scholarly journals Predicting the Stability of Homologous Gene Duplications in a Plant RNA Virus

2016 ◽  
Vol 8 (9) ◽  
pp. 3065-3082 ◽  
Author(s):  
Anouk Willemsen ◽  
Mark P. Zwart ◽  
Pablo Higueras ◽  
Josep Sardanyés ◽  
Santiago F. Elena
Keyword(s):  
Rna Virus ◽  
Homologous Gene ◽  
Gene Duplications ◽  
The Stability

scholarly journals Predicting the stability of homologous gene duplications in a plant RNA virus

2016 ◽  
Author(s):  
Anouk Willemsen ◽  
Mark P. Zwart ◽  
Pablo Higueras ◽  
Josep Sardanyés ◽  
Santiago F. Elena
Keyword(s):  
Gene Duplication ◽  
Rna Viruses ◽  
Rna Virus ◽  
Genomic Stability ◽  
Gene Copy ◽  
Homologous Gene ◽  
Gene Duplications ◽  
Evolutionary Potential ◽  
Rate Dependent ◽  
The Stability

AbstractOne of the striking features of many eukaryotes is the apparent amount of redundancy in coding and non-coding elements of their genomes. Despite the possible evolutionary advantages, there are fewer examples of redundant sequences in viral genomes, particularly those with RNA genomes. The low prevalence of gene duplication in RNA viruses most likely reflects the strong selective constraints against increasing genome size. Here we investigated the stability of genetically redundant sequences and how adaptive evolution proceeds to remove them. We generated plant RNA viruses with potentially beneficial gene duplications, measured their fitness and performed experimental evolution, hereby exploring their genomic stability and evolutionary potential. We found that all gene duplication events resulted in a loss of viability or significant reductions in fitness. Moreover, upon evolving the viable viruses and analyzing their genomes, we always observed the deletion of the duplicated gene copy and maintenance of the ancestral copy. Interestingly, there were clear differences in the deletion dynamics of the duplicated gene associated with the passage duration, the size of the gene and the position for duplication. Based on the experimental data, we developed a mathematical model to characterize the stability of genetically redundant sequences, and showed that the fitness of viruses with duplications is not enough information to predict genomic stability as a recombination rate dependent on the genetic context – the duplicated gene and its position – is also required. Our results therefore demonstrate experimentally the deleterious nature of gene duplications in RNA viruses, and we identify factors that constrain the maintenance of duplicated genes.

scholarly journals Molecular Dynamics Reveals the Effects of Temperature on Critical SARS-CoV-2 Proteins

2021 ◽  
Author(s):  
Paul Morgan ◽  
Chih-Wen Shu
Keyword(s):  
Molecular Dynamics ◽  
Drug Targets ◽  
Rna Virus ◽  
Nonstructural Protein ◽  
Md Simulations ◽  
Effect Of Temperature ◽  
Temperature Variations ◽  
Serious Infection ◽  
Critical Residues ◽  
The Stability

ABSTRACTSevere Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a newly identified RNA virus that causes the serious infection Coronavirus Disease 2019 (COVID-19). The incidence of COVID-19 is still increasing worldwide despite the summer heat and cool winter. However, little is known about seasonal stability of SARS-CoV-2. Herein, we employ Molecular Dynamics (MD) simulations to explore the effect of temperature on four critical SARS-CoV-2 proteins. Our work demonstrates that the spike Receptor Binding Domain (RBD), Main protease (Mpro), and nonstructural protein 3 (macro X) possesses extreme thermos-stability when subjected to temperature variations rendering them attractive drug targets. Furthermore, our findings suggest that these four proteins are well adapted to habitable temperatures on earth and are largely insensitive to cold and warm climates. Furthermore, we report that the critical residues in SARS-CoV-2 RBD were less responsive to temperature variations as compared to the critical residues in SARS-CoV. As such, extreme summer and winter climates, and the transition between the two seasons, are expected to have a negligible effect on the stability of SARS-CoV-2 which will marginally suppress transmission rates until effective therapeutics are available world-wide.

scholarly journals STABILITY OF A STOCHASTICALLY PERTURBED MODEL OF INTRACELLULAR SINGLE-STRANDED RNA VIRUS REPLICATION

2019 ◽  
Vol 27 (01) ◽  
pp. 69-82
Author(s):  
LEONID SHAIKHET ◽  
SANTIAGO F. ELENA ◽  
ANDREI KOROBEINIKOV
Keyword(s):  
Virus Replication ◽  
Rna Virus ◽  
Sufficient Conditions ◽  
Direct Lyapunov Method ◽  
Heterogeneous Model ◽  
Stochastic Perturbations ◽  
Ssrna Virus ◽  
The Stability ◽  
Perturbed Model ◽  
Stochastically Perturbed

