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(Hypertension. 2001;38:216.)
© 2001 American Heart Association, Inc.

Scientific Contributions

Genetic Dissection of Region Around the Sa Gene on Rat Chromosome 1

Evidence for Multiple Loci Affecting Blood Pressure

Simon Frantz; Jenny-Rebecca Clemitson; Marie-Therese Bihoreau; Dominique Gauguier; Nilesh J. Samani

From the Department of Cardiology, University of Leicester (S.F., J.-R.C., N.J.S), Leicester, United Kingdom; and the Wellcome Trust Centre for Human Genetics, University of Oxford (M.T.B, D.G), Oxford, United Kingdom.

Correspondence to Dr N.J. Samani, Department of Cardiology, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Groby Rd, Leicester LE3 9QP, United Kingdom. E-mail njs{at}le.ac.uk

	Abstract

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Abstract—— A region with a major effect on blood pressure (BP) is located on rat chromosome 1 in the vicinity of the Sa gene, a candidate gene for BP regulation. Previously, we observed a single linkage peak for BP in this region in second filial generation rats derived from a cross of the spontaneously hypertensive rat (SHR) with the Wistar-Kyoto rat (WKY), and we have reported the isolation of the region containing the BP effect in reciprocal congenic strains (WKY.SHR-Sa) and (SHR.WKY-Sa) derived from these animals. Here, we report the further genetic dissection of this region. Two congenic substrains each were derived from WKY.SHR-Sa (WISA1 and WISA2) and SHR.WKY-Sa (SISA1 and SISA2) by backcrossing to WKY and SHR, respectively. Although there was some overlap of the introgressed regions retained in the various substrains, the segments in WISA1 and SISA1 did not overlap. Furthermore, although the Sa allele in WISA1, WISA2, and SISA2 remained donor in origin, recombination in SISA1 reverted it back to the recipient (SHR) allele. Surprisingly, all 4 substrains demonstrated a highly significant BP difference compared with that of their respective parental strain, which was of a magnitude similar to those seen in the original congenic strains. The findings strongly indicate that there are at least 2 quantitative trait loci (QTLs) affecting BP in this region of rat chromosome 1. Furthermore, the BP effect seen in SISA1 indicates that at least a proportion of the BP effect of this region of rat chromosome 1 cannot be due to the Sa gene. SISA1 contains an introgressed segment of <3 cM, and this will facilitate the physical mapping of the BP QTL(s) located within it and the identification of the susceptibility-conferring genes. Our observations serve to illustrate the complexity of QTL dissection and the care needed to interpret findings from congenic studies.

Key Words: hypertension, experimental • genetics • models, experimental • rats, inbred SHR • genes

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Rat chromosome 1 was one of the first chromosomes shown by cosegregation analysis to harbor a quantitative trait locus (QTL) regulating blood pressure (BP) and contributing to hypertension in several genetically hypertensive rat strains.^1–12 Initial interest focused around the potential candidacy in hypertension of the Sa gene,¹³ which is located on this chromosome. However, by itself, cosegregation analysis can identify only a broad region that harbors the putative QTL and cannot implicate a specific gene. Therefore, to facilitate identification of the chromosome 1 BP QTL, several groups have successfully isolated the region around the Sa gene containing the QTL in congenic strains.^11,14–16 Congenic strains are novel strains in which a specified region of the genome of a donor strain (eg, a hypertensive strain) is introgressed into a recipient strain (eg, normotensive strain) through meiotic recombination followed by selective breeding.¹⁷ If the QTL is present within the introgressed region, provided there are no genetic background effects, the BP of the congenic strain should be different (higher in the above example) from that of the recipient strain. One can then move toward narrowing the segment containing the QTL by further genetic dissection of the introgressed segment.¹⁷ Indeed, recent reports of secondary strains derived from some of the initial chromosome 1 congenic strains suggest that at least 1 BP QTL on chromosome 1 lies outside the region containing the Sa gene.^18–20

