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PubMed1998

The 5' region of intron 11 of the dystrophin gene contains target sequences for mobile elements and three overlapping ORFs.

We have characterised the 2371 bp 5' end of intron 11 of the dystrophin gene. Comparative analysis of this intronic region revealed homologies with the following sequences: regions containing mobile elements; target sites for numerous transcription factors, two resolvases, and a histone-like DNA binding protein; three eukaryotic promoters. In addition, we identified three partially overlapping ORFs, and transcription analysis confirmed that one of these is expressed, representing the first gene reported to overlap the human dystrophin gene. We have also characterised a 136 bp sequence rearranged in intron 11 in a patient affected by X-linked dilated cardiomyopathy due to a dystrophinopathy. This is a multiple copy sequence with features of a repetitive element. Its comparative analysis showed a very high homology with human genomic and EST regions, adjacent and clustered with Alu, LINE1, and THE elements. The pattern of homology suggests that it may represent a novel Alu-like, transcriptionally active sequence with a possible retrotransposable capacity. We hypothesise that the 5' region of the dystrophin intron 11, containing common target areas for the insertion of mobile elements, may have a role in the rearrangement of this novel Alu-like sequence.

Cardiomyopathy, Dilated↗
PubMed2004

Identification of a lens-specific cis-acting element within the basal promoter of the human lens intrinsic membrane protein MP19 gene (LIM2).

Using overlapping and mutant oligonucleotides as probes, gel mobility assays and competition experiments identified a sequence from -47 to -32 bp upstream of the LIM2 CAP site, which a lens protein complex bound with high affinity which appeared to bind only to the "sense" strand of the double-stranded DNA molecule. This sequence consisted of a string of four guanine residues followed by seven other nucleotides (AACCTAA) and followed by another four guanines, i.e. GGGGAACCTAAGGGG, called the Hsu element. Promoter-CAT constructs containing this sequence or mutations of the sequence indicated that the Hsu element is located within the basal promoter, and is essential for expression of the LIM2 gene. The trans factors binding to the Hsu element are present throughout development, and appear to be lens-specific. Since the LIM2 gene promoter does not contain a classic TATA box, the Hsu element may serve as the site for binding the RNA polymerase complex.

Base Sequence↗
PubMed2000

Forkhead genes in transcriptional silencing, cell morphology and the cell cycle. Overlapping and distinct functions for FKH1 and FKH2 in Saccharomyces cerevisiae.

The SIR1 gene is one of four specialized genes in Saccharomyces cerevisiae required for repressing transcription at the silent mating-type cassettes, HMLalpha and HMRa, by a mechanism known as silencing. Silencing requires the assembly of a specialized chromatin structure analogous to heterochromatin. FKH1 was isolated as a gene that, when expressed in multiple copies, could substitute for the function of SIR1 in silencing HMRa. FKH1 (Forkhead Homologue One) was named for its homology to the forkhead family of eukaryotic transcription factors classified on the basis of a conserved DNA binding domain. Deletion of FKH1 caused a defect in silencing HMRa, indicating that FKH1 has a positive role in silencing. Significantly, deletion of both FKH1 and its closest homologue in yeast, FKH2, caused a form of yeast pseudohyphal growth, indicating that the two genes have redundant functions in controlling yeast cell morphology. By several criteria, fkh1Delta fkh2Delta-induced pseudohyphal growth was distinct from the nutritionally induced form of pseudohyphal growth observed in some strains of S. cerevisiae. Although FKH2 is redundant with FKH1 in controlling pseudohyphal growth, the two genes have different functions in silencing HMRa. High-copy expression of CLB2, a G2/M-phase cyclin, prevented fkh1Delta fkh2Delta-induced pseudohyphal growth and modulated some of the fkhDelta-induced silencing phenotypes. Interestingly, deletions in either FKH1 or FKH2 alone caused subtle but opposite effects on cell-cycle progression and CLB2 mRNA expression, consistent with a role for each of these genes in modulating the cell cycle and having opposing effects on silencing. The differences between Fkh1p and Fkh2p in vivo were not attributable to differences in their DNA binding domains.

