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At least 343 records · Page 19Linked to original sources
PubMed2001

Low-level antibacterial resistance: a gateway to clinical resistance.

The huge amount of antibiotic substances released in the human environment has probably resulted in an acceleration in the rate of bacterial evolution. It is to note that most interactions between chemotherapeutic agents and microbial populations occur at very low antibiotic concentrations. Thus, natural selection is expected to act on very small increases in the bacterial ability to resist to antibiotic inhibitory effects. On the other hand, there is a wealth of mechanisms to resist to these low antibiotic concentrations. The progressive enrichment in low-level resistant populations favours secondary selections for more specific and effective mechanisms of resistance, particularly in treated patients. These adaptations may have a biological cost in the absence of antibiotics, but frequently compensatory mutations occur, minimizing such genetic burden. In this way, a phenomenon of directional selection takes place, with low possibilities of return to susceptibility. Moreover, low antibiotic concentrations are not only able to select low-level antibiotic resistant variants, but may produce a substantial stress in bacterial populations, that eventually influences the rate of genetic variation and the diversity of adaptive responses. More attention should be devoted to the mechanisms of low-level resistance in microorganisms, as they can serve as stepping stones to develop high level, clinically relevant resistance. These mechanisms should be identified early in the development of drugs in order to adapt the therapeutic strategies (for instance dosage) to minimize the selection of low-level resistant variants, as frequently they emerge by means of concentration-specific selection. At the same time, conventional susceptibility testing should probably be able to detect low-level resistance, and not only clinically-relevant resistance. We should be vigilant of the evolutionary trends of microorganisms; for that a purpose, knowledge of the biology and epidemiology of low-level resistance is becoming a real need.

Animals↗
PubMed2005

Adventitial dysfunction: an evolutionary model for understanding atherosclerosis.

Endothelial and smooth muscle dysfunctions are widely implicated in the pathogenesis of atherosclerosis. Modern mechanical and pharmacologic treatments aim to remodel abnormalities of the vessel intima and media. We hypothesize that adventitial dysfunction comprises the dominant source of atherosclerosis by originating many endothelial and smooth muscle abnormalities. The autonomic nervous system innervates the adventitia, and autonomic dysfunction induces many end-organ dysfunctions including inflammation and thrombosis. The link between diabetes and atherosclerosis may operate through adventitial autonomic neuropathy. Smoking may promote atherosclerosis by inducing adventitial autonomic dysfunction related to nicotine-mediated compensatory upregulation of sympathetic bias independent of endothelial injury induced by purported tobacco toxins. While hypertension is thought to cause atherosclerosis, the two conditions may instead represent independent consequences of autonomic dysfunction. The link between aging and atherosclerosis may operate through adventitial dysfunction induced by autonomic dysregulations. Exercise may ameliorate atherosclerosis by restoring adventitial autonomic function, thereby normalizing adventitial regulation of medial and intimal biology. Feed-forward adventitial vascular baroreceptor and chemoreceptor dysregulation may further exacerbate atherosclerosis as intimal plaque interferes with these sensors. Since penetrating external physical injury likely represented a dominant selective force during evolution, the adventitia may be preferentially equipped with sensors and response systems for vessel trauma. The convergent response of adrenergia, inflammation, and coagulation, which is adaptive for physical trauma, may be maladaptive today when different stressors trigger the cascade. Endoluminal therapies including atherectomy, angioplasty, and stent deployment involve balloon expansion that traumatizes all layers of the vessel wall. These interventions may paradoxically reinitiate the cascade of atherogenesis that begins with adventitial dysfunction and leads to restenosis. Methods to reduce adventitial trauma, a maladaptive trigger of adventitial dysfunction, may reduce the risk of restenosis. We envision novel mechanical and biopharmaceutical solutions that target the adventitia to prevent or treat atherosclerosis including novel drug delivery strategies, exo-stents that wrap vessels, and neuromodulation of vessels.

