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Two Linked Blood Pressure Quantitative Trait Loci on
Chromosome 10 Defined by Dahl Rat Congenic Strains
Michael R. Garrett, Xiaotong Zhang, Oksana I. Dukhanina, Alan Y. Deng, 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.
(Hypertension. 2001;38:779-785.)
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Key Words: sodium 䡲 genetics 䡲 blood pressure
R
at chromosome 10 (RNO10) has been shown by linkage
analysis to contain a quantitative trait locus (QTL) that
influences blood pressure (BP). This result was obtained in
experiments using spontaneously hypertensive rats (SHR) or
stroke-prone SHR crossed with various normotensive
strains,1– 6 with Dahl salt-sensitive (S) rats crossed with
various normotensive strains7–10 and with a cross of the
genetically hypertensive (GH) strain to Brown Norway.11 We
also previously confirmed the rat BP QTL on RNO10 by
constructing congenic strains in which low BP alleles from
normotensive strains were placed on the genetic background
of the S rat.9,12 Thus, this is one of the more impressive and
consistently observed QTLs found in the hypertensive rat
models. The homologous region of human chromosome 17
(HSA17) was subsequently shown by sib-pair analysis to
influence BP in two studies.13,14
The definition of QTL by linkage analysis provides only a
very crude localization of the causative locus. For this reason,
the initial congenic strains constructed to verify the existence
of a QTL span relatively large segments of chromosome to
ensure that the QTL is encompassed. The purpose of the
present study was to develop congenic substrains from the
existing congenic strains on RNO10 to define the BP QTL
location for ultimate gene identification. These substrains are
constructed in such a way as to systematically reduce the
introgressed donor chromosomal segment. A reduced segment that still retains a BP effect in the congenic substrain
refines the position of the QTL on the genetic map.
In our previous studies with linkage analysis that involved
S rats crossed with various normotensive strains, we concluded that RNO10 was likely to contain two linked BP
QTLs.8 This was based mainly on the very broad region with
significant linkage to BP in a cross of S with the Milan
normotensive strain (MNS). The present work proves that this
is in fact the case, and one of these QTLs aligns within reason
to the homologous region of HSA17 that reportedly contains
a BP QTL.
Methods
All rats used in the present study were bred in our colony, and we
followed procedures in accordance with institutional guidelines.
Inbred Dahl salt-sensitive (SS/Jr) rats were bred in our colony15 and
are referred to as S rats. Congenic strains used as starting strains in
this work were reported previously. Congenic strain S.MNS(10b)
contains a segment of RNO10 from the MNS on the S rat genetic
background.12 Congenic strain S.LEW(10) contains a segment of
RNO10 from Lewis (LEW) rats on the S rat genetic background.9
Congenic substrains were constructed from progenitor congenic
strains as follows. The congenic strain was crossed to S, and the F1
population was intercrossed to produce a large F2 population of 250
rats. The F2 rats were genotyped using microsatellite markers
throughout the congenic region. DNA for genotyping was prepared
from tail biopsy tissue using the QIAamp Tissue Kit (Qiagen Inc).
Congenic substrains were developed from rats that had useful
recombinant chromosomes in the region of interest. Such rats were
crossed with S to duplicate the recombinant chromosome and then
selectively bred to fix the recombinant chromosome in the homozygous state on the S background. Techniques for microsatellite
genotyping by the polymerase chain reaction and construction of
linkage maps have been described previously.7,9,12
Received December 7, 2000; first decision January 25, 2001; revision accepted March 14, 2001.
From the Department of Physiology and Molecular Medicine, Medical College of Ohio, Toledo. Dr Dukhanina is now with the Laboratory of Cell
Regulation and Carcinogenesis, National Institutes of Health, Bethesda, Md. Dr Deng is now with the Research Centre-CHUM, Montreal, Quebec,
Canada.
Correspondence to John P. Rapp, DVM, PhD, Department of Physiology and Molecular Medicine, Medical College of Ohio, 3035 Arlington Ave,
Toledo, OH 43614-5804. E-mail [email protected]
© 2001 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
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Figure 1. Congenic strains for RNO10 with LEW as
the donor strain on the S rat genetic background.
