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Deafblindness in French Canadians from Quebec:: a predominant founder mutation in the USH1C gene provides the first genetic link with the Acadian population

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GENOME BIOLOGY 2007年第4期8卷 R47-R47页

作者： Ebermann, Inga Lopez, Irma Bitner-Glindzicz, Maria Brown, Carolyn Koenekoop, Robert Karel Bolz, Hanno Joern Univ Hosp Cologne Inst Human Genet D-50931 Cologne Germany Montreal Childrens Hosp Res Inst McGill Ocular Genet Lab Montreal PQ H3H 1P3 Canada UCL Inst Child Hlth Unit Clin & Mol Genet London WC1N 1EH England

Background: Usher syndrome type I ( USHI) is the leading cause of deafblindness. In most populations, many private mutations are distributed across the five known USHI genes. We investigated patients from the French Canadian population of Quebec ( approximately 6 million people) that descends from about 8,500 French settlers who colonized the St Lawrence River valley between 1608 and 1759. We hypothesized that founder mutations in USHI genes exist in this population. Results: We have genetically characterized 15 patients from different regions of Quebec who were clinically diagnosed as USHI. Of these cases, 60% carried mutations of the USHIC gene, a genetic subtype that is rare outside the Acadian population. We have discovered a founder effect of the c.216G > A mutation, which has previously been designated the 'Acadian allele' because it accounts for virtually all Acadian USHI cases. It represents 40% of disease alleles in Quebec, and a carrier of c.216G > A was identified in the general population. Mutations in other genes, except CDH23, are very rare. Conclusion: Based on our findings, approximately 0.5% of congenitally deaf children in Quebec are at risk of developing retinal degeneration due to homozygosity for c.216G > A. Although the Acadians and French Canadians from Quebec are descended from French ancestors, they have always been considered genetically distinct. The genetic conditions common in Quebec are generally not found in Acadians, or they are due to different mutations. Our results, however, show that carriers of the c.216G > A allele haplotype belonged to the early founders of both the Acadian and the Quebec population.

关键词： additional data file Founder Mutation Deaf Child Usher Syndrome Ashkenazi Jewish Population

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Tumour-associated tenascin-C isoforms promote breast cancer cell invasion and growth by matrix metalloproteinase-dependent and independent mechanisms

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BREAST CANCER RESEARCH 2009年第2期11卷 1-13页

作者： Hancox, Rachael A. Allen, Michael D. Holliday, Deborah L. Edwards, Dylan R. Pennington, Caroline J. Guttery, David S. Shaw, Jacqueline A. Walker, Rosemary A. Pringle, J. Howard Jones, J. Louise Univ Leicester Dept Canc Studies & Mol Med Infirm Close Leicester Royal Infirm Leicester LE1 5WW Leics England Univ London Barts & London Sch Med & Dent Inst Canc Tumor Biol Ctr London EC1M 6BQ England Univ E Anglia Sch Biol Sci Norwich NR4 7TJ Norfolk England

Introduction The stromal microenvironment has a profound influence on tumour cell behaviour. In tumours, the extracellular matrix (ECM) composition differs from normal tissue and allows novel interactions to influence tumour cell function. The ECM protein tenascin-C (TNC) is frequently up-regulated in breast cancer and we have previously identified two novel isoforms one containing exon 16 (TNC-16) and one containing exons 14 plus 16 (TNC-14/16). Methods The present study has analysed the functional significance of this altered TNC isoform profile in breast cancer. TNC-16 and TNC-14/16 splice variants were generated using PCR-ligation and over-expressed in breast cancer cells (MCF-7, T47D, MDA-MD-231, MDA-MB-468, GI101) and human fibroblasts. The effects of these variants on tumour cell invasion and proliferation were measured and compared with the effects of the large (TNC-L) and fully spliced small (TNC-S) isoforms. Results TNC-16 and TNC-14/16 significantly enhanced tumour cell proliferation (P < 0.05) and invasion, both directly (P < 0.01) and as a response to transfected fibroblast expression (P < 0.05) with this effect being dependent on tumour cell interaction with TNC, because TNC-blocking antibodies abrogated these responses. An analysis of 19 matrix metalloproteinases (MMPs) and tissue inhibitor of matrix metalloproteinases 1 to 4 (TIMP 1 to 4) revealed that TNC upregulated expression of MMP-13 and TIMP-3 two to four fold relative to vector, and invasion was reduced in the presence of MMP inhibitor GM6001. However, this effect was not isoform-specific but was elicited equally by all TNC isoforms. Conclusions These results demonstrate a dual requirement for TNC and MMP in enhancing breast cancer cell invasion, and identify a significant role for the tumour-associated TNC-16 and TNC-14/16 in promoting tumour invasion, although these isoform-specific effects appear to be mediated through MMP-independent mechanisms.

