Also, congenic strains can be created to test a candidate gene to be a BP QTL. Taking full advantage of these features, we produced 10 congenic strains by replacing various segments of chromosome (Chr) 10 of the Dahl salt-sensitive (DSS) Rat with those of the Lewis (LEW) Rat. These strains were made to systematically cover an entire section of Chr 10. Three of the strains were designed to narrow the intervals that harbor previously mapped QTL1 and QTL2. Two of the strains were designed for the express purpose of testing the QTL candidacy of loci for inducible nitric oxide synthase ( Nos2 ) and angiotensin-converting enzyme ( Ace ) genes. BPs of these strains were measured by telemetry and compared with those of the DSS Rat. Consequently, QTL1 and QTL2 were narrowed to segments of 53.5 and 100.4 centiRays, respectively. A new QTL, QTL3, was found between QTL1 and QTL2. Both Nos2 and Ace have been disqualified as QTLs in the DSS and LEW comparison. Therefore, there are no obvious candidate genes in the segments that harbor these 3 QTLs, which represent genes previously not thought to be involved in BP regulation. These QTLs will likely have an influence on studies of human hypertension because of their homology with the human CHR 17 region in which QTLs for BP have been found.

John P Rapp - One of the best experts on this subject based on the ideXlab platform.

  • two linked blood pressure quantitative trait loci on chromosome 10 defined by Dahl Rat congenic strains
    Hypertension, 2001
    Co-Authors: Michael R Garrett, Alan Y Deng, Xiaotong Zhang, Oksana I Dukhanina, John P Rapp
    Abstract:

    A quantitative trait locus (QTL) for blood pressure was previously detected on Rat chromosome 10 (RNO10) by linkage analysis and confirmed by the construction of congenic strains that encompass large regions of RNO10. In the present study, the Rat RNO10 blood pressure QTL was dissected by the further construction of congenic substrains. The original congenic region was shown to contain 2 blood pressure QTLs (QTL 1 and QTL 2) ≈24 cM apart. These were localized to a <2.6-cM region between markers D10Rat27 and D10Rat24 for QTL 1 and to a <3.2-cM region between D10Rat12 and D10Mco70 for QTL 2. CompaRative mapping suggests that the Rat RNO10 QTL 2 could be localized very close to a blood pressure QTL described by sib-pair analysis on human chromosome 17, but this is not definitively established because of multiple and complex chromosomal rearrangements between rodents and humans.

  • Two Linked Blood Pressure Quantitative Trait Loci on Chromosome 10 Defined by Dahl Rat Congenic Strains
    Hypertension, 2001
    Co-Authors: Michael R Garrett, Alan Y Deng, Xiaotong Zhang, Oksana I Dukhanina, John P Rapp
    Abstract:

    A quantitative trait locus (QTL) for blood pressure was previously detected on Rat chromosome 10 (RNO10) by linkage analysis and confirmed by the construction of congenic strains that encompass large regions of RNO10. In the present study, the Rat RNO10 blood pressure QTL was dissected by the further construction of congenic substrains. The original congenic region was shown to contain 2 blood pressure QTLs (QTL 1 and QTL 2) ≈24 cM apart. These were localized to a

  • high resolution mapping of the blood pressure qtl on chromosome 7 using Dahl Rat congenic strains
    Genomics, 2001
    Co-Authors: George T Cicila, Michael R Garrett, Howard Dene, John P Rapp
    Abstract:

    It was previously shown using Dahl salt-sensitive (S) and salt-resistant (R) Rats that a blood pressure quantitative trait locus (QTL) was present on Rat chromosome 7. In the present work, this QTL was localized to a region less than 0.54 cM in size on the linkage map using a series of congenic strains. This region was contained in a single yeast artificial chromosome that was 220 kb long. This small segment still contained the primary candidate locus Cyp11b1 (11b-hydroxylase), but the adjacent candidate genes Cyp11b2 (aldosterone synthase) and Cyp11b3 were ruled out. It is concluded that 11b-hydroxylase, through its known genetic variants altering the production of 18-hydroxy11-deoxy corticosterone, is very likely to account for the blood pressure QTL on chromosome 7 in the Dahl Rat model of hypertension. This QTL accounts for about 23 mm Hg under the condition of 2% NaCl diet for 24 days. © 2001 Academic Press

  • multiple blood pressure qtl on Rat chromosome 1 defined by Dahl Rat congenic strains
    Physiological Genomics, 2001
    Co-Authors: Yasser Saad, Michael R Garrett, John P Rapp
    Abstract:

