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(Hypertension. 2000;35:179.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Applicability of a "Speed" Congenic Strategy to Dissect Blood Pressure Quantitative Trait Loci on Rat Chromosome 2
From the Department of Medicine and Therapeutics (B.J., C.D.N., D.G., J.S.C., N.H.A., A.F.D.), University of Glasgow, Western Infirmary, Glasgow, UK; and The Wellcome Trust Centre for Human Genetics (D.G.), Oxford, UK.
Correspondence to Prof Anna F. Dominiczak, Department of Medicine and Therapeutics, Western Infirmary, Glasgow G11 6NT, UK. E-mail anna.dominiczak{at}clinmed.gla.ac.uk
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Abstract |
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Abstract—The identification of any quantitative trait locus (QTL) via a genome scan is only the first step toward the ultimate goal of gene identification. The next step is the production of congenic strains by which the existence of a QTL may be verified and the implicated chromosomal region be reduced to a size applicable to positional cloning of the causal gene. We used a speed congenic breeding protocol previously verified in mice for 2 blood pressure QTLs on rat chromosome 2. Four congenic strains were produced through introgression of various segments of chromosome 2 from Wistar-Kyoto rats from Glasgow colonies [WKY(Gla) rats] into the recipient stroke-prone spontaneously hypertensive rats from Glasgow colonies [SHRSP(Gla)], and vice versa. The number of backcross generations required for each strain to achieve complete homozygosity at 83 background genetic markers in a "best" male varied between 3 and 4. Transfer of the region of rat chromosome 2 containing both QTLs from WKY(Gla) into an SHRSP(Gla) genetic background lowered both baseline and salt-loaded systolic blood pressure by
20 and 40 mm Hg in male congenic rats compared with the SHRSP parental strain (F=53.4, P<0.005; F=28.0, P< 0.0005, respectively). In contrast, control animals for stowaway heterozygosity presented no deviation from the blood pressure values recorded for the SHRSP(Gla), indicating that if such heterozygosity exists, its effect on blood pressure is negligible. A reciprocal strategy in which 1 or both QTLs on rat chromosome 2 were transferred from SHRSP(Gla) into a WKY(Gla) genetic background resulted in statistically significant but smaller blood pressure increases for 1 of these QTLs. These results confirm the existence of blood pressure QTLs on rat chromosome 2 and demonstrate the applicability of a speed congenic strategy in the rat and emphasize the important role of the genetic background.
Key Words: hypertension, genetic • genes • rats, inbred strokeprone SHR
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Introduction |
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Genome wide linkage analysis has proved to be successful during the past decade in the localization of large chromosomal regions containing putative quantitative trait loci (QTLs) for high blood pressure,1 2 3 left ventricular hypertrophy,3 and ischemic stroke4 in F2 crosses derived from the stroke-prone spontaneously hypertensive rat (SHRSP) and its normotensive reference strain, the Wistar-Kyoto (WKY) rat. In particular, we previously identified 2 separate blood pressure QTLs on rat chromosome 2.3 The most significant of these had its peak (logarithm of the odds [LOD] 3.6) close to the microsatellite marker D2Mit6 and was determined for both baseline and salt-loaded systolic and diastolic blood pressures in male and female F2 cohorts. The second QTL (LOD 3.1) was localized 73 cM from D2Mit6 and contributed to salt-loaded blood pressure in the male F2 cohort only.
The identification of such a blood pressure QTL is only the first step toward the ultimate goal of gene identification, which can be achieved through genetic and physiological analyses of congenic lines derived from the locus.5 A congenic strain is one in which the chromosomal region harboring the QTL of interest in one strain (the recipient) has been selectively replaced by the homologous region from another strain (the donor). If the blood pressure of the congenic strain is significantly different from that of the recipient strain, it can be concluded that this particular chromosomal fragment does indeed possess a QTL that contributes to a difference in blood pressure between the donor and recipient strains.
