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1.
Lucie ?edová Michal Pravenec Drahomíra K?enová Ludmila Kazdová Václav Zídek Michaela Krupková Franti?ek Li?ka Vladimír K?en Ond?ej ?eda 《PloS one》2016,11(3)
Metabolic syndrome is a highly prevalent human disease with substantial genomic and environmental components. Previous studies indicate the presence of significant genetic determinants of several features of metabolic syndrome on rat chromosome 16 (RNO16) and the syntenic regions of human genome. We derived the SHR.BN16 congenic strain by introgression of a limited RNO16 region from the Brown Norway congenic strain (BN-Lx) into the genomic background of the spontaneously hypertensive rat (SHR) strain. We compared the morphometric, metabolic, and hemodynamic profiles of adult male SHR and SHR.BN16 rats. We also compared in silico the DNA sequences for the differential segment in the BN-Lx and SHR parental strains. SHR.BN16 congenic rats had significantly lower weight, decreased concentrations of total triglycerides and cholesterol, and improved glucose tolerance compared with SHR rats. The concentrations of insulin, free fatty acids, and adiponectin were comparable between the two strains. SHR.BN16 rats had significantly lower systolic (18–28 mmHg difference) and diastolic (10–15 mmHg difference) blood pressure throughout the experiment (repeated-measures ANOVA, P < 0.001). The differential segment spans approximately 22 Mb of the telomeric part of the short arm of RNO16. The in silico analyses revealed over 1200 DNA variants between the BN-Lx and SHR genomes in the SHR.BN16 differential segment, 44 of which lead to missense mutations, and only eight of which (in Asb14, Il17rd, Itih1, Syt15, Ercc6, RGD1564958, Tmem161a, and Gatad2a genes) are predicted to be damaging to the protein product. Furthermore, a number of genes within the RNO16 differential segment associated with metabolic syndrome components in human studies showed polymorphisms between SHR and BN-Lx (including Lpl, Nrg3, Pbx4, Cilp2, and Stab1). Our novel congenic rat model demonstrates that a limited genomic region on RNO16 in the SHR significantly affects many of the features of metabolic syndrome. 相似文献
2.
Pravenec M Kren V Krenová D Zídek V Simáková M Musilová A Vorlícek J Lezin ES Kurtz TW 《Physiological research / Academia Scientiarum Bohemoslovaca》2003,52(3):285-289
Total genome scans of genetically segregating populations derived from spontaneously hypertensive rats (SHR) and other rat models of essential hypertension suggested a presence of quantitative trait loci (QTL) regulating blood pressure on multiple chromosomes, including chromosome 5. The objective of the current study was to test directly a hypothesis that chromosome 5 of the SHR carries a blood pressure regulatory QTL. A new congenic strain was derived by replacing a segment of chromosome 5 in the SHR/Ola between the D5Wox20 and D5Rat63 markers with the corresponding chromosome segment from the normotensive Brown Norway (BN/Crl) rat. Arterial pressures were directly monitored in conscious, unrestrained rats by radiotelemetry. The transfer of a segment of chromosome 5 from the BN strain onto the SHR genetic background was associated with a significant decrease of systolic blood pressure, that was accompanied by amelioration of renal hypertrophy. The heart rates were not significantly different in the SHR compared to SHR chromosome 5 congenic strain. The findings of the current study demonstrate that gene(s) with major effects on blood pressure and renal mass exist in the differential segment of chromosome 5 trapped within the new SHR.BN congenic strain. 相似文献
3.
Michal Pravenec Vladimir Ken Drahomira Krenova Vaclav Zidek Jiaming Wang Theodore W. Kurtz Elizabeth St. Lezin 《Journal of Experimental Animal Science》2000,41(1-2)
Recently, we have found that transfer of a segment of chromosome 4 between I16 and Npy markers from the Brown Norway (BN) rat into the spontaneously hypertensive rat (SHR) significantly attenuated both hypertension (measured by telemetry) and insulin resistance (measured as plasma insulin/glucose ratios before and after a high fructose diet) in the SHR progenitor strain. To map the putative quantitative trait loci (QTL) more precisely, we derived an (SHR×SHR.BN-chr.4)F2 population to search for recombinants that will enable us to produce congenic sublines. The F2 animals were genotyped in markers equally distributed along the interval of the chromosome 4 differential segment. Altogether, five new congenic sublines with overlapping segments of the differential chromosome 4 are being produced. New congenic sublines will enable us to test the hypothesis that insulin resistance and hypertension can be influenced by closely linked genes or perhaps even the same gene(s) on chromosome 4. 相似文献
4.