Cell Cycle↗
PubMed1990

Two members of the mouse mdr gene family confer multidrug resistance with overlapping but distinct drug specificities.

We report the cloning and functional analysis of a complete clone for the third member of the mouse mdr gene family, mdr3. Nucleotide and predicted amino acid sequence analyses showed that the three mouse mdr genes encode highly homologous membrane glycoproteins, which share the same length (1,276 residues), the same predicted functional domains, and overall structural arrangement. Regions of divergence among the three proteins are concentrated in discrete segments of the predicted polypeptides. Sequence comparison indicated that the three mouse mdr genes were created from a common ancestor by two independent gene duplication events, the most recent one producing mdr1 and mdr3. When transfected and overexpressed in otherwise drug-sensitive cells, the mdr3 gene, like mdr1 and unlike mdr2, conferred multidrug resistance to these cells. In independently derived transfected cell clones expressing similar amounts of either MDR1 or MDR3 protein, the drug resistance profile conferred by mdr3 was distinct from that conferred by mdr1. Cells transfected with and expressing MDR1 showed a marked 7- to 10-fold preferential resistance to colchicine and Adriamycin compared with cells expressing equivalent amounts of MDR3. Conversely, cells transfected with and expressing MDR3 showed a two- to threefold preferential resistance to actinomycin D over their cellular counterpart expressing MDR1. These results suggest that MDR1 and MDR3 are membrane-associated efflux pumps which, in multidrug-resistant cells and perhaps normal tissues, have overlapping but distinct substrate specificities.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Interspecies conservation of gene order and intron-exon structure in a genomic locus of high gene density and complexity in Plasmodium.

A 13.6 kb contig of chromosome 5 of Plasmodium berghei, a rodent malaria parasite, has been sequenced and analysed for its coding potential. Assembly and comparison of this genomic locus with the orthologous locus on chromosome 10 of the human malaria Plasmodium falciparum revealed an unexpectedly high level of conservation of the gene organisation and complexity, only partially predicted by current gene-finder algorithms. Adjacent putative genes, transcribed from complementary strands, overlap in their untranslated regions, introns and exons, resulting in a tight clustering of both regulatory and coding sequences, which is unprecedented for genome organisation of PLASMODIUM: In total, six putative genes were identified, three of which are transcribed in gametocytes, the precursor cells of gametes. At least in the case of two multiple exon genes, alternative splicing and alternative transcription initiation sites contribute to a flexible use of the dense information content of this locus. The data of the small sample presented here indicate the value of a comparative approach for Plasmodium to elucidate structure, organisation and gene content of complex genomic loci and emphasise the need to integrate biological data of all Plasmodium species into the P.falciparum genome database and associated projects such as PlasmodB to further improve their annotation.

Alternative Splicing↗
PubMed1987

Immunoglobulin VH region genes of the mouse are organized in overlapping clusters.

Restriction fragment length polymorphism has been compared between the Igh loci of C57BL/6 and MOLF/EI (Mus musculus molossinus) mice utilizing probes which detect the C gamma 2b gene and genes from nine VH-gene families. Distinct restriction site patterns were found for the CH genes and for VH families PC7183, Q52 and X24. VH families V31 and J558 showed identical patterns. Mixed patterns of identical and distinct bands were detected in VH families S107, J606, V3660 and VGAM3.8. This indicates that a recombination took place involving the Igh loci of a M. m. molossinus and a progenitor of the C57BL/6 strain. The breakpoint of recombination maps to the chromosomal region carrying VH families S107, J606, VGAM3.8 and V3660. VH families PC7183, Q52 and X24 map 3' to the recombination breakpoint and proximal to the DH-JH-CH region, whereas VH families V31 and J558 accordingly map 5' to the recombination breakpoint and distal to DH-JH-CH. This order of VH families was confirmed by deletion mapping utilizing hybridomas which are haploid either for the Ighb or for the Igha locus. The mapping data indicate that the VH families of the mouse are organized in overlapping clusters. This notion is confirmed by demonstration of the physical linkage of VH genes from families V31 and J558 in the Igha locus.