Congenic strains have traditionally been produced by serially backcrossing the donor strain with the recipient strain, accompanied at every generation by selection for progeny heterozygous for the desired chromosomal region. According to mendelian principles, from 8 to 12 backcrosses are necessary to ensure that >99% of the donor’s genetic background has been replaced by that of the recipient. On completion of these backcrosses, brother-sister mating makes the desired chromosomal region homozygous for the donor’s alleles. This relatively simple breeding strategy has resulted in the emergence of several rat congenic lines during the past 2 years that confirm the existence of QTLs involved in blood pressure regulation on rat chromosomes 1,6 7 2,8 3,9 5,10 7,11 8,12 9,13 10,14 13,15 16 17 and 19.18 However, these have all taken 3 to 4 years to produce,7 a length of time that has significantly delayed the speed of progress toward the identification of the gene or genes involved.
Theoretical calculations by Lander and Schork19 suggested that congenic strain production may be "speeded up" with repeated screening of polymorphic marker loci distributed throughout the entire genetic background, thereby allowing the specific selection of a male from each backcross with the least amount of donor alleles remaining in the genetic background. Breeding with these "best" males would allow the rate of background donor elimination to be dramatically accelerated, thereby reducing the number of generations necessary to construct a congenic strain. Computer simulations have indicated that a relatively modest selection effort (60 background markers, 25-cM marker spacing, 16 males per generation) would typically reduce unlinked donor genome contamination to <1% by 4 backcross generations.20 21 The development of 10 "speed" congenic mice strains carrying defined genomic intervals derived from nonobese diabetic or NZM2410 strains on the C57BL/6 genome22 23 provided results that closely parallel these predicted outcomes. Recent improvements in the density of microsatellite-based genetic maps for the rat,24 25 as well as the production of similarly informative high-resolution radiation hybrid maps,26 27 28 have greatly increased the range of molecular tools available in this species. It follows that the purpose of the current study was to use a speed congenic strategy to dissect the QTLs on rat chromosome 2.
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Methods |
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Rat Strains
Inbred colonies of SHRSP from Glasgow colonies [SHRSP(Gla)] and WKY rats from Glasgow colonies [WKY(Gla)] have been established at the University of Glasgow since December 1991. These colonies result from the strain-specific brother-sister mating of 13 SHRSP and 13 WKY (6 males and 7 females of each) that were obtained from Dr D.F. Bohr (Department of Physiology, University of Michigan [Ann Arbor]), where they had been maintained as inbred colonies for >15 years. Their breeding stocks were originally obtained from the National Institutes of Health (Bethesda, Md). All rats were housed under controlled conditions of temperature (21°C) and light (12-hour light/dark cycle; 7 AM to 7 PM) and maintained on normal rat chow (rat and mouse No.1 maintenance diet; Special Diet Services) and water ad libitum. These studies were approved by the Home Office according to regulations regarding experiments with animals in the United Kingdom.
Congenic Crosses
The development of the speed congenic strains used in this study involved the transfer of various segments of rat chromosome 2 from WKY(Gla) to the genetic background of SHRSP(Gla), and in the reciprocal direction from SHRSP(Gla) to the genetic background of WKY(Gla). This required the production of an F1 generation through the crossing of WKY(Gla) and SHRSP(Gla). Male F1 hybrids were then mated to the desired recipient strain [WKY(Gla) or SHRSP(Gla)]. Microsatellite markers throughout the desired QTL (Figure 1) and an additional 83 broadly spanning the remaining genome (Table 1) were genotyped in the offspring from this first backcross. The selection of these markers was based on the need for thorough coverage of the entire rat genome and location around the QTLs we previously identified.3 Databases used to fulfill this selection included Ratmap: The Rat Genome Database (Göteborg University, Sweden; http://ratmap.gen.gu.se/), The Whitehead Institute Center for Genome Research Rat Mapping Project (http://www.genome.wi.mit.edu/rat/public/), and The Wellcome Trust Centre for Human Genetics Genetic Linkage Maps of the Rat Genome (http://www.well.ox.ac.uk/~bihoreau/). The males identified as heterozygous for the marker alleles within the various segments of rat chromosome 2 but mostly homozygous for the recipient alleles throughout the remaining genome were selected as the "best" for breeding and thus backcrossed again to the recipient strain to produce a second backcross generation. This procedure was repeated in all offspring after every backcross until the donor’s genetic background was eradicated as indicated by the 83 background markers. Once a male and a female were identified in which all visible background heterozygosity had been removed, they were crossed to obtain rats homozygous for the donor alleles throughout the chromosome 2 regions of interest. These congenic strains were maintained through brother-sister mating.
