Comprehensive Congenic Coverage Revealing Multiple Blood Pressure Quantitative Trait Loci on Dahl Rat Chromosome 10

Palijan, Ana; Lambert, Raphaëlle; Dutil, Julie; Sivo, Zsuzsa; Deng, Alan Y.

doi:10.1161/01.hyp.0000090096.88509.15

Cited by 32 publications

(67 citation statements)

References 25 publications

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“…15 In brief, rats of the DSS and S.M (or S.M1 or S.M5 or S.M6) (Mispro, Montreal, Canada) were used to derive congenic substrains (see the online supplement for details, available at http://www.hypertensionaha.org). In the end, the authenticity of each congenic substrain has been established by genotyping the markers for the region of interest and 57 additional markers scattered throughout the rat genome (data not shown).…”

Section: Constructions Of Congenic Substrainsmentioning

confidence: 99%

Multiple Quantitative Trait Loci for Blood Pressure Interacting Epistatically and Additively on Dahl Rat Chromosome 2

Dutil¹,

Eliopoulos²,

Tremblay³

et al. 2005

Hypertension

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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. ver since the revelation of a quantitative trait locus (QTL) for blood pressure (BP) on chromosome 2 (Chr 2) of Dahl salt-sensitive (DSS) rats, 1,2 Chr 2 seems to play a role in the development of hypertension in several of the hypertensive strains. [3][4][5][6][7][8][9][10][11][12][13] In our initial work, 2 BP QTLs designated C2QTL1 and C2QTL2 were localized to regions on Chr 2 of the DSS rat. 5,6 C2QTL1 was found between the markers D2Rat303 and D2Rat166, 6 and C2QTL2 was found between the markers D2Rat166 and D2Rat131. 5 However, at the time, the position of C2QTL1 was solely inferred from comparing 2 overlapping congenic strains, one having and the other lacking a BP effect. 6 It was uncertain whether this deduction was valid in localizing a QTL for a polygenic trait. Another issue was that C2QTL1 defined by S.M1 6 and C2QTL2 defined by S.M5 and S.M6 5 shared a chromosome region of ambiguity. As a result, it could not be ruled out that there might be just 1 QTL instead of 2 in the Chr 2 region in question.Subsequent to our original work on Chr 2 QTL localizations, 1,2,5,6,14 another group found several QTLs situated adjacent to one another in 1 Chr 2 segment of DSS rats. 7 However, it was not clear how these QTLs could act with reference to one another.Based on these observations, 2 questions were addressed: are there truly multiple BP QTLs in a Chr 2 segment of the DSS rat? If there are, how do they interact with reference to one another in determining BP? Materials and Methods AnimalsCongenic strains, S.M, S.M1, S.M2, S.M5, and S.M6 and DSS strains are the same as used previously 5,6 (Figure 1). Constructions of Congenic SubstrainsS.M, S.M1, S.M5, and S.M6 5,6 were used to derive congenic substrains. The basic design was to systematically and as completely as possible cover the entire Chr 2 region of interest....

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Section: Constructions Of Congenic Substrainsmentioning

confidence: 99%

Multiple Quantitative Trait Loci for Blood Pressure Interacting Epistatically and Additively on Dahl Rat Chromosome 2

Dutil¹,

Eliopoulos²,

Tremblay³

et al. 2005

Hypertension

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“…Their cumulative effects exceeded 400 mm Hg (Figure 1). This value, however, cannot, and does not, reflect the true BP difference between the two parental strains, DSS and LEW (or MNS), which is around 88 mm Hg (Palijan et al, 2003b;Ariyarajah et al, 2004;Charron et al, 2005a, b;Dutil et al, 2005). Apparently, the real physiological effects of the 10 QTLs do not combine additively.…”

Section: Linkage Versus Congenic Resultsmentioning

confidence: 97%

“…DSS, LEW and MNS rats have previously been described (Palijan et al, 2003a, b;Ariyarajah et al, 2004;Moujahidine et al, 2004;Charron et al, 2005a, b;Dutil et al, 2005;Eliopoulos et al, 2005;Grondin et al, 2005). Nine congenic strains had trapped BP QTLs and were largely based on those isolated previously (Palijan et al, 2003b;Ariyarajah et al, 2004;Moujahidine et al, 2004;Charron et al, 2005a;Dutil et al, 2005;Grondin et al, 2005).…”

