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Mutational analysis of Ras hotspots in patients with urothelial carcinoma of the bladder

World Journal of Clinical Oncology 2020年第8期11卷 614-628页

作者： Kiran Tripathi Apul Goel Atin Singhai Minal Garg Department of Biochemistry University of LucknowLucknow 226007India Department of Urology King George Medical UniversityLucknow 226003 Department of Pathology King George Medical UniversityLucknow 226003India

BACKGROUND Mutational activation of Ras genes is established as a prognostic factor for the genesis of a constitutively active RAS-mitogen activated protein kinase pathway that leads to *** among the distribution of the most frequent mutations in Ras isoforms is reported in different patient populations with urothelial carcinoma of the bladder(UCB).AIM To determine the presence/absence of mutations in Ras isoforms in patients with UCB in order to predict disease *** This study was performed to determine the mutational spectrum at the hotspot regions of H-Ras,K-Ras and N-Ras genes by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP)and DNA sequencing followed by their clinical impact(if any)by examining the relationship of mutational spectrum with clinical histopathological variables in 87 UCB *** None of the 87 UCB patients showed point mutations in codon 12 of H-Ras gene;codon 61 of N-Ras gene and codons 12,13 of K-Ras gene by *** DNA sequencing of tumor and normal control bladder mucosal specimens followed by Blastn alignment with the reference wild-type sequences failed to identify even one nucleotide difference in the coding exons 1 and 2 of H-Ras,NRas and K-Ras genes in the tumor and control bladder mucosal *** Our findings on the lack of mutations in H-Ras,K-Ras and N-Ras genes could be explained on the basis of different etiological mechanisms involved in tumor development/progression,inherent genetic susceptibility,tissue specificity or alternative Ras dysfunction such as gene amplification and/or overexpression in a given cohort of patients.

关键词： coding exons Oncogenic activation Polymerase chain reaction-restriction fragment length polymorphism Point mutations Ras genes Urothelial carcinoma of bladder

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Why Do Phylogenomic Data Sets Yield Conflicting Trees? Data Type Influences the Avian Tree of Life more than Taxon Sampling

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SYSTEMATIC BIOLOGY 2017年第5期66卷 857-879页

作者： Reddy, Sushma Kimball, Rebecca T. Pandey, Akanksha Hosner, Peter A. Braun, Michael J. Hackett, Shannon J. Han, Kin-Lan Harshman, John Huddleston, Christopher J. Kingston, Sarah Marks, Ben D. Miglia, Kathleen J. Moore, William S. Sheldon, Frederick H. Witt, Christopher C. Yuri, Tamaki Braun, Edward L. Loyola Univ Chicago Dept Biol 1032 W Sheridan Rd Chicago IL 60660 USA Univ Florida Dept Biol Gainesville FL 32607 USA Univ Florida Florida Museum Nat Hist Gainesville FL 32607 USA Univ Maryland Behav Ecol Evolut & Program College Pk MD 20742 USA Field Museum Nat Hist Chicago IL 60605 USA 74869 Pepperwood Way San Jose CA 95124 USA Smithsonian Inst Collect Program Natl Museum Nat Hist 4210 Silver Hill Rd Suitland MD 20746 USA Dept Biol & Coastal Studies Ctr Bowdoin Coll Coll Stn Brunswick ME 04011 USA Wayne State Univ Dept Biol Sci 5047 Gullen Mall Detroit MI 48202 USA Louisiana State Univ Museum Nat Sci & Dept Biol Sci 119 Foster Hall Baton Rouge LA 70803 USA

Phylogenomics, the use of large-scale data matrices in phylogenetic analyses, has been viewed as the ultimate solution to the problem of resolving difficult nodes in the tree of life. However, it has become clear that analyses of these large genomic data sets can also result in conflicting estimates of phylogeny. Here, we use the early divergences in Neoaves, the largest clade of extant birds, as a "model system" to understand the basis for incongruence among phylogenomic trees. We were motivated by the observation that trees from two recent avian phylogenomic studies exhibit conflicts. Those studies used different strategies: 1) collecting many characters [similar to 42 mega base pairs (Mbp) of sequence data] from 48 birds, sometimes including only one taxon for each major clade;and 2) collecting fewer characters (similar to 0.4 Mbp) from 198 birds, selected to subdivide long branches. However, the studies also used different data types: the taxon-poor data matrix comprised 68% non-coding sequences whereas coding exons dominated the taxon-rich datamatrix. This difference raises the question of whether the primary reason for incongruence is the number of sites, the number of taxa, or the data type. To test among these alternative hypotheses we assembled a novel, large-scale data matrix comprising 90% non-coding sequences from 235 bird species. Although increased taxon sampling appeared to have a positive impact on phylogenetic analyses the most important variable was data type. Indeed, by analyzing different subsets of the taxa in our data matrix we found that increased taxon sampling actually resulted in increased congruence with the tree from the previous taxon-poor study (which had a majority of non-coding data) instead of the taxon-rich study (which largely used coding data). We suggest that the observed differences in the estimates of topology for these studies reflect data-type effects due to violations of the models used in phylogenetic analyses, some of whic