Animals↗
PubMed2006

Genetic variation in MHC class II expression and interactions with MHC sequence polymorphism in three-spined sticklebacks.

Genes of the major histocompatibility complex (MHC) have been studied for several decades because of their pronounced allelic polymorphism. Structural allelic polymorphism is, however, not the only source of variability subjected to natural selection. Genetic variation may also exist in gene expression patterns. Here, we show that in a natural population of three-spined sticklebacks (Gasterosteus aculeatus) the expression of MHC class IIB genes was positively correlated with parasite load, which indicates increased immune activation of the MHC when infections are frequent. To experimentally study MHC expression, we used laboratory-bred sticklebacks that were exposed to three naturally occurring species of parasite. We found strong differences in MHC class IIB expression patterns among fish families, which were consistent over two generations, thus demonstrating a genetic component. The average number of MHC class IIB sequence variants within families was negatively correlated to the MHC expression level suggesting compensatory up-regulation in fish with a low (i.e. suboptimal) MHC sequence variability. The observed differences among families and the negative correlation with individual sequence diversity imply that MHC expression is evolutionary relevant for the onset and control of the immune response in natural populations.

Alleles↗
PubMed2004

Fitness costs limit viral escape from cytotoxic T lymphocytes at a structurally constrained epitope.

The intense selection pressure exerted by virus-specific cytotoxic T lymphocytes (CTL) on replicating human immunodeficiency virus and simian immunodeficiency virus results in the accumulation of CTL epitope mutations. It has been assumed that fitness costs can limit the evolution of CTL epitope mutations. However, only a limited number of studies have carefully examined this possibility. To explore the fitness costs associated with viral escape from p11C, C-M-specific CTL, we constructed a panel of viruses encoding point mutations at each position of the entire p11C, C-M epitope. Amino acid substitutions at positions 3, 4, 5, 6, 7, and 9 of the epitope significantly impaired virus replication by altering virus production and Gag protein expression as well as by destabilizing mature cores. Amino acid substitutions at position 2 of the epitope were tolerated but required reversion or additional compensatory mutations to generate replication-competent viruses. Finally, while amino acid substitutions at positions 1 and 8 of the p11C, C-M epitope were functionally tolerated, these substitutions were recognized by p11C, C-M-specific CTL and therefore provided no selection advantage for the virus. Together, these data suggest that limited sequence variation is tolerated by the region of the capsid encoding the p11C, C-M epitope and therefore that only a very limited number of mutations can allow successful viral escape from the p11C, C-M-specific CTL response.

Amino Acid Sequence↗
PubMed2004

Therapeutic potential of oxidant mechanisms in Alzheimer's disease.

Oxidative stress is a major feature and one of the earliest changes in Alzheimer's disease. The complex nature and genesis of oxidative damage in Alzheimer's disease can be partly answered by mitochondrial and redox-active metal abnormalities. Evidence indicates that in the initial phase of Alzheimer's disease development, amyloid-beta deposition and hyperphosphorylated tau, hallmarks of the disease, are consequences of oxidative stress. Therefore, the authors propose that oxidative modifications in early stages of Alzheimer's disease may actually serve as a homeostatic response or compensatory mechanism against stressful agents resulting in a shift of neuronal priority from normal function to basic survival. Since the cause of Alzheimer's disease pathophysiology remains controversial, several and distinct therapeutic strategies have been tried to avoid, or at least reduce, the development of this neurodegenerative disorder. In this line, the inherent theoretical limitations of secretase inhibitors and immunotherapy, aimed to avoid the production or clear amyloid-beta from the brain is discussed. Promising antioxidant strategies, with the focus on fighting oxidative stress, are highlighted. Currently, antioxidant strategies appear to be the most encouraging therapeutics in reducing the clinical manifestation and evolution of Alzheimer's disease.