Compared to the replication of double-stranded RNA and DNA viruses, the replication of single-stranded viruses requires the production of a number of intermediate strands that serve as templates for the synthesis of genomic-sense strands. Two theoretical extreme mechanisms for replication for such single-stranded viruses have been proposed; one extreme being represented by the so-called linear stamping machine and the opposite extreme by the exponential growth. Of course, real systems are more complex and examples have been described in which a combination of such extreme mechanisms can also occur: a fraction of the produced progeny resulting from a stamping-machine type of replication that uses the parental genome as template, whereas other fraction of the progeny results from the replication of other progeny genomes. Martínez et al. 1 , Sardanyés et al. 2 and Fornés et al. 3 suggested and analyzed a deterministic model of single-stranded RNA (ssRNA) virus intracellular replication that incorporated variability in the replication mechanisms. To explore how stochasticity can affect this mixed-model principal properties, in this paper, we consider the stability of a stochastically perturbed model of ssRNA virus replication within a cell. Using the direct Lyapunov method, we found sufficient conditions for the stability in probability of equilibrium states for this model. This result confirms that this heterogeneous model of single-stranded RNA virus replication is stable with respect to stochastic perturbations of the environment.

scholarly journals Purification of the Cucumber Necrosis Virus Replicase from Yeast Cells: Role of Coexpressed Viral RNA in Stimulation of Replicase Activity

2004 ◽  
Vol 78 (15) ◽  
pp. 8254-8263 ◽  
Author(s):  
Zivile Panaviene ◽  
Tadas Panavas ◽  
Saulius Serva ◽  
Peter D. Nagy
Keyword(s):  
De Novo ◽  
Rna Virus ◽  
Rna Replication ◽  
Viral Rna ◽  
Yeast Cells ◽  
Highly Active ◽  
Replicase Complex ◽  
Internal Initiation ◽  
The Stability

ABSTRACT Purified recombinant viral replicases are useful for studying the mechanism of viral RNA replication in vitro. In this work, we obtained a highly active template-dependent replicase complex for Cucumber necrosis tombusvirus (CNV), which is a plus-stranded RNA virus, from Saccharomyces cerevisiae. The recombinant CNV replicase showed properties similar to those of the plant-derived CNV replicase (P. D. Nagy and J. Pogany, Virology 276:279-288, 2000), including the ability (i) to initiate cRNA synthesis de novo on both plus- and minus-stranded templates, (ii) to generate replicase products that are shorter than full length by internal initiation, and (iii) to perform primer extension from the 3′ end of the template. We also found that isolation of functional replicase required the coexpression of the CNV p92 RNA-dependent RNA polymerase and the auxiliary p33 protein in yeast. Moreover, coexpression of a viral RNA template with the replicase proteins in yeast increased the activity of the purified CNV replicase by 40-fold, suggesting that the viral RNA might promote the assembly of the replicase complex and/or that the RNA increases the stability of the replicase. In summary, this paper reports the first purified recombinant tombusvirus replicase showing high activity and template dependence, a finding that will greatly facilitate future studies on RNA replication in vitro.

scholarly journals The Nedd4-Type Rsp5p Ubiquitin Ligase Inhibits Tombusvirus Replication by Regulating Degradation of the p92 Replication Protein and Decreasing the Activity of the Tombusvirus Replicase

2009 ◽  
Vol 83 (22) ◽  
pp. 11751-11764 ◽  
Author(s):  
Daniel Barajas ◽  
Zhenghe Li ◽  
Peter D. Nagy
Keyword(s):  
Protein Interactions ◽  
Rna Virus ◽  
Replication Proteins ◽  
Ww Domain ◽  
Replication Assay ◽  
Protein Ubiquitination ◽  
Negative Effect ◽  
A Cell ◽  
The Stability

ABSTRACT Recent in vitro proteomics screens revealed that many host proteins could interact with the replication proteins of Tomato bushy stunt virus (TBSV), which is a small, plus-stranded RNA virus (Z. Li, D. Barajas, T. Panavas, D. A. Herbst, and P. D. Nagy, J. Virol. 82:6911-6926, 2008). To further our understanding of the roles of host factors in TBSV replication, we have tested the effect of Rsp5p, which is a member of the Nedd4 family of E3 ubiquitin ligases. The full-length Rsp5p, via its WW domain, is shown to interact with p33 and the central portion of p92pol replication proteins. We find that overexpression of Rsp5p inhibits TBSV replication in Saccharomyces cerevisiae yeast, while downregulation of Rsp5p leads to increased TBSV accumulation. The inhibition is caused by Rsp5p-guided degradation of p92pol, while the negative effect on the p33 level is less pronounced. Interestingly, recombinant Rsp5p also inhibits TBSV RNA replication in a cell-free replication assay, likely due to its ability to bind to p33 and p92pol. We show that the WW domain of Rsp5p, which is involved in protein interactions, is responsible for inhibition of TBSV replication, whereas the HECT domain, involved in protein ubiquitination, is not necessary for Rsp5p-mediated inhibition of viral replication. Overall, our data suggest that direct binding between Rsp5p and p92pol reduces the stability of p92pol, with consequent inhibition of TBSV replicase activity.