    A series of congenic strains were constructed in which segments of chromosome (chr) 1 from Lewis (LEW) Rats were introgressed into the Dahl salt-sensitive (S) strain. Three blood pressure quantitative trait loci (QTL) were defined. Two of these (QTL 1a and QTL 1b) were closely linked in the region between 1q31 and 1q35. The third blood pressure QTL (QTL region 2) was close to the centromere between 1p11 and 1q12, which includes the candidate gene Slc9a3 for sodium/hydrogen exchange. The blood pressure QTL 1a and QTL 1b defined here overlap significantly with QTL for disease phenotypes of renal failure, stroke, ventricular mass, and salt susceptibility defined in other Rat strains, implying that these disease phenotypes and our blood pressure phenotype have causes in common. QTL 1b also corresponded approximately with a blood pressure QTL described on human chr 15. The QTL region 2 corresponded approximately with blood pressure QTL described on mouse chr 10 and human chr 6.

  • localization of a blood pressure qtl on Rat chromosome 1 using Dahl Rat congenic strains
    Physiological Genomics, 1999
    Co-Authors: Yasser Saad, Michael R Garrett, Howard Dene, John P Rapp
    Abstract:

    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...

George T Cicila - One of the best experts on this subject based on the ideXlab platform.

  • high resolution mapping of the blood pressure qtl on chromosome 7 using Dahl Rat congenic strains
    Genomics, 2001
    Co-Authors: George T Cicila, Michael R Garrett, Howard Dene, John P Rapp
    Abstract:

    It was previously shown using Dahl salt-sensitive (S) and salt-resistant (R) Rats that a blood pressure quantitative trait locus (QTL) was present on Rat chromosome 7. In the present work, this QTL was localized to a region less than 0.54 cM in size on the linkage map using a series of congenic strains. This region was contained in a single yeast artificial chromosome that was 220 kb long. This small segment still contained the primary candidate locus Cyp11b1 (11b-hydroxylase), but the adjacent candidate genes Cyp11b2 (aldosterone synthase) and Cyp11b3 were ruled out. It is concluded that 11b-hydroxylase, through its known genetic variants altering the production of 18-hydroxy11-deoxy corticosterone, is very likely to account for the blood pressure QTL on chromosome 7 in the Dahl Rat model of hypertension. This QTL accounts for about 23 mm Hg under the condition of 2% NaCl diet for 24 days. © 2001 Academic Press

  • regulation of the genes for 11β hydroxysteroid dehydrogenase type 1 and type 2 in the kidney of the Dahl Rat
    Journal of Hypertension, 1999
    Co-Authors: Roberto Francosaenz, George T Cicila, Peijuan Shen, William L Henrich
    Abstract:

    Background An isoenzyme of 11β-hydroxysteroid dehydrogenase (11β-HSD), 11β-HSD-2 confers aldosterone specificity on the mineralocorticoid receptor (MR) and is found collocated in renal cortical collecting duct cells with the MR. To investigate whether the salt sensitivity of the Dahl salt-sensitive (S) Rat is due to 11β-HSD deficiency, we measured 11β-HSD-1 and 11β-HSD-2 mRNA levels in the kidneys of Dahl-S and Dahl salt-resistant (R) Rats. In addition, we studied the effects of gender, age and dietary sodium on expression of mRNA for the two isoforms. S and R Rats were placed on low- or high-sodium (HNa) diets and sacrificed after 33 and 115 days. Rat kidney RNA was isolated and 11β-HSD-1 and 11β-HSD-2 mRNA levels were measured on Northern filter hybridization using isoform-specific probes. Results No strain differences were observed in the mRNA expression of the two isoforms of 11β-HSD under any of the experimental conditions. No gender or age differences were observed in 11β-HSD-2 mRNA but HNa diet almost doubled 11β-HSD-2 mRNA (P< 0.0009). 11β-HSD-1 mRNA levels were consistently higher, more than double, in male Rats versus females Rats (P< 0.0001), and in the 115-day-old Rats versus the 33-day-old Rats (P< 0.0001). Dietary sodium intake did not affect 11β-HSD-1 mRNA levels. Conclusions There is no difference in the expression of the two isoforms of 11 β-HSD in the kidneys of the S and R Rats, which might explain the salt sensitivity and higher blood pressure of the S Rat Renal 11β-HSD-1 mRNA levels are higher in male than in female Rats, and in the older Rats of both strains. In the kidney, the 11β-HSD-2 gene is regulated by sodium status but is not affected by gender or age.