Animals↗
PubMed2004

GadY, a small-RNA regulator of acid response genes in Escherichia coli.

A previous bioinformatics-based search for small RNAs in Escherichia coli identified a novel RNA named IS183. The gene encoding this small RNA is located between and on the opposite strand of genes encoding two transcriptional regulators of the acid response, gadX (yhiX) and gadW (yhiW). Given that IS183 is encoded in the gad gene cluster and because of its role in regulating acid response genes reported here, this RNA has been renamed GadY. We show that GadY exists in three forms, a long form consisting of 105 nucleotides and two processed forms, consisting of 90 and 59 nucleotides. The expression of this small RNA is highly induced during stationary phase in a manner that is dependent on the alternative sigma factor sigmaS. Overexpression of the three GadY RNA forms resulted in increased levels of the mRNA encoding the GadX transcriptional activator, which in turn caused increased levels of the GadA and GadB glutamate decarboxylases. A promoter mutation which abolished gadY expression resulted in a reduction in the amount of gadX mRNA during stationary phase. The gadY gene was shown to overlap the 3' end of the gadX gene, and this overlap region was found to be necessary for the GadY-dependent accumulation of gadX mRNA. We suggest that during stationary phase, GadY forms base pairs with the 3'-untranslated region of the gadX mRNA and confers increased stability, allowing for gadX mRNA accumulation and the increased expression of downstream acid resistance genes.

AraC Transcription Factor↗
PubMed1992

Molecular characterization of vascular smooth muscle decorin: deduced core protein structure and regulation of gene expression.

Two overlapping clones containing sequences homologous to bovine, human and chicken decorin have been recovered from poly A+ RNA isolated from rat vascular smooth muscle cells (VSMC) using cDNA cloning and reverse transcription-polymerase chain reaction (PCR) methodologies. Results of nucleotide sequence analysis performed on these clones demonstrated that they encode the complete mature rat decorin protein expressed by VSMC. Within the coding region, rat decorin exhibits 76% nucleotide sequence homology to human and bovine decorin, and 69% homologous to chicken decorin indicating a significant level of conservation among these species. This level of conservation among species was also maintained at the protein level with rat decorin being 77% homologous to its human, bovine and chicken homologues. As previously observed its human homologue, rat decorin, is made up of seven, tandem, leucine-rich repeat sequences. Furthermore, within the core of these repeats was the consensus protein sequence NKISK which has been proposed to be the fibronectin binding region of decorin (G. Schmidt et al., Biochem. J. 280, 411-414 (1991)). The vast majority of amino acid substitutions within rat decorin were of the conservative type. The highest frequency of amino acid substitutions were found to be localized within a hypervariable region located near the amino terminus of the decorin core protein. Unlike rat biglycan, rat decorin mRNA levels were found to increase significantly in density-arrested VSMC cultures. In contrast to rat biglycan gene expression, no quantitative differences in rat decorin mRNA levels were observed between proliferating VSMC and VSMC made quiescent through serum depletion. Finally, specific extracellular matrix (ECM) proteins were able to regulate the expression of decorin at the mRNA level in a slightly different manner than previously observed for biglycan.

Amino Acid Sequence↗
PubMed2026

Integrative transcriptomic, spatial and functional-genomic analysis identifies a UFMylation-related vascular-stromal program and prioritizes WWTR1 in glioblastoma.

