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At least 1,513 records · Page 84Linked to original sources
PubMed1981

Replication of herpes simplex virus DNA: localization of replication recognition signals within defective virus genomes.

Serially passaged herpes simplex virus type 1 (HSV-1) strain Justin was previously shown to contain defective virus genomes consisting of head-to-tail reiterations of sequences derived from the end of the S component of the standard virus DNA. Cotransfection of purified monomeric defective genome repeat units with foster helper virus DNAs onto rabbit skin cells resulted in regeneration and replication of concatemeric defective DNA molecules which were successfully encapsidated. Thus, defective HSV-1 (Justin) genomes contain, within their limited DNA sequences, a sufficient set of recognition sites required for HSV DNA replication and packaging. The arrangement of repeat units within the regenerated defective virus genomes was consistent with their replication by a rolling circle mechanism in which a single repeat unit served as the circularized template. This replication occurred most actively late after infection and could be shown to be inhibited by low concentrations of phosphonoacetate known to inhibit the HSV-specified viral DNA polymerase selectively. The resultant concatemers were shown to be cleaved to Mr 100 X 10(6) DNA molecules which were terminated at one end with the proper ac end sequence of the parental standard virus DNA.

Animals↗
PubMed2005

Efficient algorithms and software for detection of full-length LTR retrotransposons.

LTR retrotransposons constitute one of the most abundant classes of repetitive elements in eukaryotic genomes. In this paper, we present a new algorithm for detection of full-length LTR retrotransposons in genomic sequences. The algorithm identifies regions in a genomic sequence that show structural characteristics of LTR retrotransposons. Three key components distinguish our algorithm from that of current software - (i) a novel method that preprocesses the entire genomic sequence in linear time and produces high quality pairs of LTR candidates in running time that is constant per pair, (ii) a thorough alignment-based evaluation of candidate pairs to ensure high quality prediction, and (iii) a robust parameter set encompassing both structural constraints and quality controls providing users with a high degree of flexibility. Validation of both our serial and parallel implementations of the algorithm against the yeast genome indicates both superior quality and performance results when compared to existing software.

Algorithms↗
PubMed2006

Efficient algorithms and software for detection of full-length LTR retrotransposons.

LTR retrotransposons constitute one of the most abundant classes of repetitive elements in eukaryotic genomes. In this paper, we present a new algorithm for detection of full-length LTR retrotransposons in genomic sequences. The algorithm identifies regions in a genomic sequence that show structural characteristics of LTR retrotransposons. Three key components distinguish our algorithm from that of current software--(i) a novel method that preprocesses the entire genomic sequence in linear time and produces high quality pairs of LTR candidates in run-time that is constant per pair, (ii) a thorough alignment-based evaluation of candidate pairs to ensure high quality prediction, and (iii) a robust parameter set encompassing both structural constraints and quality controls providing users with a high degree of flexibility. We implemented our algorithm into a software program called LTR_par, which can be run on both serial and parallel computers. Validation of our software against the yeast genome indicates superior results in both quality and performance when compared to existing software. Additional validations are presented on rice BACs and chimpanzee genome.

Algorithms↗
PubMed2006

Genome restructuring in mouse embryos during reprogramming and early development.

Although a growing number of studies investigates functional genome organization in somatic cell nuclei, it is largely unknown how mammalian genome organization is established during embryogenesis. To address this question, we investigated chromo center formation and the peculiar arrangements of chromosome domains in early mouse embryos. At the one-cell stage, we observed characteristic arrangements of chromosomes and chromo center components. Subsequently, starting with the burst of zygotic genome transcription major rearrangements led to the establishment of somatic type chromo centers with a defined spatio-temporal organization. These processes appeared to be completed at the blastocyst stage with the onset of cell differentiation. During the same developmental period, a fraction of pericentric heterochromatin that was late replicating in the first cycle underwent switches in replication timing, spatial organization and epigenetic marks. Cloning experiments revealed that the genome organization typical for more advanced stages was quickly reverted into the one-cell stage-specific form after nuclear transfer, supporting the idea that reprogramming associated genome remodeling in normal and cloned embryos is determined by cytoplasmic factors. Together, the results suggest that distinct but characteristic forms of nuclear genome organization are required for genome reprogramming in early embryos and for proper regulation of differential gene expression patterns at later stages.