5.
A region on rat Chromosome (Chr) 2 of the Dahl salt-sensitive rat (S) was shown previously to contain a quantitative trait
locus (QTL) for blood pressure (BP). This was achieved first by linkage, followed by the use of congenic strains. A congenic
strain, designated S.MNS-D2Mit6/Adh, contained a segment of Chr 2 from the Milan Normotensive (MNS) rat in the S genetic background. Since the region containing
the QTL was roughly 80 cM in size, a further reduction was needed towards the positional or candidate gene cloning. Currently,
two congenic substrains were made from the original strain S.MNS-D2Mit6/Adh. One of these two substrains showed a BP-lowering effect, whereas the other substrain did not. Deducing the segment not shared
in the two substrains, the BP QTL has to be present in a chromosome region of roughly 5.7 cM between the marker D2Rat303 and the locus for the neutroendopeptidase gene (Nep). Nep is not included within the segment. This region does not seem to contain any candidate genes well known for the BP control.
Thus, the final identification of the QTL will most likely lead to the discovery of a brand new gene for the BP regulation.
Received: 14 December 2000 / Accepted: 18 January 2001 相似文献
6.
M. Pravenec V. Zidek M. Zdobinska V. Kren D. Krenova A. Bottger L. F. M. van Zutphen J. -M. Wang E. St. Lezin 《Mammalian genome》1997,8(6):387-389
The genes that determine the baseline hematocrit level in humans and experimental animals are unknown. The spontaneously
hypertensive rat (SHR), the most widely used animal model of human essential hypertension, exhibits an increased hematocrit
when compared with the normotensive Brown Norway (BN-Lx) strain (0.54 ± 0.02 vs. 0.44 ± 0.02, p < 0.01). Distribution of hematocrit values among recombinant inbred (RI) strains
derived from SHR and BN-Lx progenitors was continuous, which suggests a polygenic mode of inheritance. The narrow heritability of the hematocrit was
estimated to be 0.32. The Eno2 marker on Chromosome (Chr) 4 showed the strongest association (p < 0.0001) with the observed variability of hematocrit among
RI strains. The erythropoietin (Epo) gene, originally reported to be syntenic with Eno2, has been mapped to Chr 12, thus excluding it as a potential candidate gene for the increased hematocrit in the SHR. The current
linkage data extend homologies between rat, mouse, and human chromosomes.
Received: 11 December 1996 / Accepted: 17 February 1997 相似文献
7.
Michal Pravenec Václav Zídek Alena Musilová Miroslava Simáková Vlastimil Kostka Petr Mlejnek Vladimír Kren Drahomíra Krenova Vlasta Bílá Blanka Míková Marie Jáchymová Karel Horký Ludmila Kazdová Elizabeth St. Lezin Theodore W. Kurtz 《Mammalian genome》2002,13(5):253-258
Abnormalities in carbohydrate and lipid metabolism are common in patients with essential hypertension and in the spontaneously
hypertensive rat (SHR). To identify chromosome regions contributing to this clustering of cardiovascular risk factors in the
SHR, we searched for quantitative trait loci (QTL) associated with insulin resistance, glucose intolerance, and dyslipidemia
by using the HXB/BXH recombinant inbred (RI) strains. Analysis of variance in RI strains suggested significant effects of
genetic factors. A genome screening of the RI strains with more than 700 markers revealed QTL significantly associated with
insulin resistance on Chromosomes (Chrs) 3 and 19. The Chr 19 QTL was confirmed by testing a previously derived SHR-19 congenic
strain: transfer of a Chr 19 segment delineated by markers D19Rat57 and D19Mit7 from the Brown Norway (BN/Cr) strain onto the genetic background of the SHR/Ola was associated with decreased insulin and
glucose concentrations and ameliorated insulin resistance at the tissue level. These findings suggest that closely linked
genes on Chr 19, or perhaps even a single gene with pleiotropic effects, influence the clustering of metabolic disturbances
in the SHR-BN model. 相似文献
8.