Section: Animalsmentioning

confidence: 99%

“…For example, our previous work revealed the presence of a QTL in a 46-cM region on rat Chr 10 (Deng and Rapp, 1995;Garrett et al, 1998), whereas, in fact, there are four QTLs in this segment. Three of them are clustered within a section of less than 15 cM (Palijan et al, 2003b;Charron et al, 2005a). Second, false negatives or false positives can appear.…”

Section: Introductionmentioning

confidence: 99%

“…The gene encoding the inducible form of nitric oxide synthase (Nos2) is an example of a false positive. Nos2 was initially identified as marking a probable BP QTL location (Deng and Rapp, 1995), but was subsequently excluded (Palijan et al, 2003b).…”

Section: Introductionmentioning

confidence: 99%

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Individual QTLs controlling quantitative variation in blood pressure inherited in a Mendelian mode

Duong

Charron

Deng³

et al. 2006

Heredity

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We studied three possible genotypes at 10 well-defined blood pressure (BP) QTLs using congenic rat lines. The central question was whether the hypertensive or normotensive allele is dominant, or whether there is partial dominance. The congenic strains were employed to investigate the BP effects of alleles originating from normotensive rats in the background of hypertensive Dahl salt-sensitive (DSS) rats. The normotensive alleles at eight QTLs were fully dominant over DSS alleles, which we tentatively interpreted as indicating that DSS rats incurred a loss of function at these loci and that the QTLs produced BP-reducing agents. In contrast, the normotensive allele of only one QTL was recessive over its DSS counterpart, implying a gain of function at this QTL or a null allele involved in generating a BP-elevating agent. Only one locus, C17QTL, had alleles exhibiting partial dominance. These estimates of dominance differ considerably from those obtained by QTL analysis in a F2 cross. This disagreement demonstrates the importance of establishing a cause-effect relationship between a QTL and its phenotypic effect via congenic strains. The dominance relationships suggest pertinent strategies for gene identification and pharmaceutical intervention.

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Molecular Genetics of Polygenic Hypertension

Deng

2017

Encyclopedia of Life Sciences

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Essential hypertension is one of the most damaging health risk factors; however, its underlying mechanisms of pathogeneses continue to be undeciphered. To assist this endeavour, investigations utilising human populations and rodent models have revealed numerous genetic building blocks known as quantitative trait loci (QTLs) for blood pressure (BP). Although BP is a quantitatively measured trait manifesting in a continuous variation in heterogeneous populations, each QTL governing it appears to functionally behave as an independent and ‘monogenic’ Mendelian determinant. Mechanistically, multiple QTLs are functionally modularised by epistasis that implies a common pathway or cascade among them, whereas others belong to parallel epistatic modules/pathways. These insights suggest that similar genetic mechanisms probably shepherd the genetic architectures in physiological functions for essential hypertension. Translations of gene discovery to therapeutic targets and diagnostic tools will require biology‐based function validations of specific genes constituting BP QTLs in appropriate animal models. Key Concepts There is a regulatory hierarchy in the genetic architecture governing the functional biology of BP determination. When a master control is removed, modularity and epistatic hierarchy, not a cumulation of minuscule effects, determine the functionality of multiple QTLs on BP. Mechanistically, separate epistatic modules integrating BP QTLs are best explained by independent pathways, each consisting of multiple components that act in sequential cascades in a pathway. As there are fewer pathways than the components comprising them, a defective protein product per se encoded by a mutated QTL, either qualitatively or quantitatively, can lead to a deficient BP‐regulating pathway of pathogenesis and does not have to directly act on BP as a physiological agent.

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Comprehensive Congenic Coverage Revealing Multiple Blood Pressure Quantitative Trait Loci on Dahl Rat Chromosome 10

Cited by 32 publications

References 25 publications

Multiple Quantitative Trait Loci for Blood Pressure Interacting Epistatically and Additively on Dahl Rat Chromosome 2

Multiple Quantitative Trait Loci for Blood Pressure Interacting Epistatically and Additively on Dahl Rat Chromosome 2

Individual QTLs controlling quantitative variation in blood pressure inherited in a Mendelian mode

Molecular Genetics of Polygenic Hypertension

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