The Mouse Genome Database (MGD): from genes to mice--a community resource for mouse biology.

The Mouse Genome Database (MGD) forms the core of the Mouse Genome Informatics (MGI) system (http://www.informatics.jax.org), a model organism database resource for the laboratory mouse. MGD provides essential integration of experimental knowledge for the mouse system with information annotated from both literature and online sources. MGD curates and presents consensus and experimental data representations of genotype (sequence) through phenotype information, including highly detailed reports about genes and gene products. Primary foci of integration are through representations of relationships among genes, sequences and phenotypes. MGD collaborates with other bioinformatics groups to curate a definitive set of information about the laboratory mouse and to build and implement the data and semantic standards that are essential for comparative genome analysis. Recent improvements in MGD discussed here include the enhancement of phenotype resources, the re-development of the International Mouse Strain Resource, IMSR, the update of mammalian orthology datasets and the electronic publication of classic books in mouse genetics.

The Mouse Genome Database (MGD): integrating biology with the genome.

The Mouse Genome Database (MGD) is one component of the Mouse Genome Informatics (MGI) system (http://www.informatics.jax.org), a community database resource for the laboratory mouse. MGD strives to provide a comprehensive knowledgebase about the mouse with experiments and data annotated from both literature and online sources. MGD curates and presents consensus and experimental data representations of genetic, genotype (sequence) and phenotype information including highly detailed reports about genes and gene products. Primary foci of integration are through representations of relationships between genes, sequences and phenotypes. MGD collaborates with other bioinformatics groups to curate a definitive set of information about the laboratory mouse and to build and implement the data and semantic standards that are essential for comparative genome analysis. Recent developments in MGD discussed here include an extensive integration of the mouse sequence data and substantial revisions in the presentation, query and visualization of sequence data.

Genetic susceptibility to carrageenan-induced innate inflammatory response in inbred strains of rats.

Rat models are useful for the genetic dissection of the biology of innate immunity. Inbred rat strains were evaluated for carrageenan-induced innate inflammatory responses. Results indicated that the genetic control of innate immune responses is polygenic and influenced by gender, and may not necessarily be consistent with the genetics of experimental arthritis. The newly identified susceptible strains, in order of decreasing susceptibility, include Dahl salt-sensitive (S), Dahl salt-resistant (R), Milan normotensive strain (MNS) and Wistar Kyoto (WKY) rats. Similarly, the newly identified relatively resistant strains, in decreasing order of resistance, include DA rats, spontaneously hypertensive rats (SHRs) and Brown Norway (BN) rats. Linkage analyses using combinations of these susceptible and resistant strains are proposed.

High-resolution mapping of the blood pressure QTL on chromosome 7 using Dahl rat congenic strains.

It was previously shown using Dahl salt-sensitive (S) and salt-resistant (R) rats that a blood pressure quantitative trait locus (QTL) was present on rat chromosome 7. In the present work, this QTL was localized to a region less than 0.54 cM in size on the linkage map using a series of congenic strains. This region was contained in a single yeast artificial chromosome that was 220 kb long. This small segment still contained the primary candidate locus Cyp11b1 (11beta-hydroxylase), but the adjacent candidate genes Cyp11b2 (aldosterone synthase) and Cyp11b3 were ruled out. It is concluded that 11beta-hydroxylase, through its known genetic variants altering the production of 18-hydroxy-11-deoxy corticosterone, is very likely to account for the blood pressure QTL on chromosome 7 in the Dahl rat model of hypertension. This QTL accounts for about 23 mm Hg under the condition of 2% NaCl diet for 24 days.

Blood pressure QTL that differentiate Dahl salt-sensitive and spontaneously hypertensive rats.