Animals↗
PubMed2005

Genome-wide linkage analyses and candidate gene fine mapping for HDL3 cholesterol: the Framingham Study.

High density lipoprotein cholesterol (HDL-C) is inversely associated with coronary heart disease and has a genetic component; however, linkage to HDL-C is not conclusive. Subfractions of HDL, such as HDL(3)-C, may be better phenotypes for linkage studies. Using HDL(3)-C levels measured on 907 Framingham Heart Study subjects from 330 families around 1987, we conducted a genome-wide variance components linkage analysis with 401 microsatellite markers spaced approximately 10 centimorgan (cM) apart. Nine candidate genes were identified and annotated using a bioinformatics approach in the region of the highest linkage peak. Twenty-eight single nucleotide polymorphisms (SNPs) were selected from these candidate genes, and linkage and family-based association fine mapping were conducted using these SNPs. The highest multipoint log-of-the-odds (LOD) score from the initial linkage analysis was 3.7 at 133 cM on chromosome 6. Linkage analyses with additional SNPs yielded the highest LOD score of 4.0 at 129 cM on chromosome 6. Family-based association analysis revealed that SNP rs2257104 in PLAGL1 at approximately 143 cM was associated with multivariable adjusted HDL(3) (P = 0.03). Further study of the linkage region and exploration of other variants in PLAGL1 are warranted to define the potential functional variants of HDL-C metabolism.

Adult↗
PubMed2000

Identification, evolution, and essentiality of the mevalonate pathway for isopentenyl diphosphate biosynthesis in gram-positive cocci.

The mevalonate pathway and the glyceraldehyde 3-phosphate (GAP)-pyruvate pathway are alternative routes for the biosynthesis of the central isoprenoid precursor, isopentenyl diphosphate. Genomic analysis revealed that the staphylococci, streptococci, and enterococci possess genes predicted to encode all of the enzymes of the mevalonate pathway and not the GAP-pyruvate pathway, unlike Bacillus subtilis and most gram-negative bacteria studied, which possess only components of the latter pathway. Phylogenetic and comparative genome analyses suggest that the genes for mevalonate biosynthesis in gram-positive cocci, which are highly divergent from those of mammals, were horizontally transferred from a primitive eukaryotic cell. Enterococci uniquely encode a bifunctional protein predicted to possess both 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and acetyl-CoA acetyltransferase activities. Genetic disruption experiments have shown that five genes encoding proteins involved in this pathway (HMG-CoA synthase, HMG-CoA reductase, mevalonate kinase, phosphomevalonate kinase, and mevalonate diphosphate decarboxylase) are essential for the in vitro growth of Streptococcus pneumoniae under standard conditions. Allelic replacement of the HMG-CoA synthase gene rendered the organism auxotrophic for mevalonate and severely attenuated in a murine respiratory tract infection model. The mevalonate pathway thus represents a potential antibacterial target in the low-G+C gram-positive cocci.

Acetyl-CoA C-Acetyltransferase↗
PubMed2005

Genomic instability in laminopathy-based premature aging.

Premature aging syndromes often result from mutations in nuclear proteins involved in the maintenance of genomic integrity. Lamin A is a major component of the nuclear lamina and nuclear skeleton. Truncation in lamin A causes Hutchinson-Gilford progerial syndrome (HGPS), a severe form of early-onset premature aging. Lack of functional Zmpste24, a metalloproteinase responsible for the maturation of prelamin A, also results in progeroid phenotypes in mice and humans. We found that Zmpste24-deficient mouse embryonic fibroblasts (MEFs) show increased DNA damage and chromosome aberrations and are more sensitive to DNA-damaging agents. Bone marrow cells isolated from Zmpste24-/- mice show increased aneuploidy and the mice are more sensitive to DNA-damaging agents. Recruitment of p53 binding protein 1 (53BP1) and Rad51 to sites of DNA lesion is impaired in Zmpste24-/- MEFs and in HGPS fibroblasts, resulting in delayed checkpoint response and defective DNA repair. Wild-type MEFs ectopically expressing unprocessible prelamin A show similar defects in checkpoint response and DNA repair. Our results indicate that unprocessed prelamin A and truncated lamin A act dominant negatively to perturb DNA damage response and repair, resulting in genomic instability which might contribute to laminopathy-based premature aging.