关键词： Breast Cancer Cell Conditioned Medium additional data file Tumour Cell Invasion Breast Cancer Cell Invasion

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Time- and exercise-dependent gene regulation in human skeletal muscle

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GENOME BIOLOGY 2003年第10期4卷 R61-R61页

作者： Zambon, AC McDearmon, EL Salomonis, N Vranizan, KM Johansen, KL Adey, D Takahashi, JS Schambelan, M Conklin, BR Univ Calif San Francisco Dept Med Gladstone Inst Cardiovasc Dis San Francisco CA 94141 USA Northwestern Univ Dept Neurobiol & Physiol Howard Hughes Med Inst Evanston IL 60208 USA Univ Calif San Francisco Dept Med San Francisco CA 94141 USA

Background: Skeletal muscle remodeling is a critical component of an organism's response to environmental changes. Exercise causes structural changes in muscle and can induce phase shifts in circadian rhythms, fluctuations in physiology and behavior with a period of around 24 hours that are maintained by a core clock mechanism. Both exercise-induced remodeling and circadian rhythms rely on the transcriptional regulation of key genes. Results: We used DNA microarrays to determine the effects of resistance exercise (RE) on gene regulation in biopsy samples of human quadriceps muscle obtained 6 and 18 hours after an acute bout of isotonic exercise with one leg. We also profiled diurnal gene regulation at the same time points (2000 and 0800 hours) in the non-exercised leg. Comparison of our results with published circadian gene profiles in mice identified 44 putative genes that were regulated in a circadian fashion. We then used quantitative PCR to validate the circadian expression of selected gene orthologs in mouse skeletal muscle. Conclusions: The coordinated regulation of the circadian clock genes Cry1, Per2, and BmaII 6 hours after RE and diurnal genes 18 hours after RE in the exercised leg suggest that RE may directly modulate circadian rhythms in human skeletal muscle.

关键词： Resistance Exercise additional data file Circadian Gene Circadian Regulation Circadian Clock Gene

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MetaReg: a platform for modeling, analysis and visualization of biological systems using large-scale experimental data

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GENOME BIOLOGY 2008年第1期9卷 R1-R1页

作者： Ulitsky, Igor Gat-Viks, Irit Shamir, Ron Tel Aviv Univ Sch Comp Sci IL-69978 Tel Aviv Israel Max Planck Inst Mol Genet Computat Mol Biol Dept D-14195 Berlin Germany

MetaReg http://***/metareg/*** is a computational tool that models cellular networks and integrates experimental results with such models. MetaReg represents established knowledge about a biological system, available today mostly in informal form in the literature, as probabilistic network models with underlying combinatorial regulatory logic. MetaReg enables contrasting predictions with measurements, model improvements and studying what-if scenarios. By summarizing prior knowledge and providing visual and computational aids, it helps the expert explore and understand her system better.

关键词： additional data file Rapamycin Treatment High Throughput data Regulatory Logic Model Canvas

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Genome-wide prioritization of disease genes and identification of disease-disease associations from an integrated human functional linkage network

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GENOME BIOLOGY 2009年第9期10卷 R91-R91页

作者： Linghu, Bolan Snitkin, Evan S. Hu, Zhenjun Xia, Yu DeLisi, Charles Boston Univ Bioinformat Program Boston MA 02215 USA Boston Univ Dept Chem Boston MA 02215 USA

We integrate 16 genomic features to construct an evidence-weighted functional-linkage network comprising 21,657 human genes. The functional-linkage network is used to prioritize candidate genes for 110 diseases, and to reliably disclose hidden associations between disease pairs having dissimilar phenotypes, such as hypercholesterolemia and Alzheimer's disease. Many of these disease-disease associations are supported by epidemiology, but with no previous genetic basis. Such associations can drive novel hypotheses on molecular mechanisms of diseases and therapies.