We have previously reported mapping of a rat chromosome 1 BP QTL in F₂ rats derived from a cross of the spontaneously hypertensive rat (SHR) with the Wistar-Kyoto rat (WKY) and isolation of the region containing the QTL in reciprocal congenic strains (WKY.SHR-Sa) and (SHR.WKY-Sa) derived from these animals.¹⁶ In the present study, we report our analysis of 4 substrains derived from these initial congenic strains. We have narrowed the region containing 1 BP QTL to <3 cM, which should greatly facilitate physical mapping and identification of the susceptibility gene(s). More important, our findings suggest that there is >1 BP QTL located in this region of rat chromosome 1. This observation is important because it has significant implications for the interpretation of linkage analysis data and for the use of exclusion mapping as a tool to exclude the candidacy of individual candidate genes.

	Methods

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Construction of Congenic Substrains
Two congenic substrains each were derived from WKY.SHR-Sa (WKY.SHR-D1Rat56/D1M7mit206 [WISA1] and WKY.SHR-D1Rat236/D1M7mit206 [WISA2]) and from SHR.WKY-Sa (SHR.WKY-D1Wox34/D1Rat164 [SISA1] and SHR.WKY-D1Wox34/Sa [SISA2]) by backcrossing to WKY and SHR, respectively, and, in each case, intercrossing the progeny, selecting individual F₂ animals showing a recombination event within the introgressed segment (see Genotyping, below), generating heterozygous animals by mating to the recipient strain, and fixing the new narrower segment in the homozygote state by mating 2 heterozygous animals and selecting appropriate animals.¹⁷ All 4 lines were subsequently maintained by brother-sister mating. Animals (parental and congenic) were housed under identical controlled conditions (temperature, 21±1°C; humidity, 60±10%; and 12-hour day/night cycle), fed standard rat chow (Rat & Mouse No. 3 Breeding Diet, Special Diet Services Ltd) containing 0.25% sodium and 0.66% potassium, and given free access to tap water. All procedures were carried out in accordance with our institutional guidelines.

Genotyping
DNA genotyping was used to select animals for breeding at the F₂ generation and subsequently for defining the introgressed regions in the congenic substrains. Briefly, DNA was extracted, as previously described, from a segment of tail removed with the animals (age 4 to 6 weeks) under anesthesia.⁴ Markers on the rat linkage maps (Wellcome Trust Center for Human Genetics, which can be accessed online at http://www.well.ox.ac.uk, and the Whitehead Institute for Biomedical Research/MIT Rat Genome Map, which can be accessed online at http://www.waldo.wi.mit.edu/rat/public) that localized to the area of interest on rat chromosome 1 and were polymorphic between our SHR and WKY were used to genotype animals by polymerase chain reaction amplification.¹⁶ Fragments were resolved on agarose or acrylamide gels as appropriate. In the initial phase, when recombination in the F₂ progeny was sought, the markers used were D1Wox10, D1M7mit206, D1Wox19, D1Smu6, D1Smu7, D1Smu8, SA, D1M7mit66, D1Smu11, D1M7mit17, D1Wox34, D1Wox33, D1Mit3, D1Mit2, and D1Wox29. Subsequently, several additional markers were also used to more precisely define the segments present in each substrain (see Figure 1). The consensus linkage map shown in Figure 1 has been constructed by using most of the microsatellite markers that were generated in different laboratories and were likely to map to rat chromosome 1 in the WISA/SISA regions. Markers showing allelic variation between the Brown Norway (BN) and Goto Kakizaki (GK) rats were typed in a large and highly polymorphic intercross derived between the 2 strains, as previously described.²¹ This map allows direct and accurate integration of physical and genetic maps of the rat derived in different laboratories. All markers of the consensus genetic map and those that did not show allelic variations between GK and BN were tested for polymorphism between SHR and WKY strains and subsequently used for the genetic characterization of the SISA/WISA congenics. Distances (cM) are derived from the GKxBN cross.

