A Curly-Tail Modifier Locus,mct1,on Mouse Chromosome 17
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Genetic linkage
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Chromosome 16
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Iakoubova, Olga, Holly Dushkin, Lisa Pacella, and David R. Beier. Genetic analysis of modifying loci on mouse chromosome 1 that affect disease severity in a model of recessive PKD. Physiol. Genomics: 101–105, 1999.—Using a cross between C57BL/6J and FVB/N mice, we have confirmed the localization on chromosome 1 of a modifying locus that affects the severity of polycystic kidney disease (PKD) in the juvenile cystic kidney ( jck) mouse. Despite the highly significant contribution of this locus in F2 progeny of a cross between C57BL/6J and DBA/2J mice ( 4 ), a series of congenic strains carrying regions of chromosome 1 on a DBA/2J background did not show a severe disease phenotype. One possible explanation for these results is that this phenotype is caused by two linked loci, which have been separated in the congenic lines that were generated. This hypothesis is supported by the demonstration that severe PKD occurs in mice carrying a large congenic interval.
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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.
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To dissect the genetic architecture controlling blood pressure (BP) regulation in the spontaneously hypertensive rat (SHR) we derived congenic rat strains for four previously mapped BP quantitative trait loci (QTLs) in chromosomes 2, 4, and 16. Target chromosomal regions from the Brown Norway rat (BN) averaging 13-29 cM were introgressed by marker-assisted breeding onto the SHR genome in 12 or 13 generations. Under normal salt intake, QTLs on chromosomes 2a, 2c, and 4 were associated with significant changes in systolic BP (13, 20, and 15 mmHg, respectively), whereas the QTL on chromosome 16 had no measurable effect. On high salt intake (1% NaCl in drinking water for 2 wk), the chromosome 16 QTL had a marked impact on SBP, as did the QTLs on chromosome 2a and 2c (18, 17, and 19 mmHg, respectively), but not the QTL on chromosome 4. Thus these four QTLs affected BP phenotypes differently: 1) in the presence of high salt intake (chromosome 16), 2) only associated with normal salt intake (chromosome 4), and 3) regardless of salt intake (chromosome 2c and 2a). Moreover, salt sensitivity was abrogated in congenics SHR.BN2a and SHR.BN16. Finally, we provide evidence for the influence of genetic background on the expression of the mapped QTLs individually or as a group. Collectively, these data reveal previously unsuspected nuances of the physiological roles of each of the four mapped BP QTLs in the SHR under basal and/or salt loading conditions unforeseen by the analysis of the F2 cross.
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A region with a major effect on blood pressure (BP) is located on rat chromosome 1. We have previously isolated this region in reciprocal congenic strains (WKY.SHR-Sa and SHR.WKY-Sa) derived from a cross of the spontaneously hypertensive rat (SHR) with the Wistar-Kyoto rat (WKY) and shown that there are 2 distinct BP quantitative trait loci, BP1 and BP2, in this region. Sisa1, a congenic substrain from the SHR.WKY-Sa animals carrying an introgressed segment of 4.3Mb, contains BP1. Here, we report further dissection of BP1 by the creation of 2 new mutually exclusive congenic substrains (Sisa1a and Sisa1b) and interrogation of candidate genes by expression profiling and targeted transcript sequencing. Only 1 of the substrains (Sisa1a) continued to demonstrate a BP difference but with a reduced introgressed segment of 3Mb. Exonic sequencing of the 20 genes located in the Sisa1a region did not identify any major differences between SHR and WKY. However, microarray expression profiling of whole kidney samples and subsequent quantitative RT-PCR identified a single gene, Spon1 that exhibited significant differential expression between the WKY and SHR genotypes at both 6 and 24 weeks of age. Western blot analysis confirmed an increased level of the Spon1 gene product in SHR kidneys. Spon1 belongs to a family of genes with antiangiogenic properties. These findings justify further investigation of this novel positional candidate gene in BP control in hypertensive rat models and humans.
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ABSTRACT Body weight and fatness are quantitative traits of agricultural and medical importance. In previous genome‐wide quantitative trait locus (QTL) analyses, two QTLs for body weight and weight gain at an early postnatal growth period were discovered on mouse chromosome 10 from a gene pool of wild subspecies mice, Mus musculus castaneus . In this study, we developed a congenic strain with an approximately 63‐Mb wild‐derived genomic region on which the two growth QTLs could be located, by recurrent backcrossing to the common inbred strain C57BL/6J. We compared body weights at 1–10 weeks of age, body weight gains at 1–3, 3–6 and 6–10 weeks, internal organ weights and body lengths between the congenic strain developed and C57BL/6J. Unfortunately, no effects of the two growth QTLs on body weights and weight gains were confirmed. However, at least two new QTLs affecting fatness traits were discovered within the introgressed congenic region. The wild‐derived allele at one QTL increased body mass index, whereas at another one it decreased white fat pad weight and adiposity index. Thus, the congenic mouse strain developed here is a useful model animal for understanding the genetic and molecular basis of fat deposition in livestock as well as humans.
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Abstract —Linkage studies in segregating populations derived from the spontaneously hypertensive rat (SHR) indicate that a blood pressure quantitative trait locus exists on rat chromosome 1 in the vicinity of the Sa gene. On the basis of these findings and the observation of increased renal expression of the Sa gene in SHR versus normotensive rats, the Sa gene has been proposed as a candidate gene for spontaneous hypertension. In SHR congenic strains, we and others have found that replacement of a segment of SHR chromosome 1 that contains the Sa gene with the corresponding chromosome segment from a normotensive Brown Norway (BN) rat or Wistar-Kyoto rat can reduce blood pressure. To test whether the Sa gene is necessary for the effect of this region of chromosome 1 on blood pressure, we studied a new SHR congenic subline that harbors a smaller segment of BN chromosome 1 that does not include the Sa gene. Transfer of this subregion of chromosome 1 from the BN rat onto the SHR background was associated with significant reductions in blood pressure comparable to those previously observed on transfer of a larger region of chromosome 1 that included the Sa gene. Thus, in the SHR-BN model of hypertension, the results of these mapping studies (1) demonstrate that molecular variation in the Sa gene is not required for the effect of this region of chromosome 1 on blood pressure and (2) should direct attention toward other candidate genes within the differential chromosome segment of the new congenic subline.
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Spontaneously hypertensive rat
Chromosome 4
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Chromosome 18
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Chromosome 12
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