The linkage map is at the right, and the numbers
denote map distances in cM. The centromere is
toward the top of the map. The filled bars to the
left of the linkage map indicate the extent of the
LEW donor regions for each congenic strain. The
open bars on the ends of these congenic segments indicate the interval in which recombination
occurred. The effect on BP of each strain compared with S rats is shown on the graph at the
bottom. BP effect is defined as the BP of congenic
rats (n⫽20) minus BP of concomitantly studied S
rats (n⫽20); the standard error of this difference is
indicated.. Filled columns indicate a significant
effect on BP (at least P⬍0.001) between the congenic strain and S. An open column indicates that
the BP effect was not significant (P⬎0.05). A negative BP deviation means that the congenic strain
had a lower BP than concomitantly studied S rats.
BP was measured by the tail-cuff method on conscious restrained
rats warmed to 28°C using semiautomatic equipment (IITC, Inc, Life
Science Instruments) as described in detail previously.12 Briefly, 20
male S and 20 male congenic rats were age matched, housed in the
same cages, and raised and studied concomitantly. Starting at 40 to
42 days of age, the rats were fed a 2% NaCl diet (Teklad diet
TD94217; Harlan Teklad). BP measurements were taken on 4
consecutive days starting on the 24th day on the 2% NaCl diet. The
final BP of a rat was taken as the average of the 4 consecutive day
determinations.
Radiation Hybrid and Comparative Mapping
The radiation hybrid maps were compiled from data obtained from
the Rat Genome Database at the Medical College of Wisconsin
(www.rgd.mcw.edu) and The Wellcome Trust Center for Human
Genetics (www.well.ox.ac.uk/rat_mapping_resources). Markers not
already on the radiation hybrid map from these two sources,
including markers denoted as D10Mco (Medical College of Ohio
microsatellite markers) and genes Pdk2, Mapt, Srp68, Galr2, and
Aanat, were mapped by testing all 106 samples in the rat radiation
hybrid panel (Research Genetics). Primers for these markers are
available on our Web site (www.mco.edu/depts/physiology/
research). The regions in mice and humans homologous to our BP
QTL regions were identified using The Mouse Genome Informatics
Database (www.informatics.jax.org) and Online Mendelian Inheritance in Man (OMIM) at The National Center for Biotechnology
(www.ncbi.nlm.nih.gov).
Development of New Gene Markers
For a better comparison of the QTL region across species, all of the
genes that map to our QTL regions in mice and humans were
checked for the availability of rat sequence data. If the rat sequence
was available for any gene that mapped to the QTL region in mice
or humans, a primer set was developed and placed on the rat
radiation hybrid map. The genes placed on the rat radiation hybrid
map in this way were Pdk2, Mapt, Srp68, Galr2, and Aanat.
Results
Two series of congenic strains that define BP QTLs on
RNO10 are presented. In the first case, the donor strain was
LEW on the S background, and in the second case, the donor
strain was MNS on the S background.
Garrett et al
HW/BW Ratio for Comparison of S and Congenic Strains
HW/BW Ratio, mg/g
Congenic Strain
Tested
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S
Congenic
t Test P
S.LEW(10)
4.161 (0.046)
3.758 (0.027)
⬍0.0001
S.LEW⫻1
4.265 (0.032)
3.890 (0.034)
⬍0.0001
S.LEW⫻5
4.048 (0.034)
4.008 (0.053)
0.53
S.LEW⫻6
4.386 (0.054)
3.885 (0.021)
⬍0.0001
S.LEW⫻11
4.346 (0.066)
4.005 (0.038)
⬍0.0001
S.LEW⫻12
4.260 (0.067)
4.020 (0.036)
0.003
S.MNS(10b)
4.308 (0.061)
3.839 (0.043)
⬍0.0001
S.MNS⫻1
4.105 (0.043)
3.944 (0.033)
0.005
S.MNS⫻2
4.221 (0.064)
4.016 (0.047)
0.014
S.MNS⫻3
4.086 (0.031)
3.968 (0.033)
0.013
S.MNS⫻3⫻2
4.239 (0.087)
4.281 (0.046)
0.67
S.MNS⫻3⫻4
4.162 (0.037)
3.995 (0.035)
0.003
S.MNS⫻3⫻5
4.084 (0.038)
4.193 (0.049)
0.088
S.MNS⫻4
4.297 (0.094)
3.817 (0.026)
⬍0.001
S.MNS⫻5
4.266 (0.054)
3.978 (0.035)
⬍0.001
S.MNS⫻12
4.418 (0.061)
4.161 (0.058)
0.005
S.MNS⫻13
4.241 (0.033)
4.219 (0.043)
0.69
S and congenic strains were always studied concomitantly; there were 20
male rats in each group. Values are group mean values with SEM in
parentheses.