T Katsuya J Higaki T Miki K Kohara H Yagisawa H Tanase H Mikami T Serikawa H Nojima T Ogihara 《Biochemical and biophysical research communications》1992,187(3):1359-1366
To identify the genes responsible for blood pressure in the spontaneously hypertensive rat strain, we performed a cosegregation analysis between the genotype and blood pressure in a set of male F2 rats obtained by crossmating SHR with Wistar-Kyoto rats, a parental normotensive strain. Our investigation revealed that the phospholipase C-delta 1 polymorphism, which resulted in missense mutation, cosegregates with the lower blood pressure in SHR, and that PLC-delta 1 gene is located on chromosome 8. On the other hand, we found the lack of cosegregation between blood pressure and the nerve growth factor receptor gene, which is linked to a hypertensinogenic gene locus (denoted as BP/SP-1) on chromosome 10. We propose that PLC-delta 1 gene itself of closely linked gene on chromosome 8 is a new candidate with the hypotensive effect, and that BP-SP1 locus does not directly contribute to blood pressure elevation in original SHR. 相似文献
9.
Q. Y. Zhang H. Dene A. Y. Deng M. R. Garrett H. J. Jacob J. P. Rapp 《Mammalian genome》1997,8(9):636-641
The renin locus (Ren) on rat Chromosome (Chr) 13 had previously been shown to cosegregate with blood pressure in crosses involving Dahl salt-sensitive
(S) and Dahl salt-resistant (R) rats. In the present work, interval mapping of blood pressure on Chr 13 with a large F2 (S × R), n = 233, population yielded a maximum LOD = 4.2 for linkage to blood pressure, but the quantitative trait locus
(QTL) was only poorly localized to a large 35-centiMorgan (cM) segment of Chr 13. In the linkage analysis, the S-rat QTL allele
(S) was associated with higher, and the R-rat QTL allele (R) with lower blood pressure, the difference between homozygotes being about 20 mm Hg. A congenic strain was made by introgressing
the R-rat Ren allele into the recipient S strain. This congenic strain showed a 24 mm Hg reduction (P = 0.004) in blood pressure compared
with S rats for rats fed 2% NaCl diet for 24 days; this difference was confirmed by two other independent tests. Two congenic
substrains were derived from the first congenic strain with shorter R Chr 13 segments on the S background. Comparisons among
these congenic strains showed that a blood pressure QTL was in the 24-cM chromosomal segment between Syt2 and D13M1Mit108. This segment does not include the renin locus, which is thus excluded from being the gene on rat Chr 13 responsible for genetic
differences in blood pressure detected by linkage analysis.
Received: 20 December 1996 / Accepted: 7 April 1997 相似文献
10.
Congenic BB.SHR rats introgressing a segment of SHR chromosome 6 onto BB/OK background showed a reduction of diabetes frequency by 72% compared with BB/OK. To identify underlying gene(s), the introgressed segment was shortened and the expression of seven genes (Yy1, Dlk1/Pref-1, Wd40 repeat, Cdc42, Rtl1, Traf3, and Tnfaip2) was studied in blood and spleen of non-diabetic BB/OK, BB.6S, and SHR males and females at an age of 30, 70, and 90 days. The phenotype of congenic sublines narrowed the diabetes-protective region to 4 Mb. The relative expression of Yy1 and Pref-1 in blood and of Pref-1 in spleen was significantly reduced by 50-90% in male and female BB.6S and SHR compared with BB/OK favouring Yy1 and Pref-1 as candidate genes. All other genes were differently expressed according to gender and strain. 相似文献
11.
12.