Alzheimer Disease↗
PubMed2004

A secondary structural model of the 28S rRNA expansion segments D2 and D3 from rootworms and related leaf beetles (Coleoptera: Chrysomelidae; Galerucinae).

We analysed the secondary structure of two expansion segments (D2, D3) of the 28S rRNA gene from 229 leaf beetles (Coleoptera: Chrysomelidae), the majority of which are in the subfamily Galerucinae. The sequences were compared in a multiple sequence alignment, with secondary structure inferred primarily from the compensatory base changes in the conserved helices of the rRNA molecules. This comparative approach yielded thirty helices comprised of base pairs with positional covariation. Based on these leaf beetle sequences, we report an annotated secondary structural model for the D2 and D3 expansion segments that will prove useful in assigning positional nucleotide homology for phylogeny reconstruction in these and closely related beetle taxa. This predicted structure, consisting of seven major compound helices, is mostly consistent with previously proposed models for the D2 and D3 expansion segments in insects. Despite a lack of conservation in the primary structure of these regions of insect 28S rRNA, the evolution of the secondary structure of these seven major motifs may be informative above the nucleotide level for higher-order phylogeny reconstruction of major insect lineages.

Animals↗
PubMed2025

Enhanced RNA replication and pathogenesis in recent SARS-CoV-2 variants harboring the L260F mutation in NSP6.

The COVID-19 pandemic has been driven by SARS-CoV-2 variants with enhanced transmission and immune escape. Apart from extensive evolution in the Spike protein, non-Spike mutations are accumulating across the entire viral genome and their functional impact is not well understood. To address the contribution of these mutations, we reconstructed genomes of recent Omicron variants with disabled Spike expression (replicons) to systematically compare their RNA replication capabilities independently from Spike. We also used a single reference replicon and complemented it with various Omicron variant Spike proteins to quantify viral entry capabilities in single-round infection assays. Viral entry and RNA replication were negatively correlated, suggesting that as variants evolve reduced entry functions under growing immune pressure on Spike, RNA replication increases as a compensatory mechanism. We identified multiple mutations across the viral genome that enhanced viral RNA replication. NSP6 emerged as a hotspot with a distinct L260F mutation independently arising in the BQ.1.1 and XBB.1.16 variants. Using mutant and revertant NSP6 viral clones, the L260F mutation was validated to enhance viral replication in cells and increase pathogenesis in mice. Notably, this mutation reduced host lipid droplet content by NSP6. Collectively, a systematic analysis of RNA replication of recent Omicron variants defined NSP6's key role in viral RNA replication that provides insight into evolutionary trajectories of recent variants with possible therapeutic implications.

SARS-CoV-2↗
PubMed1985

Plasticity of the central nervous system--a neurosurgeon's experience of cerebral compensation and decompensation.

Cerebral plasticity constitutes one of the most decisive factors in recovery and readaptation after cerebral lesions. In contrast to the considerable progress in current studies on normal neuronal plasticity including the idea of "l'homme neuronal", the concept of plasticity postulated by Albrecht Bethe in 1929 received little attention. The author, as a neurosurgeon, has tried to describe cranial morphological plasticity, morphological and functional plasticity in infantile encephalopathies and especially in hemiatrophic lesions. It is supposed that a true morphological substrate exists due to compensatory hyperplasia of the uninvolved hemisphere. Modern neurosurgical techniques have demonstrated that the functional plastic capacity is much larger than has been supposed, even in the elderly. Some aspects of the mechanisms of compensation and decompensation of cortical and subcortical structures as well as of the central regulation systems are discussed. The full extent of the amazing recovery and functional reorganization is reached by plastic capacity, personal motivation, adequate training and sufficient time. The contribution ends with an exposition of a personal philosophy concerning psycho-somatic dualism, the body-mind problem, the future of the human brain and the ethical outlook, based on the progressive biological evolution of the basal neocortex and the immanent functional development (H. Spatz).