Glioblastoma (GBM) contains spatially organized stress-adaptive and vascular niches. Because transcript abundance does not measure UFM1 conjugation, we asked whether a UFMylation-related transcriptional axis identifies a reproducible tissue program and alters candidate prioritization. In 518 unique primary TCGA-GBM tumors profiled on the Affymetrix HT Human Genome U133A array, weighted gene co-expression network analysis of 8,000 variable genes yielded 12 modules. The 278-gene green module ranked first across nine prespecified traits (mean |r|=0.637). Direct overlap comprised 1/3 measurable UFMylation-core, 5/19 ER-stress/UPR, and 2/15 proteostasis genes; after excluding overlapping genes, correlations with the green eigengene remained significant (r = 0.373, 0.831, 0.639, and 0.699 for UFMylation-core, ER-stress/UPR, proteostasis, and composite scores, respectively). The green score was associated with overall survival per standard-deviation increase (HR 1.17, 95% CI 1.07-1.28), although clinical adjustment attenuated the estimate. In a 10-sample single-cell dataset, sample-level scores were higher in pericytes and endothelial cells than in malignant cells. Donor-aware IvyGAP analysis supported regional organization, whereas one Visium section showed stronger concordance with ER-stress/UPR and mesenchymal scores than with the UFMylation-core score. CellChat indicated pathway-selective rather than global remodeling of inferred vascular communication. Layer ablation moved WWTR1 from rank 48 using WGCNA alone to rank 4 overall and rank 1 among non-common-essential genes after cross-platform integration. These findings define an ER-stress/mesenchymal-weighted, UFMylation-related vascular-stromal transcriptional association and nominate WWTR1 for experimental testing.

Humans↗
PubMed2005

A -1 frameshift in the HIV-1 env gene is enhanced by arginine deficiency via a hungry codon mechanism.

Ribosomal frameshifting is used by various organisms to maximize protein coding potential of genomic sequences. It is commonly exploited by RNA viruses to overcome the constraint of their limited genome size. Frameshifting requires specific RNA structural features, such as a suitable heptanucleotide "slippery" sequence and an RNA pseudoknot. Previous genomic analysis of HIV-1 indicated the potential for several hidden genes encoded through frameshifting; one of these, overlapping the envelope gene, has an RNA pseudoknot just downstream from a slippery sequence, AAAAAGA that features an adenine quadruplet prior to a potential hungry arginine codon (AGA). This env-frameshift (env-fs) gene has been shown to encode a truncated glutathione peroxidase homologue, with both antioxidant and anti-apoptotic activities in transfected cells. Using a dual reporter cell-based frameshift assay, we demonstrate that the env-fs frameshift sequence is active in vitro. Furthermore, in arginine deficient media, env-fs frameshifting increased over 100% (p<0.005), consistent with the hypothesized hungry codon mechanism. As a response to arginine deficiency, increased expression of the antioxidant viral GPx gene (env-fs) by upregulation of frameshifting could be protective to HIV-infected cells, as a countermeasure to the increased oxidative stress induced by arginine deficiency (because NO is a known scavenger of hydroxyl radical).

Arginine↗
PubMed1992

Primary structure of an archaebacterial transducer, a methyl-accepting protein associated with sensory rhodopsin I.

A methylated membrane protein of 97 kDa was suggested on the basis of mutant analysis to transduce signals from the phototaxis receptor sensory rhodopsin I to the flagellar motor in Halobacterium halobium. Here we report isolation of the proposed transducer protein, cloning of its gene based on partial protein sequences, the complete gene sequence, and analysis of the encoded primary structure. The 1611-base-pair gene termination codon overlaps the initiator ATG of the sopI gene, which encodes the sensory rhodopsin I apoprotein. The predicted size of 57 kDa for the methylated protein indicates an aberrant electrophoretic migration on SDS/polyacrylamide gels, as occurs with other acidic halophilic proteins. Putative promotor elements are located in an A+T-rich region upstream of the gene. Comparison of the translated nucleotide sequence with N-terminal sequence of the purified protein shows the protein is synthesized without a processed leader peptide and the N-terminal methionine is removed in the mature protein. The deduced protein sequence predicts two transmembrane helices near the N terminal that would anchor the protein to the membrane. Beyond this hydrophobic region of 46 residues, the remainder of the protein (536-amino acid residues total) is hydrophilic. The C-terminal 270 residues contain a region homologous to the signaling domains of eubacterial transducers (e.g., Escherichia coli Tsr protein), flanked by two regions homologous to the methylation domains of the transducer family. The protein differs from E. coli Tsr in that it does not have an extramembranous-receptor binding domain but instead has a more extended cytoplasmic region. Coexpression of the methyl-accepting protein gene (designated htrI) and sopI restores sensory rhodopsin I phototaxis to a mutant (Pho81) that contains a deletion in the htrI/sopI region. These results extend the eubacterial transducer family to the archaebacteria and substantiate the proposal that the methylated membrane protein functions as a signal-transducing relay between sensory rhodopsin I and cytoplasmic sensory-pathway components.

