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

Abstract

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....

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

“…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.…”

“…The remaining five (Table 2) have been resolved only by congenic fine mapping (Charron et al, 2005a;Dutil et al, 2005). C1QTL, C16QTL, C10QTL and C2QTL showed partial dominance in linkage analyses, that is the BP of the heterozygotes fell between the two homozygotes.…”

“…Apparently, the real physiological effects of the 10 QTLs do not combine additively. Epistasis between QTLs certainly plays an important role (Palijan et al, 2003a;Charron et al, 2005a, b;Dutil et al, 2005) and genetic or epigenetic inhibition could be involved (Charron et al, 2005b).…”

“…All experimental procedures were in accordance with institutional, provincial and federal regulations. 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).…”

“…Two novel functional aspects of BP QTLs have become apparent from the analyses of congenic strains. First, each of them accounts for at least 33 mm Hg/ 88 mm Hg ¼ 38% of the total BP difference between DSS and LEW parental strains, as measured directly by telemetry (Moujahidine et al, 2004;Dutil et al, 2005;Grondin et al, 2005;Charron et al, 2005a), exhibiting the status of a major QTL. Second, each QTL appears have an individual influence on BP: no combination seems to be necessary for any one of them to affect BP, despite QTLQTL epistatic interactions (Deng and Rapp, 1992;Rapp et al, 1998;Palijan et al, 2003a;Charron et al, 2005a, b;Dutil et al, 2005).…”