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A possible criticism of this speed congenic protocol is that regardless of how complete the coverage is of the genetic background achieved through the use of microsatellite markers, it remains possible for a region of heterozygosity in the background to be missed and thus fixed along with the QTL in the final production of the congenic strain. It follows that any observed phenotypic change might not be due to the QTL but rather these hidden "stowaway" loci containing residual genetic material from the donor strain. A control congenic strain was constructed through introgression of a region of rat chromosome 2 abutting, but not overlapping, the chromosomal segments that include the 2 putative blood pressure QTLs (Figure 1). These animals have been through the same selection processes as the true congenics, and although they do not contain the donor QTLs, they will contain in their genetic background the same, if any, residual heterozygosity. Whether these animals go on to display a change in phenotype similar to that observed in the true congenics will determine not only the validity of the QTL but also the use of a speed congenic strategy.
Genotyping
To obtain DNA samples from the congenic backcrosses, the offspring were briefly anesthetized at 4 weeks of age with halothane, and a 4-mm tip from the tail was removed and placed into a 1.5-mL Microfuge tube. The wound was immediately sealed with an electric cauterizer (Engel-Loter 100S), and the tails were stored at -20°C. Genomic DNA was isolated as previously described.29 Genotyping was performed through PCR amplification of DNA around the polymorphic microsatellite markers from the total genomic DNA with the use of the appropriate PCR primer pairs (custom made by either Research Genetics or Genosys Biotechnologies) as previously described).3 4
Blood Pressure Measurement
The Dataquest IV telemetry system (Data Sciences International) was used for the direct measurement of systolic, diastolic, and mean arterial pressures as previously described.3 30 Surgical implantation of each telemetry transmitter took place under standard sterile conditions in animals at 12 weeks of age. Hemodynamic measurements were made for 10 seconds every 5 minutes. To allow complete stabilization of blood pressure after surgery, experimental measurements were made from day 7 through day 42 after surgery and were considered "baseline hemodynamic measurements." On day 43, rats on telemetry received 1% NaCl in their drinking water; this was continued for 3 weeks until the rats were euthanized. Data collected during this period were considered "salt-loaded hemodynamic measurements."
Statistical Analysis
A total of 10 080 measurements of each blood pressure phenotype were made on each animal during the 5-week baseline phase, and 6048 measurements were made during the 3-week salt-loaded phase. Within each phase, hemodynamic measurements were separated into daytime (7 AM to 7 PM) and nighttime (7 PM to 7 AM) periods. Summary statistics were provided for each combination of experimental phase and time of day through the calculation of overall mean and SEM values separately by sex and congenic strain. We calculated that this study has an 80% power to detect a 6 mm Hg blood pressure difference between a given congenic strain and its appropriate parental control. Comparisons of congenic strains with their corresponding background parental strains were made with repeated measures ANOVA of daytime or nighttime mean values for each individual week of the 2 phases, with F statistics and probability values reported that correspond to the main effects for sex and strain.
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Results |
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Two congenic strains (SP.WKYGla2a and SP.WKYGla2b) were produced through introgression of the regions of rat chromosome 2 from WKY(Gla) into the recipient SHRSP(Gla) strain (Figure 1), and two congenic strains (WKY.SPGla2c and WKY.SPGla2d) were produced through introgression of the regions of chromosome 2 from SHRSP(Gla) rats into the recipient WKY(Gla) strain (Figure 1). In the nomenclature of the congenic strains, the first abbreviation refers to the recipient, and the second refers to the donor. The number 2 refers to chromosome 2, and a, b, c, and d are arbitrarily assigned to each strain. The number of generations of backcrossing required for each strain to achieve complete homozygosity of the background genetic markers in a best male that could then be used to fix the line is highlighted in Table 2. This varied between BC3 and BC4 (in which BC indicates backcross) for all strains examined. A total of 277 progeny were screened to produce the 4 speed congenic strains, for an average of 69 animals per strain and 19 animals per backcross. Two years 6 months was required on average to produce the congenic lines (for SP.WKYGla2a, 2 years and 2 months, and for SP.WKYGla2b, 2 years and 7 months; for WKY.SPGla2c, 2 years and 9 months, and for WKY.SPGla2d, 2 years and 6 months).