关键词： Disease Gene additional data file Seed Gene Candidate Disease Gene Disease Pair

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Exon creation and establishment in human genes

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GENOME BIOLOGY 2008年第9期9卷 R141-R141页

作者： Corvelo, Andre Eyras, Eduardo Univ Pompeu Fabra Barcelona 08003 Spain Univ Porto Grad Program Areas Basic & Appl Biol P-4099002 Oporto Portugal Catalan Inst Res & Adv Studies Barcelona 08010 Spain

Background: A large proportion of species-specific exons are alternatively spliced. In primates, Alu elements play a crucial role in the process of exon creation but many new exons have appeared through other mechanisms. Despite many recent studies, it is still unclear which are the splicing regulatory requirements for de novo exonization and how splicing regulation changes throughout an exon's lifespan. Results: Using comparative genomics, we have defined sets of exons with different evolutionary ages. Younger exons have weaker splice-sites and lower absolute values for the relative abundance of putative splicing regulators between exonic and adjacent intronic regions, indicating a less consolidated splicing regulation. This relative abundance is shown to increase with exon age, leading to higher exon inclusion. We show that this local difference in the density of regulators might be of biological significance, as it outperforms other measures in real exon versus pseudo-exon classification. We apply this new measure to the specific case of the exonization of anti-sense Alu elements and show that they are characterized by a general lack of exonic splicing silencers. Conclusions: Our results suggest that specific sequence environments are required for exonization and that these can change with time. We propose a model of exon creation and establishment in human genes, in which splicing decisions depend on the relative local abundance of regulatory motifs. Using this model, we provide further explanation as to why Alu elements serve as a major substrate for exon creation in primates. Finally, we discuss the benefits of integrating such information in gene prediction.

关键词： Splice Site additional data file Inclusion Level Flank Intron Intronic Density

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Annotating genomes with massive-scale RNA sequencing

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GENOME BIOLOGY 2008年第12期9卷 R175-R175页

作者： Denoeud, France Aury, Jean-Marc Da Silva, Corinne Noel, Benjamin Rogier, Odile Delledonne, Massimo Morgante, Michele Valle, Giorgio Wincker, Patrick Scarpelli, Claude Jaillon, Olivier Artiguenave, Francois Inst Genom DSV CEA F-91057 Evry France CNRS UMR 8030 F-91057 Evry France Univ Evry F-91057 Evry France Sci & Technol Dept I-37134 Verona Italy Ist Genom Applicata I-33100 Udine Italy Univ Padua CRIBI I-35121 Padua Italy

Next generation technologies enable massive-scale cDNA sequencing (so-called RNA-Seq). Mainly because of the difficulty of aligning short reads on exon-exon junctions, no attempts have been made so far to use RNA-Seq for building gene models de novo, that is, in the absence of a set of known genes and/or splicing events. We present G-Mo.R-Se (Gene Modelling using RNA-Seq), an approach aimed at building gene models directly from RNA-Seq and demonstrate its utility on the grapevine genome.

关键词： Alternative Splice additional data file Coverage Depth Alternative Splice Event Massively Parallel Signature Sequencing

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Primate-specific evolution of an LDLR enhancer

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GENOME BIOLOGY 2006年第8期7卷 1-9页

作者： Wang, Qian-fei Prabhakar, Shyam Wang, Qianben Moses, Alan M. Chanan, Sumita Brown, Myles Eisen, Michael B. Cheng, Jan-Fang Rubin, Edward M. Boffelli, Dario Lawrence Berkeley Lab Genom Div Berkeley CA 94720 USA Joint Genome Inst US DOE Walnut Creek CA 94598 USA Harvard Univ Sch Med Dana Farber Canc Inst Boston MA 02115 USA

Background: Sequence changes in regulatory regions have often been invoked to explain phenotypic divergence among species, but molecular examples of this have been difficult to obtain. Results: In this study we identified an anthropoid primate-specific sequence element that contributed to the regulatory evolution of the low-density lipoprotein receptor. Using a combination of close and distant species genomic sequence comparisons coupled with in vivo and in vitro studies, we found that a functional cholesterol-sensing sequence motif arose and was fixed within a pre-existing enhancer in the common ancestor of anthropoid primates. Conclusion: Our study demonstrates one molecular mechanism by which ancestral mammalian regulatory elements can evolve to perform new functions in the primate lineage leading to human.