Aging, Premature↗
PubMed2004

Clustering patterns of LOD scores for asthma-related phenotypes revealed by a genome-wide screen in 295 French EGEA families.

A genome-wide scan for asthma phenotypes was conducted in the whole sample of 295 EGEA families selected through at least one asthmatic subject. In addition to asthma, seven phenotypes involved in the main asthma physiopathological pathways were considered: SPT (positive skin prick test response to at least one of 11 allergens), SPTQ score being the number of positive skin test responses to 11 allergens, Phadiatop (positive specific IgE response to a mixture of allergens), total IgE levels, eosinophils, bronchial responsiveness (BR) to methacholine challenge and %predicted FEV(1). Four regions showed evidence for linkage (P</=0.001): 6q14 for %FEV(1), 12p13 for IgE, 17q22-q24 for SPT and 21q21 for both SPTQ and %FEV(1). Nine other regions indicated smaller linkage signals (0.001<P</=0.005). While most of these regions have been reported by previous asthma and lung function screens, 6q14 appears to be a new region potentially linked to %FEV(1). To determine which of these various asthma phenotypes are more likely to share common genetic determinants, a principal component analysis was applied to the genome-wide LOD scores. This analysis revealed clustering of LODs for asthma, SPT and Phadiatop on one axis and clustering of LODs for %FEV(1), BR and SPTQ on the other, while LODs for IgE and eosinophils appeared to be independent from all other LODs. These results provide new insights into the potential sharing of genetic determinants by asthma-related phenotypes.

Adolescent↗
PubMed2001

Revisiting the lysogenization control of bacteriophage lambda. Identification and characterization of a new host component, HflD.

Upon infection to the Escherichia coli cell, the genome of bacteriophage lambda either replicates to form new progenies (lytic growth) or integrates into the host chromosome (lysogenization). The lambda CII protein is a key determinant in the lysis-lysogeny decision. It is a short-lived transcription activator for the lambda genes essential for lysogeny establishment. In this study, we isolated a new class of hfl (high frequency lysogenization) mutants of E. coli, using a new selection for enhancement of CII-stimulated transcription. The gene affected was termed hflD, which encodes a protein of 213 amino acids. An hflD-disrupted mutant indeed showed an Hfl phenotype, indicating that HflD acts to down-regulate lysogenization. HflD is associated peripherally with the cytoplasmic membrane. Its interaction with CII was demonstrated in vitro using purified proteins as well as in vivo using the bacterial two-hybrid system. Pulse-chase examinations demonstrated that the HflD function is required for the rapid in vivo degradation of CII, although it interfered with FtsH-mediated CII proteolysis in an in vitro reaction system using detergent-solubilized components. We suggest that HflD is a factor that sequesters CII from the target promoters and recruits it to the membrane where the FtsH protease is localized.

Bacteriophage lambda↗
PubMed2006

Suz12 binds to silenced regions of the genome in a cell-type-specific manner.

Suz12 is a component of the Polycomb group complexes 2, 3, and 4 (PRC 2/3/4). These complexes are critical for proper embryonic development, but very few target genes have been identified in either mouse or human cells. Using a variety of ChIP-chip approaches, we have identified a large set of Suz12 target genes in five different human and mouse cell lines. Interestingly, we found that Suz12 target promoters are cell type specific, with transcription factors and homeobox proteins predominating in embryonal cells and glycoproteins and immunoglobulin-related proteins predominating in adult tumors. We have also characterized the localization of other components of the PRC complex with Suz12 and investigated the overall relationship between Suz12 binding and markers of active versus inactive chromatin, using both promoter arrays and custom tiling arrays. Surprisingly, we find that the PRC complexes can be localized to discrete binding sites or spread through large regions of the mouse and human genomes. Finally, we have shown that some Suz12 target genes are bound by OCT4 in embryonal cells and suggest that OCT4 maintains stem cell self-renewal, in part, by recruiting PRC complexes to certain genes that promote differentiation.