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The region of rat chromosome 2 transferred into the congenic strain SP.WKYGla2a incorporates both blood pressure QTLs we previously identified (Figure 1). Baseline and salt-loaded systolic blood pressures in the SP.WKYGla2a congenic strains are shown in Figure 2, and mean and diastolic blood pressures are given in Tables 3 and 4. All blood pressure subphenotypes, either at baseline or salt loaded, are significantly lower in this congenic line compared with the SHRSP parental strain. There also are highly significant sex differences within the strains (Figure 2 and Tables 3 and 4). In comparison, the "control" congenic strain, SP.WKYGla2b, which contains no QTLs, displayed no significant difference in any blood pressure phenotype from those of the SHRSP (Figure 3). Two congenic strains with the SHRSP donor and the WKY recipient were WKY.SPGla2c (containing both chromosome 2 QTLs) and WKY.SPGla2d (containing the QTL with a peak LOD score close to D2Mit6) (Figure 1). The congenic strain WKY.SPGla2c displayed baseline but not salt-loaded systolic blood pressures that were significantly higher than those of the WKY control strain (Figure 4). However, the magnitude of difference was significantly less than that for the congenic strain SP.WKYGla2a. The congenic strain WKY.SPGla2d showed no blood pressure differences at baseline or after salt loading for any of the blood pressure subphenotypes studied. The body weight values did not differ between the congenic lines and the parental controls. Heart weight–to–body weight ratios showed a trend to follow the blood pressure differences, but this did not achieve statistical significance (eg, male SHRSP [4.5±0.3 mg/g] versus SP.WKYGla2a [4.1±0.1 mg/g]; P=0.1).
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, 
) and nighttime (
, 
) systolic blood pressure. Data points were calculated as 12-hour average daytime (7 AM to 7 PM) value and 12-hour average nighttime (7 PM to 7 AM) value. Arrows (from left to right) indicate timing of implantation of telemetry probe, beginning of baseline blood pressure measurements, and beginning of salt-loaded measurements. Values are mean±SEM.
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Discussion |
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The presentation in this study of 4 speed congenic strains derived for rat chromosome 2 clearly demonstrates the applicability of such a strategy in the rat for the fine mapping of rat QTL. Selecting the "best" male at each generation, an average of only 19 rats per backcross were necessary to reduce all unlinked donor genome contamination to below 1% within 3 or 4 backcrosses, despite the selection of a relatively modest number of 83 microsatellite markers in the genetic background. Furthermore, although transfer of the entire region of rat chromosome 2 containing both QTLs from WKY into an SHRSP genetic background significantly lowered all blood pressure phenotypes, control animals for potentially artifactual "stowaway" heterozygosity presented no deviation from the blood pressure values recorded for the SHRSP, indicating that if such heterozygosity exists, its effect on blood pressure is negligible.
Some level of contaminating donor genome in the genetic background is unavoidable, even when using the traditional protocol for the construction of a congenic strain. A potential problem with this is that during the process of fixing the chromosome region of interest for the donor strain into the homozygous state, an unlinked stowaway QTL may become trapped in the residual donor loci. The presence or absence of the unknown QTL could therefore confound the interpretation that the blood pressure effect in the congenic strain is due to the intended QTL. Interestingly, although the speed congenic strategy of the present study has provided the opportunity to monitor this in the form of the SP.WKYGla2b strain and although the effect of any stowaway loci was found to be negligible, we were also able to observe several chromosomal "hotspots" at which donor alleles appeared to be preferentially conserved, including several loci implicated in blood pressure QTLs in other rat strains. The use of a speed congenic strategy enabled these loci to be monitored and enabled best males to be selected that did not contain heterozygosity in these regions. It follows that it may prove to be necessary in all congenic strategies, regardless of the breeding protocol that is used, to include some assessment of the genetic background.