Our purpose was to define quantitative trait loci (QTL) for blood pressure that differ between two widely used hypertensive rat strains, the Dahl salt-sensitive (S) rat and the spontaneously hypertensive rat (SHR). A genome scan was done on an F(2) (S x SHR) population fed 8% NaCl for 4 wk. Three blood pressure QTL were detected, one on each of rat chromosomes (chr) 3, 8, and 9. For the chr 3 QTL the SHR allele increased blood pressure, and for chr 8 and 9 the S allele increased blood pressure. The QTL on chr 9 was exceptionally strong, having a LOD score of 7.3 and accounting for 30% of the phenotypic variance and a difference of 40 mmHg between homozygotes. A review of the literature in conjunction with the present data suggests that S and SHR are not different for the previously described prominent blood pressure QTL on chr 1, 2, 10, and 13. QTL for body weight on chr 4, 12, 18, and 20, each with an effect of about 30 g, were incidentally observed.

Two blood pressure/cardiac mass quantitative trait loci on chromosome 3 in Dahl rats.

Interval mapping was used to identify putative quantitative trait loci (QTL) for blood pressure and cardiac mass on Chromosome (Chr) 3 in F1(S x R) x S population of 150 rats raised on an 8% NaCl diet. Two genetic markers 95.7 cM apart, D3Wox3 and D3Mco5 (tightly linked to Edn3), showed "suggestive" linkage to blood pressure (LOD = 2.0 and 1.8 respectively). In addition, D3Wox3 showed "suggestive" linkage to heart weight (LOD = 2.5), and D3Mco5 showed "suggestive" linkage to body weight-adjusted heart weight (LOD = 2.1). Congenic rats (designated S.R-Edn3) were constructed by introgressing the R-rat Edn3 allele (and flanking loci) into the S strain. On a 2% NaCl diet, S.R-Edn3 rats had lower blood pressure (21.4 mm Hg, P = 0. 0005) and heart weight (59 mg, P = 0.0038) compared with S rats, confirming the existence of a blood pressure QTL on Chr 3 near Edn3 even though QTL linkage analysis of blood pressure did not achieve stringent statistical criteria for significance. The results of the congenic experiment and the large distance between the two putative QTL suggest the presence of at least two independent blood pressure/cardiac mass QTL detectable on Chr 3 in the Dahl rat model of genetic hypertension.

Localization of a blood pressure QTL on rat chromosome 1 using Dahl rat congenic strains.

We previously reported that markers on rat chromosome 1 are genetically linked to blood pressure in an F(2) population derived from Dahl salt hypertension-sensitive (S) and Lewis (LEW) rats. Because there was evidence for more than one blood pressure quantitative trait locus (QTL) on chromosome 1, an initial congenic strain introgressing a large 118-centimorgan (cM) segment of LEW chromosome 1 into the S background had been constructed. This initial congenic strain had a reduced blood pressure compared with S rats, proving the existence of a blood pressure QTL, but not giving a good localization of the QTL. In the present work a series of five overlapping congenic substrains were produced from the original congenic strain in order to localize a blood pressure QTL to a 25-cM region near the center of chromosome 1. The congenic substrains also ruled out the Sa locus as a blood pressure QTL in the S vs. LEW comparison because the Sa locus was contained in a congenic substrain that did not alter blood pressure.

Linkage analysis and construction of a congenic strain for a blood pressure QTL on rat chromosome 9.

A blood pressure quantitative trait locus was found (LOD = 5.0) on rat chromosome 9 using a large F2 population (N = 233) derived from Dahl salt-sensitive (S) and Dahl salt-resistant (R) rats. The F2 rats were fed 8% NaCl diet for 8 weeks. A congenic strain introgressing the R low-blood-pressure QTL allele on chromosome 9 into the S strain was constructed. The congenic strain, designated S.R(chr 9), had a lower blood pressure (19 mm Hg, P < 0.0001) and lower heart weight (112 mg, P < 0.0001) than S rats (2% NaCl diet for 24 days), proving the existence of a blood pressure QTL in the congenic region of about 21 cM.