Amino Acid Sequence↗
PubMed1989

Transcription of the folC gene encoding folylpolyglutamate synthetase-dihydrofolate synthetase in Escherichia coli.

The folC gene of Escherichia coli is cotranscribed with an upstream gene from two promoters located in the noncoding region 5' to the coding sequence of the upstream gene. Virtually all of the expression of the folC gene product, folylpolyglutamate synthetase-dihydrofolate synthetase, is therefore due to the upstream gene promoters. No promoter activity was found in the coding sequence of the upstream gene or in the 72-base-pair noncoding region between the two genes. It is shown that a third gene, which may overlap the coding sequence of the folC gene by 8 base pairs at the 3' end, nevertheless, has an promoter independent from that of the upstream gene-folC operon. These results contrast with those presented by Nonet et al. (M. L. Nonet, C. C. Marvel, and D. Tolan, J. Biol. Chem., 262:12209-12217, 1987), who concluded that folC was cotranscribed with the gene at its 3' end and the gene upstream to folC was cotranscribed with the gene(s) further upstream. A stable stem-loop structure resembling a rho-independent terminator is present within the noncoding region between the upstream gene and the folC gene. Folypolyglutamate synthetase expression is 6- to 15-fold lower than that of the upstream gene product, suggesting that the stem-loop terminates some of the transcription from the upstream gene promoter. We found by deletion mutagenesis and cloning sequences containing the stem-loop structure into a termination reporter plasmid that this stem-loop does not act as an effective terminator of transcription. We also found that the stem-loop does not protect the upstream gene message from degradation, since expression of the upstream gene product in maxicell experiments is the same whether the stem-loop structure is present or deleted.

DNA Mutational Analysis↗
PubMed1989

Regulation of the bacterio-opsin gene of a halophilic archaebacterium.

The protein bacterio-opsin, complexed with retinal, functions as a light-driven proton pump in the purple membrane of the halophilic archaebacterium, Halobacterium halobium. Bacterio-opsin deficient mutants have been characterized in attempts to elucidate regulation of the gene encoding bacterio-opsin (bop). Analysis of the mutational defect in Bop mutants has revealed the existence of at least two genes that affect bop gene expression and (or) purple membrane formation: (i) the brp gene, located 526 base pairs upstream of the bop gene, is transcribed in the opposite orientation, and (ii) the bat gene, located 1602 base pairs upstream of the bop gene, is transcribed in the same orientation as the brp gene. The bat gene start codon overlaps the stop codon of the brp gene. The bat gene could encode an acidic protein of 73,000 Da (674 amino acids) with a predicted secondary structure typical of a soluble alpha--beta type protein. This type of secondary structure is in contrast to the hydrophobic structure predicted for the putative brp protein. Transcriptional analyses of the wild type, 11 Bop mutants, and a Bop revertant suggest that the bat gene has a more direct role than the brp gene in bop gene expression and is involved in activating bop and brp gene expression.

Archaea↗
PubMed2003

A missense mutation in the mitochondrial ND5 gene associated with a Leigh-MELAS overlap syndrome.

A 13084 A->T missense mutation in the mitochondrial ND5 gene was identified in a 16-year-old boy affected with a progressive neurodegenerative disorder combining features of Leigh and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes) syndromes. Muscle biopsy analysis revealed partial complex I deficiency. The mutation presented a variable degree of heteroplasmy in the patient's tissues. This finding underlines the contribution of mtDNA-encoded complex I subunits in the etiology of complex I deficiency associated with encephalopathy.

Adolescent↗
PubMed2003

[Regulatory systems of genome domains with vague boundaries].

