Effective use of the human and mouse genomes requires reliable identification of genes and their products. Although multiple public resources provide annotation, different methods are used that can result in similar but not identical representation of genes, transcripts, and proteins. The collaborative consensus coding sequence (CCDS) project tracks identical protein annotations on the reference mouse and human genomes with a stable identifier (CCDS ID), and ensures that they are consistently represented on the NCBI, Ensembl, and UCSC Genome Browsers. Importantly, the project coordinates on manually reviewing inconsistent protein annotations between sites, as well as annotations for which new evidence suggests a revision is needed, to progressively converge on a complete protein-coding set for the human and mouse reference genomes, while maintaining a high standard of reliability and biological accuracy. To date, the project has identified 20,159 human and 17,707 mouse consensus coding regions from 17,052 human and 16,893 mouse genes. Three evaluation methods indicate that the entries in the CCDS set are highly likely to represent real proteins, more so than annotations from contributing groups not included in CCDS. The CCDS database thus centralizes the function of identifying well-supported, identically-annotated, protein-coding regions.[Supplemental material is available online at www.genome.org. Data sets and documentation are available in the CCDS database at http://www.ncbi.nlm.nih.gov/CCDS.]One key goal of genome projects is to identify and accurately annotate all protein-coding genes. The resulting annotations add functional context to the sequence data and make it easier to traverse to other rich sources of gene and protein information. Accurately annotating known genes, identifying novel genes, and tracking annotations over time are complex processes that are best achieved through a combination of large-scale computational analyses and expert curation. These methods must (1) process repetitive sequences in multiple categories including retrotransposons, segmental duplications, and paralogs; (2) process variation including copy number variation (CNV) (Feuk et al. 2006) and microsatellites; (3) distinguish functional genes and alleles from pseudogenes; (4) define alternate splice products; and (5) avoid erroneous interpretation based on experimental error.

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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.

SummaryIn vivo experiments were performed to determine whether the cross-linking of membrane immunoglobulin (mlg) D on mature B cells, in the absence of T cell help, leads to B cell death. Mice were injected with either a monoclonal antibody (mAb) that cross-links mlgD effectively or a mAb that binds to mlgD avidly but cross-links it to a limited extent, and effects on B cell number and B cell Ia, mlgM, and mlgD expression were observed. In most experiments, mice were pretreated with anti-interleukin 7 mAb to prevent the generation of new bone marrow B cells, and with anti-CD4 mAb to prevent the generation of T cell help. In some experiments, mice also received anti-Fc3,RII mAb to prevent cross-linking of mlgD with Fc'yRII, and cobra venom factor to prevent possible mlg-complement receptor interactions and complement-mediated T he two-signal theory of B lymphocyte activation predicted that an interaction between antigen and B cell membrane immunoglobulin (mlg) 1 would trigger a B cell-activating event that would lead, in the presence of additional signals, to clonal expansion and antibody production, but, in the absence of additional signals, to death (1). Since this theory was proposed, the cross-linking orB cell mlg has been shown to costimulate B cell proliferation and differentiation in the presence of such stimuli as T cell-produced cytokines (2, 3) and T cell membrane costimulatory molecules (4, 5), while the cross-linking of mlg on newly generated B cells has been shown to lead to B cell unresponsiveness and death (6-8). The ultimate effects of mlg cross-linking on mature B cells, in the absence of additional stimuli, have, however, been less well defined. Cross-linking of mlg, in the absence of T cell help, stimulates enhanced B cell expression of receptors involved in proliferation and cellular interactions (9-11) and, under some conditions, can stimulate DNA synthesis, al-1 Abbreviations used in this paper: GerMS, affinity-purified goat anti-mouse IgD antibody; HEL, hen egg lysozyme; HNA, HBSS supplemented with 10% newborn bovine serum and 0.2% sodium azide; mlg, membrane immunoglobulin. though clonal expansion and antibody secretion are not induced (12-16). It is not known, however, whether these activated B cells eventually return to a resting state, survive but become anergic, or die. This issue has been difficult to resolve in vitro, where unstimulated B cells have a short life span and start to undergo apoptosis within 24 h (17). Study of the effects of mlg cross-linking on B cell life span has also been difficult, in part because of a long-standing controversy about whether resting B cells live for a long or short time in vivo (18)(19)(20)(21)(22). Recent experiments that have either labeled dividing B cells and B cell precursors in vivo (21) or used antibodies to IL-7 to prevent the in vivo generation of new B cells (22) have provided compelling evidence that most mature B cells have a life span that is measurable in weeks, rather than days. This conclusion has made it reasonable to question whe...

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.

Transforming growth factor (TGF)-βs are plausible candidate tumor suppressors in the breast. They also have oncogenic activities under certain circumstances, however. Genetically altered mouse models provide powerful tools to analyze the complexities of TGF-β action in the context of the whole animal. Overexpression of TGF-β can suppress tumorigenesis in the mammary gland, raising the possibility that use of pharmacologic agents to enhance TGF-β function locally might be an effective method for the chemoprevention of breast cancer. Conversely, loss of TGF-β response increases spontaneous and induced tumorigenesis in the mammary gland. This confirms that endogenous TGF-βs have tumor suppressor activity in the mammary gland, and suggests that the loss of TGF-β receptors seen in some human breast hyperplasias may play a causal role in tumor development. http://breast-cancer-research.com/content/2/2/100

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) Ϸ24 cM apart. These were localized to a Ͻ2.6-cM region between markers D10Rat27 and D10Rat24 for QTL 1 and to a Ͻ3.2-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. Key Words: sodium Ⅲ genetics Ⅲ 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 strains 7-10 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. MethodsAll rats used in the present study were ...