Adaptation, Physiological↗
PubMed2006

A structural model for the large subunit of the mammalian mitochondrial ribosome.

Protein translation is essential for all forms of life and is conducted by a macromolecular complex, the ribosome. Evolutionary changes in protein and RNA sequences can affect the 3D organization of structural features in ribosomes in different species. The most dramatic changes occur in animal mitochondria, whose genomes have been reduced and altered significantly. The RNA component of the mitochondrial ribosome (mitoribosome) is reduced in size, with a compensatory increase in protein content. Until recently, it was unclear how these changes affect the 3D structure of the mitoribosome. Here, we present a structural model of the large subunit of the mammalian mitoribosome developed by combining molecular modeling techniques with cryo-electron microscopic data at 12.1A resolution. The model contains 93% of the mitochondrial rRNA sequence and 16 mitochondrial ribosomal proteins in the large subunit of the mitoribosome. Despite the smaller mitochondrial rRNA, the spatial positions of RNA domains known to be involved directly in protein synthesis are essentially the same as in bacterial and archaeal ribosomes. However, the dramatic reduction in rRNA content necessitates evolution of unique structural features to maintain connectivity between RNA domains. The smaller rRNA sequence also limits the likelihood of tRNA binding at the E-site of the mitoribosome, and correlates with the reduced size of D-loops and T-loops in some animal mitochondrial tRNAs, suggesting co-evolution of mitochondrial rRNA and tRNA structures.

Animals↗
PubMed2026

Gene expression is stable despite widespread cis and trans regulatory divergence in Saccharomyces yeasts.

Regulatory evolution can alter phenotypes, but cis- and trans-regulatory mechanisms may also diverge extensively while total transcript abundance remains stable. Comparisons of parental expression with allele-specific expression in F1 hybrids provide a framework for separating cis- and trans-regulatory effects because both parental alleles are measured in a shared trans-regulatory environment. Here, we analyzed RNA sequencing data from Saccharomyces cerevisiae, Saccharomyces paradoxus, and their F1 hybrid. Regulatory divergence was widespread, with 61.3% of tested orthologs showing significant divergence in at least one cis or trans component. However, hybrid expression remained largely conserved, with 81.6% of genes not significantly different from either parent. Compensatory cis-trans divergence predominated over reinforcing divergence, consistent with widespread buffering of transcript abundance. To connect genome-wide patterns to mechanism, we analyzed the strongly cis-diverged locus LYS2 and found species differences in promoter architecture, including an S. cerevisiae-specific AT-rich insertion, altered spacing among candidate regulatory features, and a promoter-proximal TATA-like element unique to S. cerevisiae. Sequence-based nucleosome prediction suggests that these differences create a broader promoter-proximal nucleosome-depleted region in S. cerevisiae than in S. paradoxus. We also quantified allele-resolved intron retention and found that splicing was broadly conserved, with only rare locus-specific hybrid-associated shifts. Together, these results show that regulatory divergence is widespread but often buffered in the hybrid, whereas post-transcriptional divergence is comparatively limited.

Gene expression↗
PubMed1989

Sequences similar to genes for two mitochondrial proteins and portions of ribosomal RNA in tandemly arrayed 6-kilobase-pair DNA of a malarial parasite.

Erythrocytic stages of mammalian malarial parasites contain acristate mitochondria whose functions are not well understood. Moreover, little is known about the genome of these organelles. We have previously reported that all species of malarial parasites examined contain highly conserved, tandemly arrayed DNA with a unit length of about 6.0 kb that is transcribed into discrete RNA molecules in erythrocytic stages. We now report the complete DNA sequence of the 5984-bp repeating unit of Plasmodium yoelii, a rodent parasite. Two slightly overlapping regions transcribed into large RNA molecules were found to have significant DNA and protein sequence similarity with mitochondrion-coded proteins, cytochrome c oxidase subunit I and cytochrome b. Significant sequence similarity with other mitochondrial protein genes could not be detected. Ribosomal RNA (rRNA)-like genes were not detected in this sequence either. However, two regions, 82 and 50 nucleotides long, specified by different strands, were found to have extensive similarity with the highly conserved central loop of the peptidyl transferase domain of the large rRNA of Escherichia coli, mitochondria, and chloroplasts. Compensatory nucleotide substitutions were present in these regions, so that the predicted secondary structure was not affected. Functional utilization of these regions, if it exists, could argue for a trans-associative origin of rRNA. In organization, size and sequence, the tandem arrays of 6.0 kb malarial DNA appear to be a very unusual form of mitochondrial DNA.