Figure 1 shows the progenitor strain S.LEW(10) and 5
congenic strains derived from the progenitor strain. This
original strain had a 74-cM segment from LEW rats introgressed into the S genetic background and showed a major
lowering of BP by ⬇43 mm Hg compared with that of S. This
has been reported previously.9 Congenic strains S.LEW⫻1
and S.LEW⫻6 were derived from opposite ends of
S.LEW(10) and overlap in the middle of S.LEW(10) (Figure
1). Both of these overlapping strains also have lower BP by
⬎40 mm Hg compared with that of S, implying that a BP
QTL resides in the overlap region. This was confirmed by the
construction of two shorter congenic strains, S.LEW⫻11 and
S.LEW⫻12, which were derived from S.LEW⫻1. Both
S.LEW⫻11 and S.LEW⫻12 have significantly lowered BP
(28 and 25 mm Hg, respectively) compared with S. Thus,
there is a BP QTL in the segment defined by the shorter of
these two smaller strains. The QTL is in the region defined by
S.LEW⫻12 (ie, ⬍12 cM between D10Mco58 and
D10Rat24). This QTL is labeled QTL 1 in Figure 1.
For contrast, Figure 1 also shows a congenic strain,
S.LEW⫻5, that has no significant BP effect compared with S.
In the Table, it can be seen that when there was a significant
BP effect of a congenic strain, this was corroborated by a
significant effect on the heart weight–to– body weight (HW/
BW) ratio. Conversely, strain S.LEW⫻5 showed no effect on
BP and no changes in the HW/BW ratio.
Figure 2 shows the first iteration of 5 congenic strains
derived from the congenic strain S.MNS(10b). This original
strain had a 32-cM segment from MNS rats introgressed into
the S genetic background and showed a BP-lowering effect of
34 mm Hg compared with S. This has been reported previously.12 In this case, the series of congenic strains constructed
Rat Chromosome 10 QTL
781
from each end of the original strain suggests that there are two
linked QTLs in the region covered by the original congenic
strain. As the strains become progressively shorter at each
end, BP effects were still retained at each end. Two nonoverlapping strains, S.MNS⫻5 and S.MNS⫻3, had significant BP
effects of 37 and 19 mm Hg. The regions spanned by these
strains are labeled QTL 1 and QTL 2 in Figure 2. Note that
QTL 1 in Figure 2 overlaps with the QTL region of Figure 1,
which is also labeled QTL 1.
Both QTL 1 and QTL 2 have been further dissected.
Figure 3 shows two congenic strains, S.MNS⫻12 and
S.MNS⫻13, derived from S.MNS⫻5 to better localize
QTL 1. S.MNS⫻12 retains the BP effect, but S.MNS⫻13
does not, which localizes the QTL 1 to the differential
segment between the two strains. Thus, QTL 1 is in the
interval between D10Rat27 and D10Rat24, a region ⬍2.6
cM (Figure 3).
Figure 4 shows 3 congenic strains derived from S.MNS⫻3
to better localize QTL 2. In this case, two nonoverlapping
strains, S.MNS⫻3⫻5 and S.MNS⫻3⫻2, derived from the
ends of the progenitor strain were constructed, and neither
showed a BP effect. This localizes QTL 2 to the interval
between D10Rat12 and D10Mco70, a region of ⬍3.2 cM
(Figure 4). This interpretation was confirmed by strain
S.MNS⫻3⫻4, which does have a significant BP-lowering
effect of 17 mm Hg and spans the newly defined QTL 2
interval.
The BP data that define QTL regions 1 and 2 in Figures 2
through 4 for congenic strains derived from the MNS donor
are corroborated by HW/BW data (Table). Thus, when there
is a significant decrease in BP of a congenic strain compared
with S, the HW/BW ratio also decreases. Conversely, when a
strain had no BP effect, the HW/BW ratio also shows no
effect.
It is noted that the QTL 2 region defined in Figure 4 was
seen only in the congenic strain series where the donor strain
was MNS. When the donor strain was LEW, QTL 2 was not
detected. In Figure 1, the strain S.LEW⫻5 derived from the
LEW donor rat spans the QTL 2 region but does not have a
BP effect.
Discussion
Genetic linkage analysis to discover BP QTLs has been
widely practiced using hypertensive rat strains. This work
was recently reviewed; in particular, a detailed analysis of
previous work on RNO10 is contained therein.16 This discussion emphasizes the present data and compares them with
pertinent data on HSA17.