关键词： Birds coding exons GTR model model fit Neoaves non-coding DNA phylogenomics taxon sampling

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Inventory of the cichlid olfactory receptor gene repertoires: identification of olfactory genes with more than one coding exon

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BMC GENOMICS 2014年第1期15卷 1-16页

作者： Azzouzi, Naoual Barloy-Hubler, Frederique Galibert, Francis Univ Rennes 1 CNRS Inst Genet & Dev UMR 6290 Rennes France

Background: To help understand the molecular mechanisms underlying the remarkable phenotypic diversity displayed by cichlids, the genome sequences of O. niloticus, P. nyererei, H. burtoni, N. brichardi and M. zebra were recently determined. Here, we present the contents of the olfactory receptor (OR) repertoires in the genomes of these five fishes. Results: We performed an exhaustive TBLASTN search of the five cichlid genomes to identify their OR repertoires as completely as possible. We used as bait a set of ORs described in the literature. The cichlid repertoires thereby extracted contained large numbers of complete genes (O. niloticus 158;H. burtoni 90;M. zebra 102;N. brichardi 69;P. nyererei 88), a small numbers of pseudogenes and many "edge genes" corresponding to incomplete genes located at the ends of contigs. A phylogenetic tree was constructed and showed these repertoires include a large number of families and subfamilies. It also allowed the identification of a large number of OR analogues between cichlids with very high amino-acid identity (>= 99%). Nearly 9% of the full-length cichlid OR genes are composed of several coding exons. This is very unusual for vertebrate OR genes. Nevertheless, the evidence is strong, and includes the donor and acceptor splice junction sequences;also, the positions of these genes in the phylogenetic tree indicate that they constitute subfamilies well apart from non-OR G protein-coupled receptor families. Conclusions: Cichlid OR repertoires are made up of a larger number of genes and fewer pseudogenes than those in other teleosts except zebrafish. These ORs share all identified properties common to all fish ORs;however, the large number of families and subfamilies, each containing few ORs implies that they have evolved more rapidly. This high level of OR diversity is consistent with the substantial phenotypic diversity that characterizes cichlids.

关键词： Zebrafish Medaka Stickleback Fugu Tetraodon Cichlids Olfactory receptors coding exons

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MOLECULAR BIOLOGY AND EVOLUTION 2009年第4期26卷 859-866页

作者： Haerty, Wilfried Golding, Brian McMaster Univ Dept Biol Hamilton ON L8S 4L8 Canada

As a consequence of alternative splicing, a gene's exons will have different frequencies of inclusion into mature mRNA and different patterns of expression. These differences affect their patterns of evolutionary divergence. Using the recently reannotated genome of Drosophila melanogaster and the genome sequences of four closely related species of the melanogaster subgroup, we investigated the effect of alternative splicing, inclusion level (defined as the number of transcripts an exon is found in), and expression pattern on exon evolution across divergence times ranging from 1 to 12.5 Ma. Genes undergoing alternative splicing have a broader pattern of expression associated with a lower divergence rate in comparison with genes with a single annotated protein isoform. Within genes undergoing alternative splicing, we report a significant effect of inclusion level on exon evolution, as alternatively spliced exons are less conserved than constitutively spliced exons. More generally, there are significant negative correlations between inclusion level and exon evolutionary rates that can be associated with relaxation of selection. A significant effect of expression pattern on evolution rates is also observed. Overall, we found that similar selective factors such as the expression level and the pattern of expression are affecting both gene and exon evolution.

关键词： alternative splicing coding exons rates of evolution inclusion level pattern of expression Drosophila

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Comprehensive mutation analysis of TSC1 and TSC2 -: and phenotypic correlations in 150 families with tuberous sclerosis

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AMERICAN JOURNAL OF HUMAN GENETICS 1999年第5期64卷 1305-1315页

作者： Jones, AC Shyamsundar, MM Thomas, MW Maynard, J Idziaszczyk, S Tomkins, S Sampson, JR Cheadle, JP Cardiff Univ Inst Med Genet Cardiff CF4 4XN S Glam Wales

Tuberous sclerosis (TSC [MIM 191090 and MIM 191100]) is an autosomal dominant disorder characterized by hamartomas in many organs. Two thirds of cases are sporadic and are thought to represent new mutations. TSC is caused by mutations affecting either of the presumed tumor-suppressor genes, TSC1 and TSC2. Both appear to function as tumor suppressors, because somatic loss or intragenic mutation of the corresponding wild-type allele is seen in the associated hamartomas. Here we report the first comprehensive mutation analysis of TSC1 and TSC2 in a cohort of 150 unrelated TSC patients and their families, using heteroduplex and SSCP analysis of all coding exons and using pulsed-field gel electrophoresis and conventional Southern blot analysis and long PCR to screen for large rearrangements. Mutations were characterized in 120 (80%) of the 150 cases, affecting TSC1 in 22 cases and TSC2 in 38 cases. TSC1 mutations were significantly underrepresented in sporadic cases (P = .000185). Twenty-two patients had TSC2 missense mutations that were found predominantly in the GAP-related domain (eight cases) and in a small region encoded in exons 16 and 17, between nucleotides 1849 and 1859 (eight cases), consistent with the presence of residues performing key functions at these sites. In contrast, all TSC1 mutations were predicted to be truncating, consistent with a structural or adapter role for the encoded protein, Intellectual disability was significantly more frequent in TSC2 sporadic cases than in TSC1 sporadic cases (P = .0145). These data provide the first representative picture of the distribution and spectrum of mutations across the TSC1 and TSC2 loci in clinically ascertained TSC and support a difference in severity of TSC1- and TSC2-associated disease.