Acyltransferases↗
PubMed2001

Selection intensity against deleterious mutations in RNA secondary structures and rate of compensatory nucleotide substitutions.

A two-locus model of reversible mutations with compensatory fitness interactions is presented; single mutations are assumed to be deleterious but neutral in appropriate combinations. The expectation of the time of compensatory nucleotide substitutions is calculated analytically for the case of tight linkage between sites. It is shown that selection increases the substitution time dramatically when selection intensity Ns > 1, where N is the diploid population size and s the selection coefficient. Computer simulations demonstrate that recombination increases the substitution time, but the effect of recombination is small when selection is weak. The amount of linkage disequilibrium generated in the process of compensatory substitution is also investigated. It is shown that significant linkage disequilibrium is expected to be rare in natural populations. The model is applied to the mRNA secondary structure of the bicoid 3' untranslated region of Drosophila. It is concluded that average selection intensity Ns against single deleterious mutations is not likely to be much larger than 1.

3' Untranslated Regions↗
PubMedDate not supplied

[The clinical picture of spinal cord tumors with different histostructures in children].

An analysis into the results of treatment accorded to 101 sick children wiht tumours of the spinal cord evidences that the clinical picture of this pathology is distinguished by a number of features that depend on the histological structure, high compensatory potentialities and extraordinary plasticity of the child's spinal cord and vertebral column. In this connection of prime importance becomes the significance of assessing the data derived from a comprehensive examination, due consideration being given to the age-specific features of the patients. As concerns their incidence in children first and foremost are tumours of the glial series, distinguished by a comparatively mild course of the disease, paucity of focal and conduction symptomatology that is incongrous with the extent of the lesion involving the spinal cord both along its vertical and transverse section. The tumours of the meningovasal series are of rare occurrence, their salient feature being malignant evolution of the affection with extradural localization. Notwithstanding their intensive growth the heterotopic tumours cause in a number of cases some difficulty in the topicodiagnostic respect, this being due to a well-pronounced memingeal syndrome with an extremely poor focal symptomatology. An early surgical and radiation treatment of tumours in the glial series renders a realively good curative effect with partial restoration of disturbed functions in the early and late post-treatment periods.

Adolescent↗
PubMed2026

Gene expression is stable despite widespread cis and trans regulatory divergence in Saccharomyces yeasts.

Regulatory evolution can alter phenotypes, but cis- and trans-regulatory mechanisms may also diverge extensively while total transcript abundance remains stable. Comparisons of parental expression with allele-specific expression in F1 hybrids provide a framework for separating cis- and trans-regulatory effects because both parental alleles are measured in a shared trans-regulatory environment. Here, we analyzed RNA sequencing data from Saccharomyces cerevisiae, Saccharomyces paradoxus, and their F1 hybrid. Among the 4,164 genes with sufficient allele-specific support for strict classification, 2,134 (51.2%) showed detectable cis and/or trans regulatory divergence. However, hybrid expression remained largely conserved, with 81.5% of genes not significantly different from either parent. Compensatory cis-trans divergence predominated over reinforcing divergence; cross-replicate estimation reduced the apparent magnitude of this excess, but opposite-sign effects remained predominant in all 20 non-overlapping replicate comparisons. To connect gene expression to genome sequence, we analyzed the strongly cis-diverged locus LYS2 and found species differences in promoter architecture, including an S. cerevisiae-specific AT-rich insertion, altered spacing among candidate regulatory features, and a promoter-proximal TATA-like element unique to S. cerevisiae. Sequence-based nucleosome prediction suggests that these differences create a broader promoter-proximal nucleosome-depleted region in S. cerevisiae than in S. paradoxus. We also quantified allele-resolved intron retention and found that allele-resolved intron retention was broadly conserved, with only rare locus-specific hybrid-associated shifts. Together, these results show that regulatory divergence is widespread but often buffered in the hybrid, whereas intron-retention divergence is comparatively limited.