Animals↗
PubMed2003

Coxiella burnetii express type IV secretion system proteins that function similarly to components of the Legionella pneumophila Dot/Icm system.

Coxiella burnetii is an obligate intracellular pathogen that replicates in large endocytic vacuoles. Genomic sequence data indicate that 21 genes encoding products that are similar to components of the Legionella pneumophila Dot/Icm type IV secretion system are located on a contiguous 35 kb region of the Coxiella chromosome. It was found that several dot/icm genes were expressed by Coxiella during host cell infection and that dot/icm gene expression preceded the formation of large replicative vacuoles. To determine whether these genes encode a functional type IV secretion system, we have amplified the Coxiella dotB, icmQ, icmS and icmW genes and produced the encoded proteins in Legionella mutants in which the native copy of each gene had been deleted. The Coxiella dotB, icmS and icmW products restored dot/icm-dependent growth of Legionella mutants in eukaryotic host cells. The Coxiella IcmQ protein and the Legionella IcmR protein did not interact, which could explain why the Coxiella icmQ gene was unable to restore growth to a Legionella icmQ mutant. Thus, Coxiella encodes functional components of a type IV secretion system expressed in vivo that is mechanistically related to the Legionella Dot/Icm apparatus. These studies suggest that a dot/icm-related secretion system could play an important role in creating the specialized vacuole that supports Coxiella replication.

Animals↗
PubMed2025

Lamin A/C Deficiency Drives Genomic Instability and Poor Survival in Small-Cell Lung Cancer through Increased R-loop Accumulation.

Lamin A/C (LMNA), a key component of the nuclear envelope, is essential for maintaining nuclear integrity and genome organization [1]. While LMNA dysregulation has been implicated in genomic instability across cancer and aging, the underlying mechanisms remain poorly understood [2]. Here, we investigate LMNA's role in small-cell lung cancer (SCLC), a highly aggressive malignancy characterized by extreme genomic instability [3, 4]. We demonstrate that LMNA depletion promotes R-loop accumulation, transcription-replication conflicts, replication stress, DNA breaks, and micronuclei formation. Mechanistically, LMNA loss disrupts nuclear pore complex distribution, reducing phenylalanine-glycine (FG)-nucleoporin incorporation and impairing RNA export efficiency. Furthermore, we show that LMNA expression is epigenetically repressed by EZH2 during SCLC differentiation from neuroendocrine (NE) to non-NE states. Clinically, low LMNA levels correlate with significantly worse survival in SCLC patients. These findings uncover a novel role for LMNA in safeguarding genome integrity and shaping tumor heterogeneity, with broad implications for cancer and aging.

Biological Sciences↗
PubMed1991

Retrotransposon-like nature of Tp1 elements: implications for the organisation of highly repetitive, hypermethylated DNA in the genome of Physarum polycephalum.

The repetitive fraction of the genome of the eukaryotic slime mould Physarum polycephalum is dominated by the Tp1 family of highly repetitive retrotransposon-like sequences. Tp1 elements consist of two terminal direct repeats of 277bp which flank an internal domain of 8.3kb. They are the major sequence component in the hypermethylated (M+) fraction of the genome where they have been found exclusively in scrambled clusters of up to 50kb long. Scrambling is thought to have arisen by insertion of Tp1 into further copies of the same sequence. In the present study, sequence analysis of cloned Tp1 elements has revealed striking homologies of the predicted amino acid sequence to several highly conserved domains characteristic of retrotransposons. The relative order of the predicted coding regions indicates that Tp1 elements are more closely related to copia and Ty than to retroviruses. Self-integration and methylation of Tp1 elements may function to limit transposition frequency. Such mechanisms provide a possible explanation for the origin and organisation of M + DNA in the Physarum genome.