  • Two blood pressure/cardiac mass quantitative trait loci on Chromosome 3 in Dahl Rats
    Mammalian Genome, 1999
    Co-Authors: George T Cicila, Howard Dene, Carl Choi, John P Rapp
    Abstract:

    Interval mapping was used to identify putative quantitative trait loci (QTL) for blood pressure and cardiac mass on Chromosome (Chr) 3 in F1(S × R) × S population of 150 Rats raised on an 8% NaCl diet. Two genetic markers 95.7 cM apart, D3Wox3 and D3Mco5 (tightly linked to Edn3), showed ``suggestive'' linkage to blood pressure (LOD = 2.0 and 1.8 respectively). In addition, D3Wox3 showed ``suggestive'' linkage to heart weight (LOD = 2.5), and D3Mco5 showed ``suggestive'' linkage to body weight–adjusted heart weight (LOD = 2.1). Congenic Rats (designated S.R-Edn3) were constructed by introgressing the R-Rat Edn3 allele (and flanking loci) into the S strain. On a 2% NaCl diet, S.R-Edn3 Rats had lower blood pressure (21.4 mm Hg, P= 0.0005) and heart weight (59 mg, P= 0.0038) compared with S Rats, confirming the existence of a blood pressure QTL on Chr 3 near Edn3 even though QTL linkage analysis of blood pressure did not achieve stringent statistical criteria for significance. The results of the congenic experiment and the large distance between the two putative QTL suggest the presence of at least two independent blood pressure/cardiac mass QTL detectable on Chr 3 in the Dahl Rat model of genetic hypertension.

  • linkage of 11 beta hydroxylase mutations with altered steroid biosynthesis and blood pressure in the Dahl Rat
    Nature Genetics, 1993
    Co-Authors: John P Rapp, George T Cicila, Jiaming Wang, Elizabeth St Lezin, Shi Chung Ng, Theodore W Kurtz
    Abstract:

    In Dahl salt-hypertension sensitive (S) and resistant (R) strains fed a high NaCI diet, 11β-hydroxylase polymorphisms cosegregate with the adrenal capacity to synthesize 18-hydroxy-11-deoxycorticosterone (18-OH-DOC) and blood pressure. The R Rat carries an 11β-hydroxylase allele that: (i) differs from those of 12 other Rat strains; (ii) is associated with a uniquely reduced capacity to synthesize 18-OH-DOC; and (iii) encodes 5 amino acid substitutions in the 11β-hydroxylase protein. The robust salt-resistance of the Dahl R Rat may be due in part to reduced synthesis of the mineralocorticoid 18-OH-DOC stemming from mutations in the 11β-hydroxylase gene. 11β-hydroxylase, located on Rat chromosome 7, is the first candidate gene identified in an animal model in which coding sequence mutations have been linked to the regulation of blood pressure.

Michael R Garrett - One of the best experts on this subject based on the ideXlab platform.

  • two linked blood pressure quantitative trait loci on chromosome 10 defined by Dahl Rat congenic strains
    Hypertension, 2001
    Co-Authors: Michael R Garrett, Alan Y Deng, Xiaotong Zhang, Oksana I Dukhanina, John P Rapp
    Abstract:

    A quantitative trait locus (QTL) for blood pressure was previously detected on Rat chromosome 10 (RNO10) by linkage analysis and confirmed by the construction of congenic strains that encompass large regions of RNO10. In the present study, the Rat RNO10 blood pressure QTL was dissected by the further construction of congenic substrains. The original congenic region was shown to contain 2 blood pressure QTLs (QTL 1 and QTL 2) ≈24 cM apart. These were localized to a <2.6-cM region between markers D10Rat27 and D10Rat24 for QTL 1 and to a <3.2-cM region between D10Rat12 and D10Mco70 for QTL 2. CompaRative mapping suggests that the Rat RNO10 QTL 2 could be localized very close to a blood pressure QTL described by sib-pair analysis on human chromosome 17, but this is not definitively established because of multiple and complex chromosomal rearrangements between rodents and humans.

