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PubMed2002

Emergence and selection of RNA virus variants: memory and extinction.

Two features of viral quasispecies are reviewed: the presence of memory genomes as minority components of their mutant spectra, and viral extinction due to enhanced mutagenesis. Memory has been documented with several genetic markers of the important animal picornavirus foot-and-mouth disease virus (FMDV). The presence of memory genomes in viral quasispecies may accelerate their adaptive response whenever a selective constraint has already been experienced by a viral population during previous stages of its evolution. Enhanced mutagenesis has been shown to lead to losses of infectivity of a number of RNA viruses: poliovirus, vesicular stomatitis virus, human immunodeficiency virus type 1 and FMDV. These observations, based on the theoretical prediction of the existence of a copying error-threshold for maintenance of genetic information, may contribute to the development of a new antiviral strategy.

Animals↗

PubMedDate not supplied

[Cytoplasmic male sterility-associated structural variation of the mitochondrial genome regions containing rps3 and orf215 in sugar beet Beta vulgaris L].

Several 5'-degenerate primers were selected by computer analysis and used for mtDNA typing in sugar beet cultivars with cytoplasms of the S (typical for cytoplasmic male sterility) or N (normal) type. A number of N- or S-specific markers were found to correspond to transcribed mitochondrial genes. One was from the orf215 region of the N-type mtDNA. A physical map of the corresponding region was constructed for the S-type mtDNA, and a substantial difference observed for the two genome types. One N-specific marker proved to contain a rearranged rps3 region and a truncated atp9 copy. With the known nucleotide sequence of this marker, three-primer PCR was designed and showed that both variants of the rps3 region simultaneously take place in the mtDNA pool, the new one occurring in a substochiometric proportion.

Base Sequence↗

PubMed1981

Pulmonary artery pressure monitoring in the surgical intensive care unit. Benefits vs difficulties.

The process of pulmonary artery pressure monitoring in 50 consecutive patients in the surgical intensive care unit was analyzed to determine the number and types of problems that occurred in relation to the benefit obtained. Twenty-six percent of the patients had a change in their cardiorespiratory therapy and their conditions were improved after the pressure data were obtained. Many technical and interpretative problems that tended to decrease the desirability of using pulmonary artery pressure monitoring were identified. Most problems could be avoided by carefully calibrating the monitor system, clearing the catheter system of air bubbles and blood clots, learning to property interpret pulmonary artery pressure tracings despite large respiratory variations, and obtaining a hard-copy printout of the pressure tracing with the simultaneous ECG signal. A protocol for avoiding many difficulties was developed.

Blood Pressure↗

PubMed1997

Quantitation of platelet-derived growth factor receptors in human arterial smooth muscle cells in vitro.

Platelet-derived growth factor (PDGF) is suggested to play an important role in the development of atherosclerosis as a migratory and mitogenic stimulus to arterial smooth muscle cells (ASMCs). Stimulated and unstimulated ASMCs were studied with respect to PDGF receptor (PDGF-R) mRNA and protein expression. Quantitative RT-PCR was developed for simultaneous evaluation of both PDGF-R alpha and -R beta mRNA expression and a quantitative ELISA for estimation of corresponding PDGF-R subunits. On the mRNA level, the overall PDGF-R beta expression was approximately 100 times lower than that of PDGF-R alpha. Furthermore, although PDGF-R alpha mRNA levels were high irrespective of hASMC phenotype, PDGF-R beta mRNA was influenced by serum stimulation with lower copy numbers in proliferating and confluent cells compared with quiescent cells. On the protein level, quiescent hASMCs expressed 10 times more PDGF-R beta than PDGF-R alpha. Serum stimulation decreased cell surface PDGF-Rs, with most prominent loss of PDGF-R alpha (ELISA and immunohistochemistry). Our results suggest a differential regulatory pattern for PDGF-R alpha and -R beta and are compatible with the usage of alternative promoters for regulation of -R alpha expression. Further, it seems that the number of available receptor subunits is not the only determinant of variations in cell stimulation with different PDGF isoforms.