View larger version (28K): [in this window] [in a new window]   Figure 1. Schematic diagram showing the consensus linkage map of rat chromosome 1 around the Sa gene (on the left), the regions introgressed in the original congenic strains (WKY.SHR-Sa and SHR.WKY-Sa) and in the 2 substrains derived from each of them (WISA1 and WISA2 and SISA1 and SISA2, respectively), and the location of the 2 putative QTLs identified from analysis of the substrains (see text). CEN indicates centromere; TEL, telomere. For the congenic strains and substrains, the black/shaded and white areas represent the minimal and potentially maximal introgressed segments, respectively, based on genotypic analysis of the strains. *Derivation of the consensus linkage map is explained in Methods. The extended panel of markers shown between D1M7mit206 and D1Rat112 are those that were analyzed for polymorphism between SHR and WKY to more accurately define the lower end of the region containing putative QTL2.

Phenotyping
Indirect tail-cuff BP and direct systolic BP (SBP) and diastolic BP (DBP) were measured by the same methods used in our initial study to map the chromosome 1 BP QTL.^4,16 Briefly, indirect tail-cuff BP was measured at 20 weeks of age in conscious but restrained animals, prewarmed to 34°C for 20 minutes, by using a photoelectric signal (Linton’s Instruments). BP was measured 3 times on 2 separate days, and the mean value of all readings was taken as the average for the animal. Direct aortic BP was measured in 28-week-old animals by use of a polyethylene catheter (internal diameter, 0.28 mm) inserted through the femoral artery under general anesthesia. The animals were allowed to recover for 24 hours, and SBP and DBP were measured beat to beat for 1 hour by a BIOPAC MP100 System (BIOPAC Systems Inc) in conscious undisturbed animals, and an average was taken. In addition to measurements in the congenic substrains, contemporaneous measurements were also made in new groups of the parental strains and in the 2 original congenic strains to allow direct comparison. All measurements were performed in male animals.

Statistical Analysis
Blood pressures were compared between strains by ANOVA.

	Results

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The donor segments present in the congenic substrains and their relation to the original congenic strains are shown in Figure 1. WISA1 and WISA2 contain a minimum/maximum of 4.3/10.7 and 12.2/20.7 cM, respectively, of SHR chromosome 1 in a WKY background, whereas SISA1 and SISA2 contain a minimum/maximum of 2.2/2.9 and 5.2/8.2 cM, respectively, of WKY chromosome 1 in an SHR background. Although there is some overlap of the introgressed segments between the various congenic substrains, note that the segments in WISA1 and SISA1 do not overlap. Furthermore, although the Sa allele in WISA1, WISA2, and SISA2 remain donor in origin, the recombination in SISA1 reverted it back to the recipient (SHR) allele.

The Table shows the 20-week indirect tail-cuff and the 28-week direct SBPs and DBPs for the congenic substrains as well as those for the original congenic strains and the parental strains. BPs in the groups being compared (ie, the 4 WKY-based strains or the 4 SHR-based strains) were measured contemporaneously and without knowledge of their status. Each substrain had BPs that were significantly different from those of the corresponding recipient strain, apart from the 28-week DBP for SISA2, which, although lower than that of the SHR, did not quite reach statistical significance (P=0.11). Interestingly, BPs of the 2 WKY-based substrains (WISA1 and WISA2) were similar to each other and also did not differ significantly from the corresponding original congenic strain (WKY.SHR-Sa) strain from which they were derived, apart from 28-week DBP, which was marginally lower (P=0.057) in WISA1 (Table). Likewise, BPs of SISA1 and SISA2 were similar to each other and to those of SHR.WKY-Sa, apart from the 28-week SBP, which was lower (P=0.016) in SISA2 (Table).