scholarly journals Ancient gene duplications in RNA viruses revealed by protein tertiary structure comparisons

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Alejandro Miguel Cisneros-Martínez ◽  
Arturo Becerra ◽  
Antonio Lazcano
Keyword(s):  
Tertiary Structure ◽  
Rna Viruses ◽  
Rna Virus ◽  
Protein Structures ◽  
Data Bank ◽  
Cysteine Proteases ◽  
Gene Duplications ◽  
Virus Family ◽  
Protein Tertiary Structure ◽  
Duplication Events

Abstract To date only a handful of duplicated genes have been described in RNA viruses. This shortage can be attributed to different factors, including the RNA viruses with high mutation rate that would make a large genome more prone to acquire deleterious mutations. This may explain why sequence-based approaches have only found duplications in their most recent evolutionary history. To detect earlier duplications, we performed protein tertiary structure comparisons for every RNA virus family represented in the Protein Data Bank. We present a list of thirty pairs of possible paralogs with <30 per cent sequence identity. It is argued that these pairs are the outcome of six duplication events. These include the α and β subunits of the fungal toxin KP6 present in the dsRNA Ustilago maydis virus (family Totiviridae), the SARS-CoV (Coronaviridae) nsp3 domains SUD-N, SUD-M and X-domain, the Picornavirales (families Picornaviridae, Dicistroviridae, Iflaviridae and Secoviridae) capsid proteins VP1, VP2 and VP3, and the Enterovirus (family Picornaviridae) 3C and 2A cysteine-proteases. Protein tertiary structure comparisons may reveal more duplication events as more three-dimensional protein structures are determined and suggests that, although still rare, gene duplications may be more frequent in RNA viruses than previously thought. Keywords: gene duplications; RNA viruses.

scholarly journals Mutation Rates, Mutation Frequencies, and Proofreading-Repair Activities in RNA Virus Genetics

Viruses ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1882 ◽  
Author(s):  
Esteban Domingo ◽  
Carlos García-Crespo ◽  
Rebeca Lobo-Vega ◽  
Celia Perales
Keyword(s):  
Error Rate ◽  
Rna Virus ◽  
Error Rates ◽  
Viral Rna ◽  
Mutation Rates ◽  
Relevant Parameter ◽  
Dna Viruses ◽  
Biologically Relevant ◽  
Host Interactions ◽  
The Stability

The error rate displayed during template copying to produce viral RNA progeny is a biologically relevant parameter of the replication complexes of viruses. It has consequences for virus–host interactions, and it represents the first step in the diversification of viruses in nature. Measurements during infections and with purified viral polymerases indicate that mutation rates for RNA viruses are in the range of 10−3 to 10−6 copying errors per nucleotide incorporated into the nascent RNA product. Although viruses are thought to exploit high error rates for adaptation to changing environments, some of them possess misincorporation correcting activities. One of them is a proofreading-repair 3′ to 5′ exonuclease present in coronaviruses that may decrease the error rate during replication. Here we review experimental evidence and models of information maintenance that explain why elevated mutation rates have been preserved during the evolution of RNA (and some DNA) viruses. The models also offer an interpretation of why error correction mechanisms have evolved to maintain the stability of genetic information carried out by large viral RNA genomes such as the coronaviruses.

scholarly journals Dynamic of a Two-strain COVID-19 Model with Vaccination

2021 ◽  
Author(s):  
Stéphane yanick Tchoumi ◽  
Herieth Rwezaura ◽  
Jean Michel Tchuenche
Keyword(s):  
Current Knowledge ◽  
Rna Virus ◽  
Sufficient Conditions ◽  
Respiratory Illness ◽  
Basic Reproductive Number ◽  
Reproductive Number ◽  
Effective Vaccine ◽  
Single Strain ◽  
The Stability ◽  
Manifold Theory