Cell Division↗

PubMed1986

Murine erythroleukemia cell variants: isolation of cells that have amplified the dihydrofolate reductase gene and retained the ability to be induced to differentiate.

A series of murine erythroleukemia cell (MELC) variants was generated by selection for the ability to grow in increasing concentrations of the folate antagonist methotrexate (MTX). Growth of the parental MELC strain DS-19 was completely inhibited by 0.1 microM MTX. We isolated cells able to grow in 5, 40, 200, 400, and 800 microM MTX. Growth rates and yields were essentially the same in the presence or absence of the selective dose of MTX for all variants. MTX resistance was not the result of a transport defect. Dihydrofolate reductase (DHFR) from our variants and DS-19 was inhibited to the same extent by MTX. Variants had increased dihydrofolate reductase activities. The specific activity of DHFR was proportional to the selective concentration of MTX employed to isolate a given variant. DNA dot blotting established that the cloned variant (MR400-3) had a 160-fold increase in DHFR gene copy number relative to the parental strain (DS-19). Hybridization studies performed in situ established the presence of amplified DHFR genes on the chromosomes of the MTX-resistant but not the MTX-sensitive (parental) cells. Quantitation of DHFR mRNA by cytoplasmic dot blotting established that the amplified DHFR gene expression was proportional to gene copy number. Thus, MTX resistance was due to amplification of the DHFR gene. The variants retained the ability to be induced to differentiate in response to dimethyl sulfoxide and hexamethylenebis(acetamide) as evaluated by the criteria of globin mRNA accumulation, hemoglobin accumulation, cell volume decreases, and terminal cell division.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

Homogenization of geographical variants at the nontranscribed spacer of rDNA in Drosophila mercatorum.

rDNA nontranscribed spacer (NTS) lengths of Drosophila mercatorum have been measured in individuals from several geographic regions. Individuals from the different geographic subpopulations share some length fragments but are in general distinct. The length differences, both within and between individuals, arise from different copy numbers of a 250-bp repeating unit that is localized to one part of the NTS. In addition to the length differences caused by the 250-bp repeat, there is a Y chromosome (male)-specific length variant elsewhere in the NTS that is approximately 70 bp shorter than the NTS fragment from the X chromosome. Sexual dimorphism seems to be present in all Drosophila. Also, D. mercatorum has fewer NTS length variants per individual than does D. melanogaster while possessing comparable levels of restriction-site polymorphism. The mechanisms that may cause this pattern of variation are selection, gene conversion, and unequal recombination.

Animals↗

PubMed2004

Divergence in gene expression related to variation in host specificity of an ectomycorrhizal fungus.

Ectomycorrhizae are formed by mutualistic interactions between fungi and the roots of woody plants. During symbiosis the two organisms exchange carbon and nutrients in a specific tissue that is formed at the contact between a compatible fungus and plant. There is considerable variation in the degree of host specificity among species and strains of ectomycorrhizal fungi. In this study, we have for the first time shown that this variation is associated with quantitative differences in gene expression, and with divergence in nucleotide sequences of symbiosis-regulated genes. Gene expression and sequence evolution were compared in different strains of the ectomycorrhizal fungus Paxillus involutus; the strains included Nau, which is not compatible with birch and poplar, and the two compatible strains Maj and ATCC200175. On a genomic level, Nau and Maj were very similar. The sequence identity was 98.9% in the 16 loci analysed, and only three out of 1075 genes analysed by microarray-based hybridizations had signals indicating differences in gene copy numbers. In contrast, 66 out of the 1075 genes were differentially expressed in Maj compared to Nau after contact with birch roots. Thirty-seven of these symbiosis-regulated genes were also differentially expressed in the ATCC strain. Comparative analysis of DNA sequences of the symbiosis-regulated genes in different strains showed that two of them have evolved at an enhanced rate in Nau. The sequence divergence can be explained by a decreased selection pressure, which in turn is determined by lower functional constraints on these proteins in Nau as compared to the compatible strains.