Amino Acid Sequence↗
PubMed2006

Screening for rapidly evolving genes in the ectomycorrhizal fungus Paxillus involutus using cDNA microarrays.

We have examined the variations in gene content and sequence divergence that could be associated with symbiotic adaptations in the ectomycorrhizal fungus Paxillus involutus and the closely related species Paxillus filamentosus. Strains with various abilities to form mycorrhizae were analysed by comparative genomic hybridizations using a cDNA microarray containing 1076 putative unique genes of P. involutus. To screen for genes diverging at an enhanced and presumably non-neutral rate, we implemented a simple rate test using information from both the variations in hybridizations signal and data on sequence divergence of the arrayed genes relative to the genome of Coprinus cinereus. C. cinereus is a free-living saprophyte and is the closest evolutionary relative to P. involutus that has been fully sequenced. Approximately 17% of the genes investigated were detected as rapidly diverging within Paxillus. Furthermore, 6% of the genes varied in copy numbers between the analysed strains. Genome rearrangements associated with this variation including duplications and deletions may also play a role in adaptive evolution. The cohort of divergent and duplicated genes showed an over-representation of either orphans, genes whose products are located at membranes, or genes encoding for components of stress/defence reactions. Some of the identified genomic changes may be associated with the variation in host specificity of ectomycorrhizal fungi. The proposed procedure could be generally applicable to screen for rapidly evolving genes in closely related strains or species where at least one has been sequenced or characterized by expressed sequence tag analysis.

Analysis of Variance↗
PubMed1997

Genome nucleotide lengths that are divisible by six are not essential but enhance replication of defective interfering RNAs of the paramyxovirus simian virus 5.

For some members of the Paramyxoviridae family of negative strand RNA viruses, efficient genome replication only occurs when the total genome length is a multiple of six (6N length, where N is any integer). To determine if this "rule of six" requirement applied to the replication of the prototype paramyxovirus simian virus 5 (SV5), defective interfering (DI) RNA genomes were generated by sequential undiluted passage of virus in tissue culture. Molecular cloning and nucleotide sequence analysis of 10 RNA genomes revealed a series of copyback DI RNAs with chain lengths between 449 and 1365 bases, but only 4 of the 10 naturally occurring RNA genomes were of 6N length. Many of the cloned DI genomes could be grouped into two distinct nested sets, with the members of each set having the same polymerase crossover junctions and extent of terminal complementarity but differing from each other by internal deletions. One of these nested sets of genomes consisted of novel DI RNAs that contained a pentameric stretch of nontemplated adenosine residues inserted precisely at the polymerase crossover junction. A reverse genetics system was established in which SV5 DI genomes were replicated in vivo entirely by cDNA-derived components. Using this system, two naturally occurring SV5 DI RNAs were examined in a mutational analysis to determine the role of genome length on SV5 RNA replication. The progressive insertion of one to six nucleotides into a 6N length DI genome (852 bases) resulted in a reduction in replication for RNAs that contained one to four additional bases (approximately 35-50% of WT levels), followed by an increase back to WT replication levels for genomes that were altered by five and six base insertions (approximately 70 and 100% of WT levels, respectively). An insertion of five nucleotides into a second non-6N length DI RNA (499 total bases) created a genome length that was a multiple of six (504 bases) and led to a approximately 10-fold stimulation of replication over that of the unaltered genome. Together, these results indicate that there was a clear influence of 6N genome length on SV5 DI RNA replication, but the stringency of this replication requirement appeared to be less than that found previously for other paramyxoviruses. This work completes the testing of the rule of six replication requirement for representatives of each of the four genera of the Paramyxoviridae family and indicates that the preference for replication of 6N length RNA genomes varies between the individual paramyxoviruses.

Animals↗
PubMed2006

Organization and variability of the maize genome.