Saccharomyces↗
PubMed2006

[Long-term behavior of ankle fusion: assessment of the same series at 7 and 23 year (19-36 years) follow-up].

PURPOSE OF THE STUDY: Theoretically, long-term functional and radiographic degradation is predictable after ankle fusion, but sound evidence from the consecutive analysis of the same cohort is lacking. The purpose of this study was to check the hypothesis by repeating assessment in the same cohort of patients who underwent ankle fusion. MATERIAL AND METHODS: The cohort included 52 ankle fusions which had been analyzed in 1984 at seven years (range 2-22 years) follow-up then again in 2000 using the same evaluation criteria. Among the 52 patients, six were lost to follow-up (11.5%) 20 had died (38.4%) and one had undergone leg amputation. The second analysis thus included 25 patients (48%). The comparison cohort thus included 25 patients (18 men and 7 women), mean age 62+/-12.6 years (range 40-94) at the 2000 assessment performed 23+/-4.5 years (range 19-36 years) after the fusion. Functional outcome was assessed with the 100-point Duquennoy scale. Osteoarthritis of the subtalar and mediotarsal joints were assessed preoperatively and at follow-up using the same scale. RESULTS: The functional outcome did not deteriorate significantly between 1984 and 2000. The mean score was 65.8+/-22.6 (range 19-92) in 1984 and 64.7+/-18.3 (range 34-90) in 2000 (p=0.67). Fifteen patients (60%) had a good or very good outcome at seven years, and 14 (56%) at 23 years. Between 1984 and 2000, ten patients improved their score (on average 10.4 points, range 1-21 points), two had an unchanged score and thirteen a lower score (on average 10 points, range -1 to -24). Ten of these thirteen patients developed severe intercurrent conditions (neurological or cardiac) explaining the degradation. At last follow-up, sixteen ankles were pain free or nearly pain free. Twelve patients considered their ankle as a forgotten problem (VAS 10) and had no regrets concerning the operation. The evolution of the subtalar joint in 16 cases (nine fusions including five at the same time as the ankle fusion and four performed within four years) showed that all developed osteoarthrtic degradation early with aggravation between 1984 and 2000, leading in the majority of cases to severe degenerative disease. This osteoarthritis was painful in less than one-third of the cases (including the four secondary subtalar fusions and the four subtalar fusions which were painful at mobilization). Twenty-three mediotarsal joints were analyzed (two fusions four years after ankle fusion). The degradation was later and less severe than for the subtalar joint with a majority showing moderate osteoarthritis. Ten ankles exhibited compensatory hypermobility of the forefoot measured at more than 15 degrees without pain. DISCUSSION: This long-term follow-up with two successive assessments using the same evaluation criteria did not demonstrated the late degradation of function expected after ankle fusion. It did show however the presence of undeniable radiographic degradation of the subtalar joint but with little or no severe clinical expression at a minimal follow-up of 19 years. There was no need for complementary fusion between 4 and 23 years follow-up.

Adult↗
PubMed1995

Main objectives and new aspects of combination treatment of hypertension.