Linkage analysis of QTL is inherently imprecise at localization of the gene or genes responsible for a QTL. If
construction of a congenic strain confirms the presence of a
QTL, subsequent construction of congenic substrains allows
more precise QTL localization and the identification of
multiple QTLs in a region that are impossible to define by
linkage analysis.
Previously, we studied F2 populations obtained by crossing S with MNS7 or by crossing S with LEW.9 Linkage
analysis indicated the presence of BP QTLs on RNO10 in
both F2 populations, and initial congenic strains confirmed
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Figure 2. Congenic strains for RNO10 with MNS
as the donor strain on the S rat genetic background. The format is identical to that in Figure 1.
the presence of QTLs with either MNS12 or LEW9 as the
donor of large regions of RNO10. In the present study, the
congenic series developed with MNS as the donor of
segments of RNO10 revealed two BP QTLs, called QTL 1
and QTL 2. The QTL 1 region from the MNS congenic
series overlaps with the QTL defined with the LEW
congenic series. This is a uniquely powerful result for the
existence and localization of a QTL from two independent
congenic series. It means that both LEW and MNS
probably carry functionally important contrasting alleles
compared with S for a gene (or genes) in the QTL 1 region.
In contrast to QTL 1, the QTL 2 region was identified in
the congenic series derived from MNS but not from LEW.
This implies that at QTL 2, the LEW and S alleles are not
functionally different with regard to BP.
Although the production of multiple congenic substrains is
tedious, it does provide a systematic way to localize the QTL.
In the case of the MNS-derived congenic series, the localiza-
tion was improved ⬇25-fold, from 74 cM in the original
congenic strain to ⬍2.6 cM for QTL 1 and ⬍3.2 cM for QTL
2. This required two iterations of substrain construction.
Noteworthy is the fact that these localizations do not include
important candidate loci ACE (ACE) and the inducible form
of NO synthase (Nos2).
It is not particularly surprising to find evidence for multiple
QTLs by congenic strain analysis of a region in which only 1
QTL peak was detected on linkage analysis. This has been
observed with QTLs for BP on rat chromosome 2 (RNO2)
(M.R.G. and J.P.R., unpublished observations), polycystic
kidney disease in mice,17 trypanosomiasis resistance in
mice,18 systemic lupus erythematosus in mice,19 and epilepsy
in mice.20 There also is evidence for 3 BP QTLs on rat
chromosome 1 (RNO1) based on congenic analysis.21 In this
case, linkage analysis had clearly suggested multiple loci,9,22,23 because some of the loci were far enough apart on the
chromosome.
Garrett et al
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Figure 3. Congenic strains on RNO10 that better define the QTL
1 from Figure 2. The format is identical to that in Figure 1.
The region of HSA17 that is homologous to RNO10 has
been studied for linkage to BP. Julier et al13 used a sib-pair
analysis and found significant linkage of BP to markers in the
region of HSA17 homologous to the BP QTL region of
RNO10 as initially crudely defined by linkage analysis. In
particular, human marker D17S934 was near the center of the
region on HSA17 associated with BP that overlapped with the
rat BP QTL. Similar data obtained by Baima et al14 confirmed
this result.
With the markedly improved QTL localization on RNO10
presented here, it is of interest to reexamine how closely the
rat BP QTLs align with the human linkage data on HSA17. It
is emphasized that although the present congenic rat data are
relatively precise, the human QTL localizations are necessarily less well defined. Thus, the following discussion should
be interpreted with caution. Figure 5 shows comparative
maps for the BP QTL region of interest for rats, mice, and
humans. Because RNO10 and mouse chromosome 11
(MMU11) are well conserved and because the mouse map
contains many more known loci than the rat map, the mouse
map serves as a good bridge for comparisons between rats
and humans. Although there certainly are many loci common
to MMU11 and HSA17, the order of the loci is not com-
Rat Chromosome 10 QTL
783
Figure 4. Congenic strains on RNO10 that better define the QTL
2 from Figure 2. The format is identical to that in Figure 1.
pletely identical between humans and mice. This has an
impact on how closely the human and rat BP QTLs can be
colocalized.
In Figure 5, the critical human marker D17S934 maps
between rat BP QTL 1 and QTL 2 on the mouse/rat maps.