Miloslava Hodúlová Lucie ?edová Drahomíra K?enová Franti?ek Li?ka Michaela Krupková Ludmila Kazdová Johanne Tremblay Pavel Hamet Vladimír K?en Ond?ej ?eda 《PloS one》2014,9(10)
The plasma profile of major lipoprotein classes and its subdivision into particular fractions plays a crucial role in the pathogenesis of atherosclerosis and is a major predictor of coronary artery disease. Our aim was to identify genomic determinants of triglyceride and cholesterol distribution into lipoprotein fractions and lipoprotein particle sizes in the recombinant inbred rat set PXO, in which alleles of two rat models of the metabolic syndrome (SHR and PD inbred strains) segregate together with those from Brown Norway rat strain. Adult male rats of 15 PXO strains (n = 8–13/strain) and two progenitor strains SHR-Lx (n = 13) and BXH2/Cub (n = 18) were subjected to one-week of high-sucrose diet feeding. We performed association analyses of triglyceride (TG) and cholesterol (C) concentrations in 20 lipoprotein fractions and the size of major classes of lipoprotein particles utilizing 704 polymorphic microsatellite markers, the genome-wide significance was validated by 2,000 permutations per trait. Subsequent in silico focusing of the identified quantitative trait loci was completed using a map of over 20,000 single nucleotide polymorphisms. In most of the phenotypes we identified substantial gradient among the strains (e.g. VLDL-TG from 5.6 to 66.7 mg/dl). We have identified 14 loci (encompassing 1 to 65 genes) on rat chromosomes 3, 4, 7, 8, 11 and 12 showing suggestive or significant association to one or more of the studied traits. PXO strains carrying the SHR allele displayed significantly higher values of the linked traits except for LDL-TG and adiposity index. Cholesterol concentrations in large, medium and very small LDL particles were significantly associated to a haplotype block spanning part of a single gene, low density lipoprotein receptor-related protein 1B (Lrp1b). Using genome-wide association we have identified new genetic determinants of triglyceride and cholesterol distribution into lipoprotein fractions in the recombinant inbred panel of rat model strains. 相似文献
13.
Ana Maria Rodriguez de Ledesma Aarti N. Desai Valerie J. Bolivar Derek J. Symula Lorraine Flaherty 《Mammalian genome》2006,17(2):111-118
By use of newly developed subcongenic strains of mice from a parental B6.129-Il10−/− knockout/congenic strain, we have narrowed the critical region for a new behavioral QTL, called Emo4, for open-field activity to a segment of Chromosome 1 between Erbb4 (68.4Mb) and B3gnt7 (86.2 Mb). We have also uncovered an additional QTL governing repetitive beam breaks in the open field. This QTL, called
Reb1, maps to the interval between Asb1 (91.4 Mb) and NM_172851 (100.0 Mb) and is one of the first QTLs mapped for this type of behavior. Genome-wide microarray
expression analyses were then undertaken to help to identify candidate genes that may be the cause of these genetic differences
in open-field performance. In this effort, we analyzed global gene expression differences in the amygdalae by use of Affymetrix
GeneChips between B6, B6.129-Il10−/−, and B6.129R4. Several probe sets representing target Chr 1 genes were found that showed significantly differential expression
in the subcongenic and congenic strains. Several candidate genes have been identified. One of these regions coincides with
an homologous region in humans that has been associated with autism, a disease whose symptoms include repetitive actions.
This study illustrates that the use of congenic strains combined with global gene expression analyses can produce a list of
viable candidates. It further shows that caution should be observed when analyzing the effects of knockout/congenic strains
because many of the gene expression differences in these comparisons could not be attributable to the ablated Il10 gene but rather to passenger gene effects. 相似文献
14.
Yasser Saad Edward J. Toland Shane Yerga-Woolwine Phyllis Farms Bina Joe 《Mammalian genome》2008,19(2):85-91
Multiple blood pressure (BP) quantitative trait loci (QTLs) are reported on rat chromosome 10 (RNO10). Of these, QTLs detected
by contrasting the genome of the hypertensive Dahl salt-sensitive (S) rat with two different relatively normotensive strains,
Lewis (LEW) and the Milan normotensive strain (MNS), are reported. Because the deduced QTL regions of both S vs. LEW and S
vs. MNS comparisons are within large genomic segments encompassing more than 2 cM, there was a need to further localize these
QTLs and determine whether the QTLs are unique to specific strain comparisons. Previously, the S.MNS QTL1 was mapped to less
than 2.6 cM as a differential segment between two congenic strains. In this study, multiple congenic strains spanning the
projected interval were studied. The BP effect of each strain was interpreted as the net effect of alleles introgressed within
that congenic strain. The results suggest that the MNS alleles within the previously proposed differential segment (D10Rat27-D10Rat24) do not independently lower BP of the S rat. However, another congenic strain, S.MNS(10) × 9, containing introgressed MNS
alleles that are outside of the previously proposed differential segment is of interest because (1) it demonstrated a BP-lowering
effect, (2) it is contained within a single congenic strain and is not based on the observed effect of a differential segment,
and, more importantly, (3) it overlaps with the previously identified S.LEW BP QTL region. Identification of the same QTL
affecting BP in multiple rat strains will provide further support for the QTL’s involvement and importance in human essential
hypertension. 相似文献
15.