With a size approximating that of the human genome, the maize genome is about to become the largest plant genome yet sequenced. Contributing to that size are a whole-genome duplication event and a retrotransposition explosion that produced a large amount of repetitive DNA. This DNA is greatly under-represented in cDNA collections, so analysis of the maize transcriptome has been an expedient way of assessing the gene content of maize. Over 2 million maize cDNA sequences are now available, making maize the third most widely studied organism, behind mouse and man. To date, the sequencing of large-sized DNA clones has been largely driven by the genetic interests of different investigators. The recent construction of a physical map that is anchored to the genetic map will aid immensely in the maize genome-sequencing effort. However, studies showing that the repetitive DNA component is highly polymorphic among maize inbred lines point to the need to sample vertically a few specific regions of the genome to evaluate the extent and importance of this variability.

Chromosome Mapping↗
PubMed1986

N-band proteins of nucleolar organizers: chromosomal mapping, subnucleolar localization and rDNA binding.

The ribosomal DNA(rDNA)-containing chromatin in eukaryotes forms a unique architecture called the "secondary constriction" or "nucleolus organiser region (NOR)" on mitotic chromosomes. To gain more insight into non-histone chromosomal proteins (NHCP), termed "N-band proteins", that are specifically associated with the NOR in a wide variety of eukaryotes, we attempted to: identify the NHCP responsible for N-band staining; determine their stoichiometry; map them on metaphase chromosomes; determine their subnucleolar localization and examine their possible ability to bind rDNA. Based on several criteria, including chromosomal localization, solubility, association with chromatin, and intra-nuclear localization, two of the nucleolus-rich NHCP, termed component B of mol.wt 55,000 and component C of mol.wt. 41,000, were tentatively identified as N-band proteins. Immunological studies using a polyclonal, monospecific antibody raised against component C show that this protein is in fact associated with the chromosomal telomeres where NORs are located. In nucleoli, N-band proteins appear to be compartmentalized into a structure that probably corresponds to fibrillar components. Both components B and C are among several NHCPs that showed, under in vitro conditions, a strong affinity for rDNA cloned in lambda phage but not for calf thymus genomic DNA or phage vector DNA. The antibody against component C effectively suppressed in vitro transcription by RNA polymerase I in nucleoli and nucleolar chromatin. Component C appears to exist in the nucleus at 3.75-5.13 X 10(3) copies per rDNA unit or 0.09-0.13 copy per nucleotide. These findings support the hypothesis that the NOR is a chromosomal site, architecturally not only unique but also different from other chromatin regions in that constituent DNA, i.e., rDNA, is organized in a specific manner by interacting with specific NHCP, i.e., N-band proteins.

Animals↗
PubMed2026

Complement component C4 and neuroimaging in psychiatry: A systematic review.

INTRODUCTION: Genomic, transcriptomic, and proteomic studies suggest that the complement system contributes to the pathophysiology of various psychiatric disorders partly through neurodevelopmental effects linked to C4A protein levels variations. We conducted a systematic review to characterize how brain micro- and macrostructure and connectivity vary with proxies of in vivo brain C4A protein levels in both psychiatric and general-population cohorts. METHODS: We used Medline, Web of Science, and Embase, and included all studies published before April 14, 2025. Inclusion criteria were: (1) inclusion of healthy controls and/or individuals with psychiatric disorders assessed according to recognized diagnostic manuals (DSM or ICD); (2) use of MRI-based neuroimaging; and (3) use of genomic, transcriptomic and/or proteomic approaches as proxies of in vivo brain C4A proteins levels. RESULTS: From 317 identified articles, 11 were included. Associations between C4A levels and brain structure were heterogeneous across regions. Only the mOFC, dlPFC, and entorhinal cortex were implicated in more than one study. Findings for the mOFC and dlPFC varied by the type of metrics and clinical status, whereas higher C4A levels were more consistently associated with smaller entorhinal cortex surface area and cortical thickness in pediatric, middle-aged, and older general-population cohorts. In addition, one study found higher genetically predicted C4A expression to be associated with higher TSPO levels. CONCLUSION: The limited number of available studies and their methodological heterogeneity make synthesis challenging. However, biological hypotheses such as excessive synaptic pruning or broader inflammatory effects on the brain may provide plausible explanatory frameworks for the reported associations.

Humans↗