Abstract COVID-19 is a respiratory illness caused by an RNA virus prone to mutations. In December 2020, variants with different characteristics that could affect transmissibility and death emerged around the world. To address this new dynamic of the disease, we formulate and analyze a mathematical model of a two-strain COVID-19 transmission dynamics with strain 1 vaccination. The model is theoretically analyzed and sufficient conditions for the stability of its equilibria are derived. In addition to the disease-free and endemic equilibria, the model also has single-strain 1 and strain 2 endemic equilibria. Using the center manifold theory, it is shown that the model does not exhibit the phenomenon of backward bifurcation, and global stability of the model equilibria when the basic reproduction number R 0 is either less or greater than unity as the case maybe are proved using various approaches. Simulations to support the model theoretical results are provided. We calculate the basic reproductive number for both strains R_1 and R_2 independently. Results indicate that - both strains will persist when both R 1 > 1 and R 2 > 1 - Stain 2 could establish itself as the dominant strain if R 1 < 1 and R 2 > 1, or when R 2 is at least two times R 1 . However, with the current knowledge of the epidemiology of the COVID-19 pandemic and the availability of treatment and an effective vaccine against strain 1, eventually, strain 2 will likely be eradicated in the population if the threshold parameter R 2 is controlled to remain below unity.

On Inferring Additive and Replacing Horizontal Gene Transfers Through Phylogenetic Reconciliation

2020 ◽  
Author(s):  
Misagh Kordi ◽  
Soumya Kundu ◽  
Mukul S. Bansal
Keyword(s):  
Gene Transfer ◽  
Horizontal Gene Transfer ◽  
Classification Accuracy ◽  
Software Package ◽  
Microbial Evolution ◽  
Homologous Gene ◽  
Gene Duplications ◽  
New Gene ◽  
Phylogenetic Reconciliation ◽  
The Impact

AbstractHorizontal gene transfer is one of the most important mechanisms for microbial evolution and adaptation. It is well known that horizontal gene transfer can be either additive or replacing depending on whether the transferred gene adds itself as a new gene in the recipient genome or replaces an existing homologous gene. Yet, all existing phylogenetic techniques for the inference of horizontal gene transfer assume either that all transfers are additive or that all transfers are replacing. This limitation not only affects the applicability and accuracy of these methods but also makes it difficult to distinguish between additive and replacing transfers.Here, we address this important problem by formalizing a phylogenetic reconciliation framework that simultaneously models both additive and replacing transfer events. Specifically, we (1) introduce the DTRL reconciliation framework that explicitly models both additive and replacing transfer events, along with gene duplications and losses, (2) prove that the underlying computational problem is NP-hard, (3) perform the first experimental study to assess the impact of replacing transfer events on the accuracy of the traditional DTL reconciliation model (which assumes that all transfers are additive) and demonstrate that traditional DTL reconciliation remains highly robust to the presence of replacing transfers, (4) propose a simple heuristic algorithm for DTRL reconciliation based on classifying transfer events inferred through DTL reconciliation as being replacing or additive, and (5) evaluate the classification accuracy of the heuristic under a range of evolutionary conditions. Thus, this work lays the methodological and algorithmic foundations for estimating DTRL reconciliations and distinguishing between additive and replacing transfers.An implementation of our heuristic for DTRL reconciliation is freely available open-source as part of the RANGER-DTL software package from https://compbio.engr.uconn.edu/software/ranger-dtl/.

scholarly journals RBP38, a Novel RNA-Binding Protein from Trypanosomatid Mitochondria, Modulates RNA Stability

2003 ◽  
Vol 2 (3) ◽  
pp. 560-568 ◽  
Author(s):  
Sandro Sbicego ◽  
Juan D. Alfonzo ◽  
Antonio M. Estévez ◽  
Mary Anne T. Rubio ◽  
Xuedong Kang ◽  
...  
Keyword(s):  
Rna Binding ◽  
Dissociation Constants ◽  
Binding Protein ◽  
Rna Stability ◽  
Rna Binding Protein ◽  
Homologous Gene ◽  
Mitochondrial Rna ◽  
Isolation And Characterization ◽  
Labeled Rna ◽  
The Stability

ABSTRACT We describe here the isolation and characterization of a novel RNA-binding protein, RBP38, from Leishmania tarentolae mitochondria. This protein does not contain any known RNA-binding motifs and is highly conserved among the trypanosomatids, but no homologues were found in other organisms. Recombinant LtRBP38 binds single and double-stranded (ds) RNA substrates with dissociation constants in the 100 nM range, as determined by fluorescence polarization analysis. Downregulation of expression of the homologous gene, TbRBP38, in procyclic Trypanosoma brucei by using conditional dsRNA interference resulted in 80% reduction of steady-state levels of RNAs transcribed from both maxicircle and minicircle DNA. In organello pulse-chase labeling experiments were used to determine the stability of RNAs in mitochondria that were depleted of TbRBP38. The half-life of metabolically labeled RNA decreased from ∼160 to ∼60 min after depletion. In contrast, there was no change in transcriptional activity. These observations suggest a role of RBP38 in stabilizing mitochondrial RNA.

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