Genome scan and congenic strains for blood pressure QTL using Dahl salt-sensitive rats.

An F2 population (n = 151) derived from Dahl salt-sensitive (S) and Lewis rats was raised on a 8% NaCl diet for 9 weeks and analyzed for blood pressure quantitative trait loci (QTL) by use of a whole genome scan. Chromosomes 5 and 10 yielded lod scores for linkage to blood pressure that were significant; chromosomes 1, 2, 3, 8, 16, 17, and 18 gave lod scores suggestive for linkage. Chromosome 7 gave a significant signal for heart weight with a lesser effect on blood pressure. Congenic strains were constructed by introgressing Lewis low-blood-pressure QTL alleles for chromosomes 1, 5, 10, and 17 into the S genetic background. Congenic strains for chromosomes 1, 5, and 10 had significantly lower blood pressure than S, proving the existence of QTL on these chromosomes, but the chromosome 17 congenic strain failed to trap a contrasting QTL allele. The QTL allele increasing blood pressure originated from S rats for all QTL except those on chromosomes 2 and 7 in which the Lewis allele increased blood pressure. Interactions between each QTL and every other locus in the genome scan yielded significant interactions between chromosomes 10 and 4, and between chromosomes 2 and 3.

An improved linkage map of rat chromosome 3 with three mapping panels.

Our purposes were to develop an improved linkage map for rat Chromosome 3 and to develop new markers polymorphic between Dahl salt-sensitive (S) and Dahl salt-resistant (R) rats. The linkage mapping panel consisted of three F2 populations totaling 359 rats. Twenty-five new markers were developed and placed on the linkage map. About half of these markers (13) were polymorphic between S and R rats. The final map spans 124.7 centiMorgans (cM) and includes 64 markers. The average distance between adjacent markers is 1.9 cM, and the largest separation is 10.5 cM.

Blood pressure and survival of a chromosome 7 congenic strain bred from Dahl rats.

11 beta-hydroxylase (Cyp11b1) mutations were previously linked to altered steroid biosynthesis and blood pressure in Dahl salt-resistant (R) and Dahl salt-sensitive (S) rats. In the present work, interval mapping identified a putative blood pressure quantitative trait locus (QTL) near Cyp11b1 in an F1(SxR)xS population (LOD = 2.0). Congenic rats (Designated S.R-Cyp11b) were constructed by introgressing the R-rat Cyp11b1 allele into the S strain. S.R-Cyp11b rats had significantly lower blood pressure and heart weight compared with S rats, proving the existence of a blood pressure QTL on Chromosome (Chr) 7 despite the fact that QTL linkage analysis of blood pressure never achieved stringent statistical criteria for significance. To test the effects of the introgressed region on blood pressure and survival, S.R.-Cyp11b and S rats were maintained on a 4% NaCl diet until they died or became moribund. Analysis of variance (ANOVA) indicated significant strain differences in blood pressure and days survived (P < 0.0001 for both) as well as gender differences in days survived (P = 0.0003). Kaplan-Meier survival analysis also found significant strain (P < 0.0001) and gender (P = 0.007) differences in days survived. However, when the effects of blood pressure were removed, significant strain differences in survival essentially disappeared. This suggests that the increased survival of S.R-Cyp11b rats was largely due to their decreased blood pressure and thus strongly corroborates the existence of a blood pressure QTL on Chr 7 near or at Cyp11b1.

Interval mapping and congenic strains for a blood pressure QTL on rat chromosome 13.

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 x 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.

Congenic strains for the blood pressure quantitative trait locus on rat chromosome 2.