Base Sequence↗

PubMed1980

Complicated organization of a single repeated DNA sequence in the chicken genome is revealed by cloning.

The structural organization of a family of repeated DNA sequences in the chicken genome has been determined by hybridization of a cloned repeated DNA sequence to Southern blots of total DNA. The length of the cloned DNA fragment is 3600 nucleotide pairs. This fragment consists principally, if not entirely, of a single repeated DNA sequence occurring only once within the cloned fragment. In the chicken genome, the family of repeated DNA sequences homologous to the cloned sequence has a limited number of alternative forms. Some of the restriction fragments of total DNA to which the cloned sequence hybridizes correspond to those expected from the location of restriction endonuclease cleavage sites within the cloned sequence. There are also a limited number of other genomic restriction fragments, each present in multiple copies, to which the cloned sequence hybridizes but which do not relate in any obvious way to the length of the cloned sequence. These various restriction fragments differ from one another in that they appear to be present in unequal amounts in total DNA, and many of them do not contain the entire cloned sequence. This study provides some new information about the structure of repeated DNA sequences in the chicken genome. The copies of a repeated DNA sequence may differ from one another both by minor variations in nucleotide sequence (divergence) and in more substantial ways as would be expected to arise from processes such as insertion, deletion, and translocation. In addition to this description of a single cloned repeated DNA sequence from the chicken genome, this paper reports the cloning of more than 100 different restriction fragments of chicken DNA, each of which contains one or more repeated DNA sequences.

Animals↗

PubMed2005

STin2 variant and family history of suicide as significant predictors of suicide completion in major depression.

BACKGROUND: Suicide is the most serious outcome of major depression, yet not all depressed patients will commit suicide. Genes, along with other factors, might account for this difference. Serotonergic alterations have been observed in suicide and depression and impulsive-aggressive behaviors. Therefore, we aimed to identify predictors of suicide, considering genetic variation at the serotonin transporter (5-HTT) gene. METHODS: We investigated the 5-HTT gene-linked polymorphic region (5-HTTLPR) and intron 2 (STin2) variants of this gene and their relationship to behavioral and clinical risk factors for suicide in a sample of depressed suicides (n =106) and depressed control subjects (n =152), diagnosed by means of proxy-based interviews. RESULTS: We found a significant association of suicide completion with having at least one copy of the STin2 10 allele [chi(2)(1) = 10.833, p = .002]. No differences were found for the 5-HTTLPR variable number of tandem repeats. After controlling for behavioral and clinical risk factors for suicide, the STin2 variant remained a significant predictor of suicide in major depression when jointly considered with a family history of suicide (odds ratio 5.560, 95% confidence interval 1.057-29.247). CONCLUSIONS: The STin2 locus might account, at least in part, for the observed familial aggregation of suicidal behavior. These results should be further explored in families where clustering of suicidal behavior is observed.

Adolescent↗

PubMed1988

Suppression of chromosomal mutations affecting M1 virus replication in Saccharomyces cerevisiae by a variant of a viral RNA segment (L-A) that encodes coat protein.

For the maintenance of "killer" M1 double-stranded RNA in Saccharomyces cerevisiae, more than 30 chromosomal genes are required. The requirement for some of these genes can be completely suppressed by a cytoplasmic element, [B] (for bypass). We have isolated a mutant unable to maintain [B] (mab) and found that it is allelic to MAK10, one of the three chromosomal MAK genes required for the maintenance of L-A. The heat curing of [B] always coincided with the loss of L-A. To confirm that [B] is located on L-A, we purified viral particles containing either L-A or M1 from strains with or without [B] activity and transfected these purified particles into a strain which did not have either L-A or M1. The transfectants harboring L-A and M1 from a [B] strain showed the [B] phenotype, but the transfectants with L-A and M1 from a [B-o] strain did not show the [B] phenotype. Furthermore, the transfectants having L-A from a [B] strain and M1 from a [B-o] strain also showed the [B] phenotype. Therefore, we concluded that [B] is a property of a variant of L-A. In the transfection experiment, we also proved that the superkiller phenotype of the [B] strain is a property of L-A and that L-A with [B] activity can maintain a higher copy number of M1 regardless of the source of M1 viruslike particles. These data suggest that MAK genes whose mutations are suppressed by [B] are concerned with the protection of M1 (+) single-stranded RNA or the formation of M1 viruslike particles and that an L-A with more efficient production of M1 viruslike particles can completely dispense with the requirement for those MAK genes.