关键词： .intragenic SSCP mutation analysis unrelated heteroduplex autosomal dominant missense coding exons Sporadic cases Long PCR Tuberous sclerosis TSC TSC mutations Analysis of TSC

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BOTH coding exons OF THE C-MYC GENE CONTRIBUTE TO ITS POSTTRANSCRIPTIONAL REGULATION IN THE QUIESCENT LIVER AND REGENERATING LIVER AND AFTER PROTEIN-SYNTHESIS INHIBITION

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MOLECULAR AND CELLULAR BIOLOGY 1995年第8期15卷 4410-4419页

作者： LAVENU, A PISTOI, S POURNIN, S BABINET, C MORELLO, D INST PASTEUR DEPT IMMUNOLUNITE BIOL DEVF-75724 PARIS 15FRANCE

In vivo, the steady-state level of c-myc mRNA is mainly controlled by posttranscriptional mechanisms. Using a panel of transgenic mice in which various versions of the human c-myc proto-oncogene were under the control of major histocompatibility complex H-2K(b) class I regulatory sequences, we have shown that the 5' and the 3' noncoding sequences are dispensable for obtaining a regulated expression of the transgene in adult quiescent tissues, at the start of liver regeneration, and after inhibition of protein synthesis. These results indicated that the coding sequences were sufficient to ensure a regulated c-myc expression. In the present study, we have pursued this analysis with transgenes containing one or the other of the two c-myc coding exons either alone or in association with the c-myc 3' untranslated region. We demonstrate that each of the exons contains determinants which control c-myc mRNA expression. Moreover, we show that in the liver, c-myc exon 2 sequences are able to down-regulate an otherwise stable H-2K mRNA when embedded within it and to induce its transient accumulation after cycloheximide treatment and soon after liver ablation. Finally, the use of transgenes with different coding capacities has allowed us to postulate that the primary mRNA sequence itself and not c-Myc peptides is an important component of c-myc posttranscriptional regulation.

关键词： .noncoding dispensable transgenes protein synthesis transgenic mice quiescent liver regeneration mRNA expression c-Myc proto-oncogene regulatory sequences coding exons MYC gene posttranscriptional regulation human myc inhibition of protein myc mRNA myc exon

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Clustering of mutations responsible for branchio-oto-renal (BOR) syndrome in the eyes absent homologous region (eyaHR) of EYA1

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HUMAN MOLECULAR GENETICS 1997年第13期6卷 2247-2255页

作者： Abdelhak, S Kalatzis, V Heilig, R Compain, S Samson, D Vincent, C LeviAcobas, F Cruaud, C LeMerrer, M Mathieu, M Konig, R Vigneron, J Weissenbach, J Petit, C Weil, D INST PASTEUR UNIT GENET DEFICITS SENSORIELS CNRS URA 1968 F-75724 PARIS 15 FRANCE GENETHON HUMAN RES CTR F-91000 EVRY FRANCE HOP NECKER ENFANTS MALAD UNITE RECH HANDICAPS GENET ENFANT INSERM U393 F-75743 PARIS 15 FRANCE CTR HOSP REG UNIV AMIENS HOP NORD F-80054 AMIENS FRANCE UNIV FRANKFURT KLINIKUM INST HUMAN GENET D-60590 FRANKFURT GERMANY MATERNITE REG SERV NEONATOL GENET F-54042 NANCY FRANCE

Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder, characterised by the association of branchial, otic and renal anomalies with variable degrees of severity, We have recently identified EYA1, a human homologue of the Drosophila eyes absent gene, as the gene underlying this syndrome, The products of both genes share a highly conserved 271 amino acid C-terminal region (eyaHR). The eyaHR was also found in the products of two other human genes (EYA2 and EYA3), demonstrating the existence of a novel gene family, We report here on the complete genomic structure of EYA1, This gene consists of 16 coding exons and extends over 156 kb, It encodes various alternatively spliced transcripts differing only in their 5' regions, Sequence analysis of the entire EYA1 coding region was performed for 20 unrelated patients affected by BOR syndrome, and six novel mutations were identified, Among these mutations, two are missense mutations, highlighting amino acid residues essential for the function of the EYA1 protein, and one mutation comprises a de novo Alu insertion into an exon, This insertion presumably occurs by retrotransposition, and the mobile Alu element has a poly(A) tail that is unstable throughout generations, To date, 14 mutations have been detected in BOR patients, all of which are different, However, all the mutations are located within or in the immediate vicinity of the eyaHR;the significance of this clustering is discussed.

关键词： .clustering branchial Cedex France coding exons eyes absent eyaHR branchio-oto-renal BOR syndrome structure of EYA

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