AIM: To review the various pharmacological approaches currently proposed for the treatment of hypertension. RESULTS: With the evolution of pharmacological treatment of hypertension, various classes of agent (diuretics, beta-blockers, angiotensin converting enzyme inhibitors, calcium antagonists and alpha 1-blockers) have become available for the initiation of antihypertensive therapy. As monotherapy, each type of agent will normalize blood pressure in about half of all hypertensive patients. Replacing one drug with another that acts through a different mechanism improves the probability of controlling blood pressure. Another way to increase the number of responders is to increase the dose; however, this often results in more side effects. A preferable way of improving efficacy is to combine low doses of drugs that have different impacts on the cardiovascular system, thus opposing the compensatory responses that tend to limit the blood pressure drop. CONCLUSION: Low-dose drug combinations are generally well tolerated and the treatment of hypertension can be simplified by using fixed-dose combinations. These combinations have the potential to become a valuable alternative in the initiation of antihypertensive therapy.

Adrenergic alpha-Antagonists↗
PubMed2003

Ribosomal ITS sequences and plant phylogenetic inference.

One of the most popular sequences for phylogenetic inference at the generic and infrageneric levels in plants is the internal transcribed spacer (ITS) region of the 18S-5.8S-26S nuclear ribosomal cistron. The prominence of this source of nuclear DNA sequence data is underscored by a survey of phylogenetic publications involving comparisons at the genus level or below, which reveals that of 244 papers published over the last five years, 66% included ITS sequence data. Perhaps even more striking is the fact that 34% of all published phylogenetic hypothesis have been based exclusively on ITS sequences. Notwithstanding the many important contributions of ITS sequence data to phylogenetic understanding and knowledge of genome relationships, a number of molecular genetic processes impact ITS sequences in ways that may mislead phylogenetic inference. These molecular genetic processes are reviewed here, drawing attention to both underlying mechanism and phylogenetic implications. Among the most prevalent complications for phylogenetic inference is the existence in many plant genomes of extensive sequence variation, arising from ancient or recent array duplication events, genomic harboring of pseudogenes in various states of decay, and/or incomplete intra- or inter-array homogenization. These phenomena separately and collectively create a network of paralogous sequence relationships potentially confounding accurate phylogenetic reconstruction. Homoplasy is shown to be higher in ITS than in other DNA sequence data sets, most likely because of orthology/paralogy conflation, compensatory base changes, problems in alignment due to indel accumulation, sequencing errors, or some combination of these phenomena. Despite the near-universal usage of ITS sequence data in plant phylogenetic studies, its complex and unpredictable evolutionary behavior reduce its utility for phylogenetic analysis. It is suggested that more robust insights are likely to emerge from the use of single-copy or low-copy nuclear genes.

DNA, Ribosomal Spacer↗
PubMed1998

Long-range translational coupling in single-stranded RNA bacteriophages: an evolutionary analysis.

In coliphage MS2 RNA a long-distance interaction (LDI) between an internal segment of the upstream coat gene and the start region of the replicase gene prevents initiation of replicase synthesis in the absence of coat gene translation. Elongating ribosomes break up the repressor LDI and thus activate the hidden initiation site. Expression studies on partial MS2 cDNA clones identified base pairing between 1427-1433 and 1738-1744, the so-called Min Jou (MJ) interaction, as the molecular basis for the long-range coupling mechanism. Here, we examine the biological significance of this interaction for the control of replicase gene translation. The LDI was disrupted by mutations in the 3'-side and the evolutionary adaptation was monitored upon phage passaging. Two categories of pseudorevertants emerged. The first type had restored the MJ interaction but not necessarily the native sequence. The pseudorevertants of the second type acquired a compensatory substitution some 80 nt downstream of the MJ interaction that stabilizes an adjacent LDI. In one examined case we confirmed that the second site mutations had restored coat-replicase translational coupling. Our results show the importance of translational control for fitness of the phage. They also reveal that the structure that buries the replicase start extends to structure elements bordering the MJ interaction.

Base Sequence↗