Chromosomes↗

PubMed2003

Quantitative cytokine gene expression in human tonsils at excision and during histoculture assessed by standardized and calibrated real-time PCR and novel data processing.

Real-time reverse transcription polymerase chain reaction (RT-PCR) assays were developed for the quantification of expression of the genes for human interleukin (IL)-1beta, IL-2, IL-6, IL-8, IL-10, IL-12, IL-15, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta and for the endogenous reference hydroxymethylbilane synthase (HMBS). The assays detected as little as five plasmid copies and were 100% specific. The creation and integration of a calibration sample into the assays permitted their calibration across experiments. To handle the high number of generated data, the correlator of advanced real-time assays (CARTA) software was designed to organize samples and to automatically control and analyze TaqMan real-time RT-PCR data. The RT-PCR assays were applied to quantify levels of cytokine gene expression in human palatine tonsils at excision and during 4 days of histoculture. Similar longitudinal patterns of cytokine gene expression were observed in all donors, but the variations in spontaneous expression levels between donors were large. The expression levels in histocultures were constant over time and similar to the expression levels at excision except for IL-6 and IL-8, which markedly increased following the first 24 h of culture, possibly due to the initial stress. The standardized and calibrated RT-PCR assays quantify gene expression of human cytokines proved sensitive and specific for the investigation of cell behavior at the molecular level and the newly established CARTA software, a reliable tool for rapid data handling. Tonsil histocultures could serve as a valuable ex vivo model system for further, donor-dependent, studies on activation or repression of cytokine gene expression.

Calibration↗

PubMed2004

A parallel graph decomposition algorithm for DNA sequencing with nanopores.

MOTIVATION: With the potential availability of nanopore devices that can sense the bases of translocating single-stranded DNA (ssDNA), it is likely that 'reads' of length approximately 10(5) will be available in large numbers and at high speed. We address the problem of complete DNA sequencing using such reads. We assume that approximately 10(2) copies of a DNA sequence are split into single strands that break into randomly sized pieces as they translocate the nanopore in arbitrary orientations. The nanopore senses and reports each individual base that passes through, but all information about orientation and complementarity of the ssDNA subsequences is lost. Random errors (both biological and transduction) in the reads create further complications. RESULTS: We have developed an algorithm that addresses these issues. It can be considered an extreme variation of the well-known Eulerian path approach. It searches over a space of de Bruijn graphs until it finds one in which (a) the impact of errors is eliminated and (b) both possible orientations of the two ssDNA sequences can be identified separately and unambiguously. Our algorithm is able to correctly reconstruct real DNA sequences of the order of 10(6) bases (e.g. the bacterium Mycoplasma pneumoniae) from simulated erroneous reads on a modest workstation in about 1 h. We describe, and give measured timings of, a parallel implementation of this algorithm on the Cray Multithreaded Architecture (MTA-2) supercomputer, whose architecture is ideally suited to this 'unstructured' problem. Our parallel implementation is crucial to the problem of rapidly sequencing long DNA sequences and also to the situation where multiple nanopores are used to obtain a high-bandwidth stream of reads.

Algorithms↗

PubMed1994

Reduced Position Effect in Mature Transgenic Plants Conferred by the Chicken Lysozyme Matrix-Associated Region.