A quantitative trait locus (QTL) for blood pressure was previously detected by linkage analysis in a region of rat chromosome 2 using segregating populations derived from crosses of the Dahl salt-sensitive (Dahl S) rat with rats of the Wistar-Kyoto (WKY) strain or Milan normotensive strain (MNS). Two congenic strains, S.WKY-D2N35/Nep and S.MNS-Adh/D2Mit5, have been constructed by replacing a region of chromosome 2 of the Dahl S rat with the homologous region (ie, low blood pressure QTL allele) of either the WKY or MNS rat, respectively. Systolic pressures of congenic strains S.WKY-D2N35/Nep and S.MNS-Adh/D2Mit5 fed a 2% NaCl diet for 24 days were 44+/-4.6 and 29+/-4.5 mm Hg lower, respectively, than that of the comparably treated Dahl S rats. The differences between congenic and Dahl S rats in blood pressure were highly significant (P<.001) and were corroborated by significantly (P<.001) lower ratio of heart weight to body weight in the congenic strains compared with Dahl S rats. The data from two congenic strains combined unequivocally establish the existence of a blood pressure QTL on rat chromosome 2.

Linkage map and congenic strains to localize blood pressure QTL on rat chromosome 10.

Our purposes were to develop a linkage map for rat Chromosome (Chr) 10, using chromosome-sorted DNA, and to construct congenic strains to localize blood pressure quantitative trait loci (QTL) on Chr 10 with the map. The linkage mapping panel consisted of three F2 populations totaling 418 rats. Thirty-two new and 29 known microsatellite markers were placed on the map, which spanned 88.9 centiMorgans (cM). The average distance between markers was 1.46 cM. No markers were separated by more than 6.8 cM. Four congenic strains were constructed by introgressing various segments of Chr 10 from the Milan normotensive strain (MNS) onto the background of the Dahl salt-sensitive (S) strain. A blood pressure QTL with a strong effect on blood pressure (35-42 mm Hg) when expressed on the S background was localized to a 31-cM region between D10Mco6 and D10Mcol. The region does not include the locus for inducible nitric oxide synthase (Nos2), which had been considered to be a candidate locus for the QTL.

[Preparation of new microsatellite markers of rat chromosome 10 in the region, containing genes regulating blood pressure level]. / Poluchenie novykh mikrosatellitnykh markerov khromosomy 10 krysy v raione, soderzhashchem geny, reguliruiushchie uroven' krovianogo davleniia.

Primer walking is a simple and efficient technique to find new microsatellites in the regions adjacent to known sequences. The method was applied to obtaining new microsatellite markers for rat chromosome 10 in the region of a blood pressure quantitative trait locus. Eight microsatellites were found, five of them were polymorphic in at least one population used for mapping. Improved genetic maps of this region for F2(SxMNS) and F2(SxLEW) populatons were constructed.

Genetic mapping of two blood pressure quantitative trait loci on rat chromosome 1.

A genetic map for rat chromosome 1 was constructed using 66 microsatellite markers typed on either or both of two populations derived from inbred Dahl salt-sensitive (S) rats: F2(LEW x S) n = 151, and F2(WKY x S) n = 159. These populations had been raised on a high salt (8% NaCl) diet. Systolic blood pressure and heart weight were found to be genetically linked to two separate regions on rat chromosome 1 in the F2(LEW x S) population. One region was centered around the anonymous SA locus and accounted for 24 mmHg of blood pressure. The other region was 55 cM from the SA locus centered around a cluster of cytochromes P450 loci, and accounted for 30 mmHg of blood pressure. Since blood pressure and heart weight were highly correlated these same regions were also linked to heart weight. These results were cross-specific as linkage of these chromosome 1 regions to blood pressure and heart weight was not observed in several other F2 populations derived by crossing S and other normotensive control strains. This is presumably due to different alleles and/or different genetic backgrounds in the various populations. The SA region of chromosome 1 was found to influence body weight in F2(LEW x S) rats. Combining the present data with our previously published data on the F2(LEW x S) population showed that four separate quantitative trait loci with additive effects accounted for 106 mmHg and 38% of the total variance of blood pressure and for 506 mg and 34% of the total variance of heart wt.