The specific features of genome domains lacking distinct boundaries are considered. These domains cannot be mapped by testing extended genome regions for nuclease sensitivity and thereby differ from structural domains determined at the level of DNA folding in chromatin. Yet they possess the properties of typical functional domains, containing a gene or several coordinated genes along with a complex of cis-regulatory elements, which control these genes. Domains with vague boundaries may be mapped with certain structural tests, e.g., by assessing histone acetylation or the distribution of tissue-specific DNase I-hypersensitive sites through extended genome regions. The mechanisms are described in detail that regulate the function of genes in domains with vague boundaries, including overlapping domains with genes differing in tissue specificity of expression.

Animals↗
PubMed1994

Sequence analysis of the Vibrio cholerae acfD gene reveals the presence of an overlapping reading frame, orfZ, which encodes a protein that shares sequence similarity to the FliA and FliC products of Salmonella.

The nucleotide (nt) sequence of the Vibrio cholerae acfD gene (encoding an accessory colonization factor) has been determined. The acfD gene encompasses 254 nt that are predicted to encode an 88-amino-acid (aa) protein. Additionally, an open reading frame of 184 aa, designated orfZ, was detected that overlaps the 3' end of acfD by 45 nt. Computer-assisted homology searches revealed that OrfZ possesses aa sequence similarity to the C terminus of the fliC product of Salmonella muenchen and S. rubislaw. Additionally, OrfZ shares limited aa sequence similarity to a region of the S. typhimurium fliA product. Interestingly, a V. cholerae acfD::TnphoA mutant demonstrates reduced motility and an altered swarming phenotype in semi-solid media when compared to wild-type V. cholerae. The possibility that the reduced motility and altered morphology result from polar effects on orfZ expression is currently being investigated.

Amino Acid Sequence↗
PubMed2026

Identification of rare maternal copy number variants by genome-wide analysis of noninvasive prenatal screening data in 113,017 pregnant women.

OBJECTIVES: Knowledge of copy number variants (CNVs) is relevant to maternal and fetal health and can be obtained from noninvasive prenatal screening (NIPS) of pregnancy. However, genome-wide analysis of maternal CNVs using NIPS data has not been conducted in large populations. METHODS: For CNV analysis, the human genome was segmented into 10 kilobase pairs (Kb) bins, and the relative sequencing depth of each bin was calculated. The circular binary segmentation algorithm was used to estimate CNVs. Detected CNVs from two pregnancies of the same participant were compared to validate the reproducibility. All CNVs were merged into CNV regions (CNVRs) to evaluate their frequency, distributions, and relationship with disease-related genes and regions. RESULTS: In this study, 113,017 pregnant women were recruited. A total of 363,886 CNVs larger than 50&#x2009;Kb were detected in 101,779 individuals and merged into 43,005 CNVRs. For evaluating the reproducibility of CNVs, 90.18% of deletions and 88.07% of duplications were consistent. In general, 78.13% of individuals carried CNVRs that overlapped protein-coding genes, while 14.76% overlapped OMIM genes. We detected 246 novel CNVRs, 134 (54.47%) involving protein-coding genes. For the perspective of maternal-fetal health, we identified 4,984 (4.41%) individuals as carriers of 5,243 CNVs containing known pathogenic or likely pathogenic regions, including 22q11.2 region and DMD gene.. CONCLUSIONS: NIPS sequencing data is a reliable source for maternal CNV detection. These CNVs constitute an integrate component in maternal-fetal health management.

Humans↗
PubMed2003

Newly identified exons encoding novel variants of p94/calpain 3 are expressed ubiquitously and overlap the alpha-glucosidase C gene.

There are two classes of an intracellular 'modulator protease', calpain: ubiquitous and tissue-specific. p94/calpain 3 is an example of the latter, predominantly expressed in muscle. A defect in the p94 gene causes muscular dystrophy. Here we report that human and mouse p94 genes have a possible novel alternative promoter expressing p94 variants in all tissues examined including human lens epithelial cells. The possible promoter region and the following novel exons overlap the 3' region of the neutral alpha-glucosidase C gene. Unlike p94, the novel p94 variants expressed in COS7 cells do not undergo rapid autolysis, suggesting basic functions different from p94.

Amino Acid Sequence↗