Transfer of the entire region of rat chromosome 2 containing both QTLs from WKY(Gla) into an SHRSP(Gla) genetic background significantly lowered both baseline and salt-loaded systolic blood pressures by 20 and 40 mm Hg, respectively, as determined through continuous and direct recording with radiotelemetry. The results of a previous study by Deng et al8 also confirmed the existence of a blood pressure QTL on rat chromosome 2 in the region corresponding to that of the present study through the construction of 2 congenic strains that introgress the relevant region from the WKY rat or the Milan normotensive (MNS) rat into the Dahl salt-sensitive background. These strains had blood pressures of 44 and 29 mm Hg lower, respectively, than those of the Dahl salt-sensitive rats receiving a 2% NaCl diet,8 although the region introgressed into the MNS congenic was a larger chromosomal segment. Deng et al8 hypothesized that this difference could have arisen (1) if the QTL allele of the WKY rat was different from that of the MNS rat, (2) if the WKY and MNS rats have the same QTL allele in the D2Mgh12 region but the larger substitution in the MNS congenic strain also contained the D2Mit6 locus, which modified the blood pressure effects of the former QTL, or (3) if there is 1 or more additional blood pressure QTL located in this region of chromosome 2. These suggestions are partially supported by our data obtained in the reciprocal congenic strains WKY.SPGla2c and WKY.SPGla2d. A small but significant blood pressure increase was observed in the strain WKY.SPGla2c, which contains both QTLs on rat chromosome 2, compared with the WKY control strain. However, the congenic strain WKY.SPGla2d, which contains only the QTL localized around D2Mit6, showed no blood pressure differences at baseline or after salt loading. These results confirm previous suggestions that the genetic background chosen for a given congenic strain might have a profound effect on the phenotype.31
The chromosome 2 region that was introgressed in both the present study and that of Deng et al8 harbors several genes that could be construed as candidates for the blood pressure QTL; these include the angiotensin type 1B receptor gene (Agtr1b), both soluble and membrane-bound guanylate cyclases (Gca), the 
1 isoform of the Na+,K+-ATPase gene (Atp1a1), and the calmodulin-dependent protein kinase II
gene (Camk2d). Speculation as to the identity of the causal gene or genes is premature because the substituted region is still large and thus requires further investigation with the use of congenic substrains.
In conclusion, we demonstrated, for the first time, that the speed congenic strategy is applicable to the genetic dissection of experimental hypertension in the rat. Moreover, we confirmed the existence of a blood pressure QTL on rat chromosome 2, and we have begun its dissection. Our results favor the region between markers Gca and D2Mgh12 as the important blood pressure QTL for further analysis and for ultimate positional cloning.
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Acknowledgments |
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This work was supported by the BHF Program and Project grants RG97009 and PG96175 and Chest, Heart and Stroke (Scotland) to Dr Dominiczak. Dr Gauguier holds a Wellcome Senior Research Fellowship in Basic Biomedical Science. Drs Dominiczak and Gauguier are also funded by the EURHYPGEN Concerted Action of the European Community. We thank Elizabeth Beattie and James McCulloch for their expert technical assistance.
Received September 13, 1999; first decision October 11, 1999; accepted October 19, 1999.