  • Two Linked Blood Pressure Quantitative Trait Loci on Chromosome 10 Defined by Dahl Rat Congenic Strains
    Hypertension, 2001
    Co-Authors: Michael R Garrett, Alan Y Deng, Xiaotong Zhang, Oksana I Dukhanina, John P Rapp
    Abstract:

    A quantitative trait locus (QTL) for blood pressure was previously detected on Rat chromosome 10 (RNO10) by linkage analysis and confirmed by the construction of congenic strains that encompass large regions of RNO10. In the present study, the Rat RNO10 blood pressure QTL was dissected by the further construction of congenic substrains. The original congenic region was shown to contain 2 blood pressure QTLs (QTL 1 and QTL 2) ≈24 cM apart. These were localized to a

  • high resolution mapping of the blood pressure qtl on chromosome 7 using Dahl Rat congenic strains
    Genomics, 2001
    Co-Authors: George T Cicila, Michael R Garrett, Howard Dene, John P Rapp
    Abstract:

    It was previously shown using Dahl salt-sensitive (S) and salt-resistant (R) Rats that a blood pressure quantitative trait locus (QTL) was present on Rat chromosome 7. In the present work, this QTL was localized to a region less than 0.54 cM in size on the linkage map using a series of congenic strains. This region was contained in a single yeast artificial chromosome that was 220 kb long. This small segment still contained the primary candidate locus Cyp11b1 (11b-hydroxylase), but the adjacent candidate genes Cyp11b2 (aldosterone synthase) and Cyp11b3 were ruled out. It is concluded that 11b-hydroxylase, through its known genetic variants altering the production of 18-hydroxy11-deoxy corticosterone, is very likely to account for the blood pressure QTL on chromosome 7 in the Dahl Rat model of hypertension. This QTL accounts for about 23 mm Hg under the condition of 2% NaCl diet for 24 days. © 2001 Academic Press

  • multiple blood pressure qtl on Rat chromosome 1 defined by Dahl Rat congenic strains
    Physiological Genomics, 2001
    Co-Authors: Yasser Saad, Michael R Garrett, John P Rapp
    Abstract:

    A series of congenic strains were constructed in which segments of chromosome (chr) 1 from Lewis (LEW) Rats were introgressed into the Dahl salt-sensitive (S) strain. Three blood pressure quantitative trait loci (QTL) were defined. Two of these (QTL 1a and QTL 1b) were closely linked in the region between 1q31 and 1q35. The third blood pressure QTL (QTL region 2) was close to the centromere between 1p11 and 1q12, which includes the candidate gene Slc9a3 for sodium/hydrogen exchange. The blood pressure QTL 1a and QTL 1b defined here overlap significantly with QTL for disease phenotypes of renal failure, stroke, ventricular mass, and salt susceptibility defined in other Rat strains, implying that these disease phenotypes and our blood pressure phenotype have causes in common. QTL 1b also corresponded approximately with a blood pressure QTL described on human chr 15. The QTL region 2 corresponded approximately with blood pressure QTL described on mouse chr 10 and human chr 6.

  • localization of a blood pressure qtl on Rat chromosome 1 using Dahl Rat congenic strains
    Physiological Genomics, 1999
    Co-Authors: Yasser Saad, Michael R Garrett, Howard Dene, John P Rapp
    Abstract:

    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...

Julie Dutil - One of the best experts on this subject based on the ideXlab platform.

  • multiple quantitative trait loci for blood pressure interacting epistatically and additively on Dahl Rat chromosome 2
    Hypertension, 2005
    Co-Authors: Julie Dutil, Vasiliki Eliopoulos, Johanne Tremblay, Pavel Hamet, Sophie Charron, Alan Y Deng
    Abstract:

    Our previous work demonstRated 2 quantitative trait loci (QTLs), C2QTL1 and C2QTL2, for blood pressure (BP) located on chromosome (Chr) 2 of Dahl salt-sensitive (DSS) Rats. However, for a lack of markers, the 2 congenic strains delineating C2QTL1 and C2QTL2 could not be sepaRated. The position of the C2QTL1 was only inferred by comparing 2 congenic strains, one having and another lacking a BP effect. Furthermore, it was not known how adjacent QTLs would interact with one another on Chr 2. In the current investigation, first, a critical chromosome marker was developed to sepaRate 2 C2QTLs. Second, a congenic substrain was created to cover a chromosome fragment thought to harbor C2QTL1. Finally, a series of congenic strains was produced to systematically and comprehensively cover the entire Chr 2 segment containing C2QTL2 and other regions previously untested. Consequently, a total of 3 QTLs were discovered, with C2QTL3 located between C2QTL1 and C2QTL2. C2QTL1, C2QTL2, and C2QTL3 reside in chromosome segments of 5.7 centiMorgan (cM), 3.5 cM, and 1.5 cM, respectively. C2QTL1 interacted epistatically with either C2QTL2 or C2QTL3, whereas C2QTL2 and C2QTL3 showed additive effects to each other. These results suggest that BP QTLs closely linked in a segment interact epistatically and additively to one another on Chr 2.