Ingrid Klöting Ph.D D.Sc. Peter Kovacs Jens van den Brandt 《Obesity (Silver Spring, Md.)》2002,10(10):1074-1077
Objective: The phenotypic characterization of congenic BB.LL rats recombining a segment of the SHR chromosome 4 (D4Mit6-Npy-Spr; 12 cM) into the BB/OK background indicated that these rats were not lymphopenic and did not develop diabetes, but they were significantly heavier (at 16 weeks of age) and showed higher serum triglycerides and total cholesterol concentration. Research Methods and Procedures: BB.LL rats were longitudinally studied for facets of metabolic syndrome (body mass index, blood glucose, serum lipids, insulin, leptin, and systolic and diastolic blood pressure) from 2 to 12 months of age. Results: In this study, it was shown that BB.LL are obese, hyperleptinemic, hyperinsulinemic, and dyslipidemic compared with their parental BB/OK rats. Discussion: It can be concluded that there is a gene(s) in the introgressed segment causing incomplete metabolic syndrome, because they do not develop hypertension and diabetes. To identify the gene(s), the introgressed chromosomal segment must be systematically whittled down to generate recombinants and new subcongenic lines carrying a much smaller segment of the SHR/Mol rat to increase the chance of identification of the appropriate gene(s). 相似文献
16.
Barbara York Alycia A. Truett Michelle P. Monteiro Sean J. Barry Craig H. Warden Jürgen K. Naggert Terry P. Maddatu David B. West 《Mammalian genome》1999,10(5):457-462
We have previously reported suggestive evidence for a locus on Chromosome (Chr) 7 that affects adiposity in F2 mice from a CAST/Ei × C57BL/6J intercross fed a high-fat diet. Here we characterize the effect of a high-fat (32.6 Kcal%
fat) diet on male and female congenic mice with a C57BL/6J background and a CAST/Ei-derived segment on Chr 7. Adiposity index
(AI) and weights of certain fat pads were approximately 50% lower in both male and female congenic mice than in control C57BL/6J
mice, and carcass fat content was significantly reduced. The reduction of fat depot weights was not seen, however, in congenic
animals fed a low-fat chow diet (12 Kcal% fat).
The congenic segment is approximately 25 cM in length, extending from D7Mit213 to D7Mit41, and includes the tub, Ucp2, and Ucp3, genes, all of which are candidate genes for this effect. Some polymorphisms have been found on comparing c-DNA sequences
of the Ucp2 gene from C57BL/6J and CAST/Ei mice. These results suggest that one or more genes present in the congenic segment modulate
the susceptibility to fat deposition on feeding a high-fat diet.
We were unable to show any significant difference between the energy intakes of the congenic and the control C57BL/6J mice
on the high-fat diet. Also, measurements of energy expenditure in male mice at 6 weeks of age, during the first 2 weeks of
exposure to the high-fat diet, failed to show any differences between control and congenic animals.
Received: 30 September 1998 / Accepted: 22 December 1998 相似文献
17.
《Chronobiology international》2013,30(3):343-352
Lengthened circadian period of locomotor activity is a characteristic of a congenic strain of mice carrying a nonsense mutation in exon 5 of the carbonic anhydrase II gene, car2. The null mutation in car2 is located on a DBA/2J inbred strain insert on proximal chromosome 3, on an otherwise C57BL/6J genomic background. Since reducing the size of the congenic region would narrow the possible candidate genes for period, two recombinant congenic strains (R1 and R2) were developed from the original congenic strain. These new congenic strains were assessed for period, genetic composition, and the presence of immunoreactive carbonic anhydrase II. R1 mice were homozygous DBA/2J for the distal portion of the original DBA/2J insert, while R2 mice were homozygous DBA/2J for the proximal portion. R1 mice had a significantly lengthened period compared to R2 mice and wild-type C57BL/6J mice, indicating that the gene(s) affecting period is likely found within the reduced DBA/2J insert (?1 cM) in the R1 mice. The R1 mice also possessed the null mutation in car2. This study confirmed the presence of a gene(s) affecting period on proximal chromosome 3 and significantly reduced the size of the congenic region and the number of candidate genes. Future studies will focus on identifying the gene influencing period. 相似文献
18.