关键词： additional data file Mouse Lemur Conservation Score Anthropoid Primate DNaseI Hypersensitive Site

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Characterization of the differentially methylated region of the Impact gene that exhibits Glires-specific imprinting

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GENOME BIOLOGY 2008年第11期9卷 R160-R160页

作者： Okamura, Kohji Wintle, Richard F. Scherer, Stephen W. Univ Toronto Dept Mol & Med Genet Toronto ON M5S 1A8 Canada Hosp Sick Children Program Genet & Genome Biol Ctr Appl Genom MaRS Ctr TMDT Toronto ON M5G 1L7 Canada

Background: Imprinted genes are exclusively expressed from one of the two parental alleles in a parent-of-origin-specific manner. In mammals, nearly 100 genes are documented to be imprinted. To understand the mechanism behind this gene regulation and to identify novel imprinted genes, common features of DNA sequences have been analyzed;however, the general features required for genomic imprinting have not yet been identified, possibly due to variability in underlying molecular mechanisms from locus to locus. Results: We performed a thorough comparative genomic analysis of a single locus, Impact, which is imprinted only in Glires (rodents and lagomorphs). The fact that Glires and primates diverged from each other as recent as 70 million years ago makes comparisons between imprinted and non-imprinted orthologues relatively reliable. In species from the Glires clade, Impact bears a differentially methylated region, whereby the maternal allele is hypermethylated. Analysis of this region demonstrated that imprinting was not associated with the presence of direct tandem repeats nor with CpG dinucleotide density. In contrast, a CpG periodicity of 8 bp was observed in this region in species of the Glires clade compared to those of carnivores, artiodactyls, and primates. Conclusions: We show that tandem repeats are dispensable, establishment of the differentially methylated region does not rely on G+ C content and CpG density, and the CpG periodicity of 8 bp is meaningful to the imprinting. This interval has recently been reported to be optimal for de novo methylation by the Dnmt3a-Dnmt3L complex, suggesting its importance in the establishment of imprinting in Impact and other genes.

关键词： Tandem Repeat additional data file Imprint Gene Wood Mouse Differentially Methylated Region

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Plant polycistronic precursors containing non-homologous microRNAs target transcripts encoding functionally related proteins

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GENOME BIOLOGY 2009年第12期10卷 R136-R136页

作者： Merchan, Francisco Boualem, Adnane Crespi, Martin Frugier, Florian INRA URGV F-91057 Evry France CNRS ISV F-91198 Gif Sur Yvette France

Background: MicroRNAs (miRNAs) are endogenous single-stranded small RNAs that regulate the expression of specific mRNAs involved in diverse biological processes. In plants, miRNAs are generally encoded as a single species in independent transcriptional units, referred to as MIRNA genes, in contrast to animal miRNAs, which are frequently clustered. Results: We performed a comparative genomic analysis in three model plants (rice, poplar and Arabidopsis) and characterized miRNA clusters containing two to eight miRNA species. These clusters usually encode miRNAs of the same family and certain share a common evolutionary origin across monocot and dicot lineages. In addition, we identified miRNA clusters harboring miRNAs with unrelated sequences that are usually not evolutionarily conserved. Strikingly, non-homologous miRNAs from the same cluster were predicted to target transcripts encoding related proteins. At least four Arabidopsis non-homologous clusters were expressed as single transcriptional units. Overexpression of one of these polycistronic precursors, producing Ath-miR859 and Ath-miR774, led to the DCL1-dependent accumulation of both miRNAs and down-regulation of their different mRNA targets encoding F-box proteins. Conclusions: In addition to polycistronic precursors carrying related miRNAs, plants also contain precursors allowing coordinated expression of non-homologous miRNAs to co-regulate functionally related target transcripts. This mechanism paves the way for using polycistronic MIRNA precursors as a new molecular tool for plant biologists to simultaneously control the expression of different genes.

关键词： additional data file Target Transcript MIRNA Precursor Plant miRNAs miRNA Cluster

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