This is based on the map position of D17S934 on the human
gene sequence map and the association of the majority of loci
in this human region with a comparable mouse region that
clearly lies between the rat BP QTL 1 and QTL 2. This region
includes GFAP (glial fibrillary acidic protein), which is in a
human BAC (bacterial artificial chromosome) contig with
D17S934; the two loci are ⬇64 kb apart. Note, however, that
two other genes in the human region around GFAP in Figure
5 (ITGA2B and ITGB3) are located in the mouse (and by
inference, in the rat) in a different location very close to rat
BP QTL 2. Thus, it is at least conceivable that because of
rearrangements of small chromosomal regions between species, the same QTL is in a different relative position between
species. That is, in Figure 5, the human QTL that is near
human loci ITGA2B and ITGB3 could be the same QTL that
is near mouse/rat loci Itga2b and Itgb3. The other alternative
is that the human and rat QTL are different and ⬇7 cM apart
on the mouse map (ie, the distance on the mouse map from
Gfap at 62 to 69 cM at approximately the center of the
RNO10 QTL 2) (Figure 5). The present data do not permit a
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Figure 5. Comparative maps for rat,
mouse, and human. The map at the left
is our radiation hybrid map for rat chromosome 10 (RNO 10) from BP QTL 1 to
QTL 2; the scale (bottom left) is in centirays (cR). The QTL regions are shown at
the extreme left next to the radiation
hybrid map. The center map is the linkage map for the homologous region of
mouse chromosome 11 (MMU 11); the
scale is in centiMorgans (cM). The right
column lists representative human loci
on human chromosome 17 (HSA 17)
common to both human and mouse
maps; the scale is in megabases (Mb).
The human loci are given in the order in
which they occur within segments of the
human gene sequence map along with
their cytogenic localizations. Note, however, that segments of HSA17 have been
rearranged to align with the mouse
sequence. The upper segment of HSA17
(69.5 to 58.4 Mb) is inverted to align with
the mouse, and the center section of
HSA17 (50.2 to 53.6 Mb) actually should
precede the inverted upper section on
the human map. The mouse and rat
maps, in contrast, have similar gene
orders without rearrangement of segments. Dashed lines are drawn only
between representative loci for orientation. D17S934 at the extreme right is a
human marker that was associated with
hypertension.13,14 The solid lines show
the shift in position of ITGA2B and
ITGB3 between human and mouse. The
human and mouse data are from
www.ncbi.nlm.nih.gov and www.
informatics.jax.org, respectively.
conclusion as to which possibility is correct because one
cannot tell which mouse/rat locus, Gfap or Itga2b/Itgb3, is
the appropriate one to locate the human QTL on the mouse/
rat maps.
In a recent study, Levy et al24 used longitudinal family BP
data from the Framingham Heart Study to perform a genome
scan. A major BP QTL was found on HSA17, which spans a
large interval that includes the region just discussed.13,14 The
best localization we can discern from their data are from
markers with the highest 2-point LOD scores. These are
D17S1299 and D17S2180 (ATC6A06), which are at 46.5 and
56.2 Mb on the human gene sequence map. This obviously
spans the critical segment that contains GFAP and D17S934,
which are at 51.2 Mb.
Another locus of interest in humans is pseudohypoaldosteronism type II, which is associated with hypertension. One
locus for this syndrome has been localized to HSA17 near
marker D17S250 located at 42.2 Mb.25 This places it ⬇10 Mb
from GFAP and the marker D17S934 in Figure 5 and does not
allow one to definitively include or exclude the pseudohy-
poaldosteronism type II locus from the BP QTL discussed
here.
Other studies by sib-pair analysis in humans have not
found BP QTLs that match with either of the RNO10 BP
QTLs. Krushkal et al26 and Perola et al27 found no linkage to
HSA17. Xu et al28 did detect BP linkage to HSA17, but this
was located in the p arm of HSA17, ⬇40 cM from the region
noted here, which was in the q arm.
Acknowledgments
This work was supported by grants from the National Institutes of
Health (Dr Rapp) and by the Helen and Harold McMaster Endowed
Chair in Biochemistry and Molecular Biology (Dr Rapp). Dr Deng is
an Established Investigator of the American Heart Association. We
thank Howard Dene for helpful discussions on computer identification of genes and for reading the manuscript.
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Two Linked Blood Pressure Quantitative Trait Loci on Chromosome 10 Defined by Dahl
Rat Congenic Strains
Michael R. Garrett, Xiaotong Zhang, Oksana I. Dukhanina, Alan Y. Deng and John P. Rapp
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Hypertension. 2001;38:779-785
doi: 10.1161/hy1001.091503
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