View this table: [in this window] [in a new window]   Table 1. BPs of Congenic Strains and Substrains Compared With Respective Parental Strains at 20 and 28 Weeks

The findings in WISA1, WISA2, and SISA2 could reflect the effects of a single BP QTL present in the congenic segment that overlaps in these strains (Figure 1). Equally, the findings in WISA2, SISA1, and SISA2 could reflect the effects of a single QTL (Figure 1). However, because there is no overlap in the congenic segments present in WISA1 and SISA1 (Figure 1), the QTL that lowers BP in the later strain (compared with SHR) must be distinct from the QTL that elevates BP in WISA1 compared with WKY. This suggests the presence of at least 2 genes influencing BP in this region of rat chromosome 1. Figure 2 is a composite of the findings in the present study and those reported by other groups^15,18–20 on their chromosome 1 congenics. Our findings in WISA1 are consistent with those of St Lezin et al,²⁰ suggesting the presence of a BP QTL, telomeric of the Sa gene locus (Figure 2). The putative QTL captured in SISA1 could be the same one captured in the congenics of Hubner et al¹⁹ and Iwai et al¹⁵ (Figure 2). However, Saad et al¹⁸ have reported a BP effect in a congenic strain derived from transfer of a segment Dahl S chromosome 1 to a Lewis background that has no overlap with the segments captured in either WISA1 or SISA1 or, indeed, the congenic strain of St Lezin et al,²⁰ suggesting that this represents the effect of a further QTL (Figure 2).

View larger version (25K): [in this window] [in a new window]   Figure 2. Composite figure comparing the regions of rat chromosome 1 influencing BP captured in SISA1 and WISA1 and in the congenic strains/substrains developed by Saad et al,18 Hubner et al,19 Iwai et al,15 and St Lezin et al.20 The BP changes shown at the top are in each case the difference in BP between the congenic strain and its respective parental strain. Please note that although they indicate the capture of a BP effect, the absolute values are not directly comparable across the studies because they represent measurements that used different methods and different conditions. However, the regions of overlap/nonoverlap between the strains support the concept of multiple QTLs affecting BP in this region of chromosome 1.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
In the last decade, genetic loci for BP and several other quantitative cardiovascular traits have been mapped to specific regions of the rat genome by using cosegregation analysis in crosses of inbred strains showing contrasting phenotypes.²² Although it is an important first step, the information provided by such mapping is limited. Even in large crosses, the regions identified are relatively broad and harbor many genes. Furthermore, the complex synteny conservation between rat and human chromosomes limits the immediate application of the data to humans. For example, the region around the Sa gene on rat chromosome 1 in which we observed significant linkage for the BP QTL shows homology relationships with segments on 4 different human chromosomes.²¹ Construction of congenic strains and substrains has become the preferred route to isolating and narrowing rat chromosomal regions containing BP QTLs.²²

Previous linkage studies in some crosses have suggested that there may be >1 region harboring a BP QTL on rat chromosome 1.^6,12 However, these regions are well separated. Around the Sa gene locus, these studies as well as our own data in an SHRxWKY cross¹⁶ had all observed a single linkage peak, suggesting that this region contains a single BP QTL. This expectation was further strengthened by the fact that in our initial reciprocal congenic strains containing this region,¹⁶ we captured the whole of the BP effect seen in our linkage analysis. Thus, the finding in the present study that we could dissect the region into at least 2 segments with each containing at least 1 QTL affecting BP was surprising. The observation serves to emphasize the limited information derived from cosegregation analysis, especially regarding estimation of the number of genes affecting a trait within a single linkage region. More important, the finding is relevant to the application of exclusion mapping to rule out candidate genes through the construction of congenic substrains. Just because an effect has been captured in a substrain, it should not be assumed that the segment (and hence the genes located within it) from the initial congenic region that is excluded in the substrain does not influence the trait unless a substrain containing this segment has been shown to have a null effect. Even this could be misleading if alleles with opposite effects on the traits are located within this segment; therefore, overall, much more caution is required in interpreting data from congenic experiments.