  • complete and overlapping congenics proving the existence of a quantitative trait locus for blood pressure on Dahl Rat chromosome 17
    Physiological Genomics, 2005
    Co-Authors: Myrian Grondin, Julie Dutil, Raphaelle Lambert, Vasiliki Eliopoulos, Sophie Charron, Anita Ariyarajah, Yishu Deng, Myriam Moujahidine, Alan Y Deng
    Abstract:

    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 0.6) 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.

  • dissecting quantitative trait loci into opposite blood pressure effects on Dahl Rat chromosome 8 by congenic strains
    Journal of Hypertension, 2004
    Co-Authors: Anita Ariyarajah, Ana Palijan, Julie Dutil, Kalyani Prithiviraj, Yishu Deng, Alan Y Deng
    Abstract:

    Objective Our previous linkage analyses showed that there was likely a quantitative trait locus (QTL) for blood pressure (BP) on chromosome 8 (Chr 8) in the strain comparison between the Dahl salt-sensitive (S) and the Lewis (LEW) Rats. The current work is to delineate the chromosome interval harboring this QTL by using congenic strains with different chromosome substitutions. Methods Two congenic strains were produced by replacing different segments of the S Rats with the homologous segments of the LEW Rats. A genome-wide marker screening was utilized to acceleRate this process. The two strains geneRated are designated as C8S.L1 and C8S.L2, respectively. BPs of the Rats were measured by telemetry. Results C8S.L1 showed a BP lower than that of S Rats. In contrast, C8S.L2 did not have chromosome overlaps with C8S.L1, but unexpectedly, exhibited a BP-raising effect, higher than that of S Rats. Conclusion There are at least two QTLs present in a section of Chr 8 that possess opposite BP effects. The current congenic work reveals not only the presence of QTLs, but the complexity of QTLs on BP. The novel congenic strain with hypertension more severe than S provides a new model for studies in elucidating physiological mechanisms controlling BP.

  • comprehensive congenic coverage revealing multiple blood pressure quantitative trait loci on Dahl Rat chromosome 10
    Hypertension, 2003
    Co-Authors: Ana Palijan, Julie Dutil, Raphaelle Lambert, Zsuzsa Sivo, Alan Y Deng
    Abstract:

    Chromosome mapping based on congenic strains can restrict quantitative trait loci (QTLs) for blood pressure (BP) into small intervals that are otherwise indistinguishable in linkage analysis. Also, congenic strains can be created to test a candidate gene to be a BP QTL. Taking full advantage of these features, we produced 10 congenic strains by replacing various segments of chromosome (Chr) 10 of the Dahl salt-sensitive (DSS) Rat with those of the Lewis (LEW) Rat. These strains were made to systematically cover an entire section of Chr 10. Three of the strains were designed to narrow the intervals that harbor previously mapped QTL1 and QTL2. Two of the strains were designed for the express purpose of testing the QTL candidacy of loci for inducible nitric oxide synthase ( Nos2 ) and angiotensin-converting enzyme ( Ace ) genes. BPs of these strains were measured by telemetry and compared with those of the DSS Rat. Consequently, QTL1 and QTL2 were narrowed to segments of 53.5 and 100.4 centiRays, respectively. A new QTL, QTL3, was found between QTL1 and QTL2. Both Nos2 and Ace have been disqualified as QTLs in the DSS and LEW comparison. Therefore, there are no obvious candidate genes in the segments that harbor these 3 QTLs, which represent genes previously not thought to be involved in BP regulation. These QTLs will likely have an influence on studies of human hypertension because of their homology with the human CHR 17 region in which QTLs for BP have been found.

  • quantitative trait loci with opposing blood pressure effects demonstRating epistasis on Dahl Rat chromosome 3
    Physiological Genomics, 2003
    Co-Authors: Ana Palijan, Julie Dutil, Alan Y Deng
    Abstract:

    Our previous linkage studies indicated that there might be a blood pressure (BP) quantitative trait locus (QTL) on chromosome 3 (Chr 3) contrasting between the Dahl salt-sensitive (S) strain and th...