Géraldine Piessevaux Virginie Lella Michèle Rivière Daniel Stieber Pierre Drèze Josiane Szpirer Claude Szpirer 《Mammalian genome》2009,20(1):43-52
We previously defined quantitative trait loci (QTLs) that control susceptibility to 7,12-dimethylbenz(α)anthracene-induced
mammary carcinoma in SPRD-Cu3 (susceptible) and WKY (resistant) rats. Two of these QTLs, assigned to chromosomes (Chr) 10
and 18, control tumor growth rate and invasiveness. In this study we characterized a congenic strain in which a large segment
of WKY Chr 10 was introduced in the SPRD-Cu3 genetic background and demonstrated that this chromosome segment controls this
tumor trait. The WKY allele at this QTL (Mcsta1) reduces the growth rate of the fastest growing tumors by 26%. We also previously showed that two SPRD-Cu3-WKY congenic strains
containing a WKY chromosome segment derived either from Chr 5 or from Chr 18 exhibit a reduction in tumor multiplicity (QTLs
Msctm1 and Mcstm2, respectively) (with no reduction in tumor growth rate in the Chr 18 congenic). In this study we generated a double congenic
strain, which contains the two WKY differential segments from Chr 5 and 18, to determine how these two segments interact with
one another. Interestingly, two types of epistatic interactions were found: no additive effect was seen with respect to tumor
multiplicity, while a reduction in tumor growth rate was observed. It thus appears that WKY alleles located on Chr 5 and Chr
8 interact epistatically in a contrasting manner to modulate tumor multiplicity (in a nonadditive manner) and growth rate
(in a synergic manner). Tumor growth rate is thus influenced by two QTLs, on Chr 10 (Mcsta1) and on Chr 18 (Mcsta2), the action of the latter being dependent on the presence of the Chr5 QTL (Mcstm1). The expression level of positional and functional candidate genes was also analyzed. On Chr 5, Pla2g2a is subject to a syntenic control while expression of the Tp53 (Chr 10) and Pmai1/Noxa (Chr 18) genes appears to be controlled by several mammary cancer resistance QTLs. 相似文献
19.
20.
C. C. Parker G. Sokoloff E. Leung S. L. Kirkpatrick A. A. Palmer 《Genes, Brain & Behavior》2013,12(7):714-722
Using chromosome substitution strains (CSS), we previously identified a large quantitative trait locus (QTL) for conditioned fear (CF) on mouse chromosome 10. Here, we used an F2 cross between CSS‐10 and C57BL/6J (B6) to localize that QTL to distal chromosome 10. That QTL accounted for all the difference between CSS‐10 and B6. We then produced congenic strains to fine‐map that interval. We identified two congenic strains that captured some or all the QTL. The larger congenic strain (Line 1: 122.387121–129.068 Mb; build 37) appeared to account for all the difference between CSS‐10 and B6. The smaller congenic strain (Line 2: 127.277–129.068 Mb) was intermediate between CSS‐10 and B6. We used haplotype mapping followed by quantitative polymerase chain reaction to identify one gene that was differentially expressed in both lines relative to B6 (Rnf41) and one that was differentially expressed between only Line 1 and B6 (Shmt2). These cis‐eQTLs may cause the behavioral QTLs; however, further studies are required to validate these candidate genes. More generally, our observation that a large QTL mapped using CSS and F2 crosses can be dissected into multiple smaller QTLs shows a weaknesses of two‐stage approaches that seek to use coarse mapping to identify large regions followed by fine‐mapping. Indeed, additional dissection of these congenic strains might result in further subdivision of these QTL regions. Despite these limitations, we have successfully fine‐mapped two QTLs to small regions and identified putative candidate genes, showing that the congenic approach can be effective for fine‐mapping QTLs . 相似文献