Matrix-associated regions may be useful for studying the role of chromatin architecture in transgene activity of transformed plants. The chicken lysozyme A element was shown to have specific affinity for tobacco nuclear matrices, and its influence on the variability of transgene expression in tobacco plants was studied. T-DNA constructs in which this element flanked either the [beta]-glucuronidase (GUS) reporter gene or both reporter and selection gene were introduced in tobacco. The variation in GUS gene activity was reduced significantly among mature first-generation transgenic plants carrying the A element. Average GUS activity became somewhat higher, but the maximum attainable level of gene expression was similar for all three constructs. Transient gene expression assays showed that the A element did not contain general enhancer functions; therefore, its presence seemed to prevent the lower levels of transgene expression. The strongest reduction in variability was found in plants transformed with the construct carrying the A elements at the borders of the T-DNA. In this population, expression levels became copy number dependent. The presence of two A elements in the T-DNA did not interfere with meiosis.

Journal Article↗

PubMed1991

Genetic variation in mouse apolipoprotein A-IV due to insertion and deletion in a region of tandem repeats.

We have detected three unique apolipoprotein A-IV (apoA-IV) charge isoforms in strains of commensal mice. The cDNA sequences for one representative of each isoform (Mus domestesticus strains C57BL/6J and 129/J and Mus castaneus) revealed a polymorphism within a series of four imperfect repeats encoding the sequence Glu-Gln-Ala/Val-Gln. Insertions or deletions of 12 nucleotides within this repetitive region have given rise to three genotypes characterized by three (129), four (C57BL/6), or five (M. castaneus) copies of the repeat unit. To ascertain the extent of this variation among other species of the Mus genus, we sequenced this region of apoA-IV cDNAs from eight additional M. domesticus inbred strains and from five wild-derived Mus species. All eight additional M. domesticus strains examined had four repeat units, as found in C57BL/6. Among wild-derived mice, however, one species (Mus spretus) had three repeats, two species (Mus cookii and Mus cervicolor) had four repeats, and two species (Mus hortulanus and Mus minutoides) had five repeats. A lack of correlation between the number of repeat units and the phylogeny of Mus species indicates that independent mutations may have occurred throughout the evolution of specific mouse lineages. We suggest that the repetitive nature of the polymorphic sequence may predispose this region to slippage errors during DNA replication, resulting in frequent deletion/insertion mutations.

Amino Acid Sequence↗

PubMed2005

Microsatellite evolution in the mitochondrial genome of Bechstein's bat (Myotis bechsteinii).

Being highly polymorphic, microsatellites are widely used genetic markers. They are abundant throughout the nuclear genomes of eukaryotes but rare in the mitochondrial genomes (mtDNA) of animals. We describe a short but highly polymorphic AT microsatellite in the mtDNA control region of Bechstein's bat and discuss the role of mutation, genetic drift, and selection in maintaining its variability. As heteroplasmy and hence mutation rate were positively correlated with repeat number, a simple mutation model cannot explain the observed frequency distribution of AT copy numbers. Because of the unimodal distribution of repeat numbers found in heteroplasmic individuals, single step mutations are likely to be the predominant mechanism of copy number alternations. Above a certain copy number (seven repeats), deletions of single dinucleotide repeats seem to be more common than additions, which results in a decrease in frequency of long alleles. Heteroplasmy was inherited from mothers to their offspring and no evidence of paternal inheritance of mitochondria was found. Genetic differences accumulated with more distant ancestry, which suggests that microsatellites can be useful genetic markers in population genetics.

Animals↗

PubMed2006

Movement planning deficits in schizophrenia: failure to inhibit automatic response tendencies.

INTRODUCTION: Explicit planning deficits have been reported frequently in patients with schizophrenia. This study addressed the question whether these patients would already encounter difficulties in a more "implicit" process of planning an optimal sequence of movements in simple actions. METHODS: Twenty patients with schizophrenia and 20 controls participated in the study. The motor tasks consisted of copying simple line drawings in which the planning of a movement sequence was taxed along various dimensions. In the first task the number of line elements varied between one and two, and the two-line figures differed with respect to the ease with which the so-called graphic production rules could be applied. In the second task the spatial position of the drawing varied between an easy centre position and a somewhat more difficult corner location. In the third task, subjects were asked to start copying either at a preferred or at a less preferred starting point. RESULTS: The results showed that the patients did not encounter planning difficulties while copying the one- or two-segment patterns. However, the variations in the spatial conditions and starting point did affect the patients' performance more than that of the controls. Whereas the patients with higher negative symptom scores tended to be slower when they were forced to start drawing at a particular point, the patients predominantly exhibiting features of disorganisation proved to be faster in this condition. CONCLUSIONS: The findings suggest a fairly intact initiation of simple movement sequences in patients with schizophrenia, but difficulties in inhibiting automatic response tendencies. It is concluded that this inhibition failure may play an important role in the planning difficulties these patients experience.