A somewhat puzzling finding is the lack of significant difference in BP between the WISA1 and WISA2 substrains (Table). The latter contains a congenic region that spans putative QTLs 1 and 2 (Figure 1). Therefore, the similarity of its BP to that of WKY.SHR-Sa is not surprising (Table). However, WISA1, which contains only QTL 2, should theoretically have a lower BP than both of these strains (ie, it should be more similar to that of WKY). Although this was marginally seen for the 28-week DBP, there was no difference in either the 20-week indirect BP or the 28-week SBP (Table). The reason for the lack of difference is unclear. A measurement error is unlikely, given the number of animals studied and the consistent results with different techniques at 2 ages. The relatively enhanced effect observed in WISA1 could reflect the influence of epistatic genetic interactions or indeed, as alluded to above, the loss of effect of alleles that are present in the larger segment of WISA2 (and WKY.SHR-Sa), which have an opposing effect on BP.

The Sa gene has attracted a lot of direct interest as a candidate gene to explain the BP effect of this region of rat chromosome 1.²³ Although its function remains unknown, the gene is much more highly expressed in the SHR kidney than in the WKY kidney, and the location of this increased expression in the proximal tubule²⁴ makes it an attractive candidate. Our finding of a BP effect in SISA1 indicates that at least a proportion of the BP effect of this region of rat chromosome 1 cannot be due to the Sa gene. In WISA1, the Sa allele is still congenic, and the data in this substrain cannot by itself exclude the Sa gene as the explanation for QTL 2 (Figure 1). However, if the BP QTL in WISA1 is the same as that captured in the congenic substrain of St Lezin et al,²⁰ then Sa would also be eliminated as the causative gene for QTL 2 (Figure 2). Findings in other congenic substrains^18,19 as well as other data²⁵ also suggest that the Sa gene is not responsible for a genetic effect on BP. Nonetheless, it should be emphasized that until its function is elucidated, a vasoactive role for Sa, including a role in BP homeostasis, cannot be completely excluded.

An interesting observation was that despite the large number of markers available between markers D1M7Mit206 and D1Rat112 (Figure 1), SHR and WKY showed an unusually low polymorphism rate (2%) in this chromosomal region; the rate was significantly lower than that previously reported in our strains (50%) on the basis of genome-wide evaluations.²⁶ If variations in the polymorphism rate of microsatellites between strains reflect the extent of genetic divergences, this observation suggests a high genetic conservation in this region between WKY and SHR strains that are derived from common ancestors. Any biological significance of this is unclear, but at this stage, it prevented the lower margin of the region containing putative QTL 2 to be defined with more accuracy.

SISA1 contains a congenic segment of <3 cM. This should facilitate the physical mapping of the BP QTLs present in this segment and identification of the susceptibility genes. A further immediate dividend is that the segment is homologous with only 1 region of the human genome, on chromosome 11p15.1–11p15.4.²² This should now form a focus of special interest in genetic studies of hypertension in humans. Analysis of this region of human chromosome 11 reveals a number of potential candidate genes, including the vasoactive peptide adrenomedullin. Initial studies have not revealed any major structural difference in the transcripts of the SHR and WKY adrenomedullin genes (S. Frantz, unpublished data, 2000). However, further studies of expression of the gene as well as similar analysis of other genes and the rapidly increasing number of expressed sequence tags being localized to this region of rat chromosome 1 should help to identify the most likely candidates.

In summary, analysis in congenic substrains of a region of rat chromosome 1 that has been shown to have an effect on BP has revealed a more complex pattern of genetic effect than would have been predicted from linkage analysis, with evidence for at least 2, if not more, QTLs affecting BP. Isolation of 1 of the QTLs in a congenic segment of <3 cM should help to facilitate identification of the responsible gene and to investigate the role of the homologous region in the genetic susceptibility to essential hypertension.

	Acknowledgments

 
This study was supported by funding from the British Heart Foundation and the EURHYPGEN Concerted Action of the European Commission. D. Gauguier holds a Wellcome Trust Senior Fellowship in basic biomedical science. We are grateful to staff from the Biomedical Services, University of Leicester, for their help with the study.

Received October 4, 2000; first decision November 7, 2000; accepted February 12, 2001.

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