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J. Dutil, V. Eliopoulos, E.-L. Marchand, A. M. Devlin, J. Tremblay, K. Prithiviraj, P. Hamet, A. Migneault, D. deBlois, and A. Y. Deng A quantitative trait locus for aortic smooth muscle cell number acting independently of blood pressure: implicating the angiotensin receptor AT1B gene as a candidate Physiol Genomics, May 11, 2005; 21(3): 362 - 369. [Abstract] [Full Text] [PDF]
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M. W. McBride, M. J. Brosnan, J. Mathers, L. I. McLellan, W. H. Miller, D. Graham, N. Hanlon, C. A. Hamilton, J. M. Polke, W. K. Lee, et al. Reduction of Gstm1 Expression in the Stroke-Prone Spontaneously Hypertension Rat Contributes to Increased Oxidative Stress Hypertension, April 1, 2005; 45(4): 786 - 792. [Abstract] [Full Text] [PDF]
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A. F. Dominiczak, D. Graham, M. W. McBride, N. J.R. Brain, W. K. Lee, F. J. Charchar, M. Tomaszewski, C. Delles, and C. A. Hamilton Cardiovascular Genomics and Oxidative Stress Hypertension, April 1, 2005; 45(4): 636 - 642. [Abstract] [Full Text] [PDF]
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J. Dutil, V. Eliopoulos, J. Tremblay, P. Hamet, S. Charron, and A. Y. Deng Multiple Quantitative Trait Loci for Blood Pressure Interacting Epistatically and Additively on Dahl Rat Chromosome 2 Hypertension, April 1, 2005; 45(4): 557 - 564. [Abstract] [Full Text] [PDF]
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M. Grondin, V. Eliopoulos, R. Lambert, Y. Deng, A. Ariyarajah, M. Moujahidine, J. Dutil, S. Charron, and A. Y. Deng Complete and overlapping congenics proving the existence of a quantitative trait locus for blood pressure on Dahl rat chromosome 17 Physiol Genomics, March 21, 2005; 21(1): 112 - 116. [Abstract] [Full Text] [PDF]
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Y. Kaneko, V. L. M. Herrera, T. Didishvili, and N. Ruiz-Opazo Sex-specific effects of dual ET-1/ANG II receptor (Dear) variants in Dahl salt-sensitive/resistant hypertension rat model Physiol Genomics, January 20, 2005; 20(2): 157 - 164. [Abstract] [Full Text] [PDF]
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 A. W. Cowley Jr, R. J. Roman, and H. J. Jacob Application of chromosomal substitution techniques in gene-function discovery J. Physiol., January 1, 2004; 554(1): 46 - 55. [Abstract] [Full Text] [PDF]
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M. W. McBride, F. J. Charchar, D. Graham, W. H. Miller, P. Strahorn, F. J. Carr, and A. F. Dominiczak Functional genomics in rodent models of hypertension J. Physiol., January 1, 2004; 554(1): 56 - 63. [Abstract] [Full Text] [PDF]
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A. Palijan, J. Dutil, and A. Y. Deng Quantitative trait loci with opposing blood pressure effects demonstrating epistasis on Dahl rat chromosome 3 Physiol Genomics, September 29, 2003; 15(1): 1 - 8. [Abstract] [Full Text] [PDF]
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M. W. McBride, F. J. Carr, D. Graham, N. H. Anderson, J. S. Clark, W. K. Lee, F. J. Charchar, M. J. Brosnan, and A. F. Dominiczak Microarray Analysis of Rat Chromosome 2 Congenic Strains Hypertension, March 1, 2003; 41(3): 847 - 853. [Abstract] [Full Text] [PDF]
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A. Alemayehu, L. Breen, D. Krenova, and M. P. Printz Reciprocal rat chromosome 2 congenic strains reveal contrasting blood pressure and heart rate QTL Physiol Genomics, September 3, 2002; 10(3): 199 - 210. [Abstract] [Full Text] [PDF]
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J. DUTIL and A. Y. DENG Further chromosomal mapping of a blood pressure QTL in Dahl rats on chromosome 2 using congenic strains Physiol Genomics, June 6, 2001; 6(1): 3 - 9. [Abstract] [Full Text] [PDF]
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C. D. Negrin, M. W. McBride, H. V. O. Carswell, D. Graham, F. J. Carr, J. S. Clark, B. Jeffs, N. H. Anderson, I. M. Macrae, and A. F. Dominiczak Reciprocal Consomic Strains to Evaluate Y Chromosome Effects Hypertension, February 1, 2001; 37(2): 391 - 397. [Abstract] [Full Text] [PDF]
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A. F. Dominiczak, D. C. Negrin, J. S. Clark, M. J. Brosnan, M. W. McBride, and M. Y. Alexander Genes and Hypertension : From Gene Mapping in Experimental Models to Vascular Gene Transfer Strategies Hypertension, January 1, 2000; 35(1): 164 - 172. [Abstract] [Full Text] [PDF]
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