Adult↗

PubMed2002

Genetic instability in cancer tissues analyzed by random amplified polymorphic DNA PCR.

OBJECTIVE: To detect DNA and chromosomes instabilities during the progression of tumors and screen new molecular markers coupled to putative or unknown oncogenes and/or tumor suppressor genes. METHODS: Five kinds of tumors, in a total of 128 specimens, were analyzed by random amplified polymorphic DNA (RAPD) PCR. Bands representing instabilities were recovered, purified, and cloned, labeled as probes for Southern and Northern blot analysis and DNA sequencing. RESULTS: Sample 5 and 3 of the gastric cancer tissues showed the highest genomic changes and the average detectability in five cancers was up to at least 40% (42.2% - 49.4%). There were significant differences in the ability of each primer to detect genomic instability, which ranged from 27% (primer 8) to 68% (primer 2). Band B is a single copy fragment, and was found to be an allelic loss in gastric and colon cancers. It is a novel sequence and was registered in GenBank with Accession Number AF151005. Further analysis revealed that it might be part of a cis-regulatory element of a new tumor suppressor gene, containing a promoter of cis-action "CACA" box, an enhancer of "GATA" family and a start codon. CONCLUSIONS: It was impossible or difficult to get great achievements for cancer treatments with the procedure of gene therapy only to one oncogene or one tumor suppressor gene because the extensive DNA variations occurred during the progression of tumor. RAPD assay connected with other techniques was a good tool for the detection of genomic instabilities and direct screening of some new molecular markers related to tumor suppressor genes or oncogenes.

Base Sequence↗

PubMed2004

Representation of an immune responsive gene family encoding fibrinogen-related proteins in the freshwater mollusc Biomphalaria glabrata, an intermediate host for Schistosoma mansoni.

Fibrinogen-related proteins (FREPs) are found in the hemolymph of the freshwater snail Biomphalaria glabrata, are up-regulated following exposure to digenetic trematode parasites, and bind to trematode larval surfaces, suggestive of a role in internal defense. Southern blot and degenerate-polymerase chain reaction (PCR) analyses were undertaken to better understand the diversity of the FREP-encoding gene family. Probes corresponding to the N-terminal IgSF domains of specific FREP gene subfamilies (FREPs 2, 3, 4, 7, 12 and 13) revealed between 1 to 8 loci per subfamily on Southern blots. Probes representing the relatively conserved C-terminal fibrinogen domain of FREPs bound many sequences in Southern blots of genomic DNA from B. glabrata, and from two related gastropod species, Biomphalaria pfeifferi and Helisoma trivolvis. Using degenerate-PCR, we obtained 42 unique fibrinogen-encoding sequences from 180 clones derived from a single individual of the M-line strain of B. glabrata, further supporting the notion of their abundant representation in the B. glabrata genome. The fibrinogen-encoding sequences of FREPs encoding one or two IgSF domains tended to separate into distinct clades, but bootstrap support for this separation was low. A novel category of fibrinogen-encoding sequence was also revealed. This study provides the approximate number of gene copies in several FREP subfamilies, confirms the existence of a diverse FREP gene family, reports additional unusual sequences encoding fibrinogen-like molecules, and provides further justification to explore the functional roles of FREPs in both B. glabrata and B. pfeifferi, both important intermediate hosts of the human pathogen, Schistosoma mansoni.

Amino Acid Sequence↗