scholarly journals Biased Mutation and Selection in RNA Viruses

2020 ◽  
Author(s):  
Talia Kustin ◽  
Adi Stern
Keyword(s):  
Rna Viruses ◽  
Rna Virus ◽  
Purifying Selection ◽  
Nucleotide Composition ◽  
Host Cells ◽  
Mutational Bias ◽  
Data Set ◽  
Coding Sequences ◽  
Sequence Composition ◽  
Selection For

Abstract RNA viruses are responsible for some of the worst pandemics known to mankind, including outbreaks of Influenza, Ebola, and COVID-19. One major challenge in tackling RNA viruses is the fact they are extremely genetically diverse. Nevertheless, they share common features that include their dependence on host cells for replication, and high mutation rates. We set out to search for shared evolutionary characteristics that may aid in gaining a broader understanding of RNA virus evolution, and constructed a phylogeny-based data set spanning thousands of sequences from diverse single-stranded RNA viruses of animals. Strikingly, we found that the vast majority of these viruses have a skewed nucleotide composition, manifested as adenine rich (A-rich) coding sequences. In order to test whether A-richness is driven by selection or by biased mutation processes, we harnessed the effects of incomplete purifying selection at the tips of virus phylogenies. Our results revealed consistent mutational biases toward U rather than A in genomes of all viruses. In +ssRNA viruses, we found that this bias is compensated by selection against U and selection for A, which leads to A-rich genomes. In −ssRNA viruses, the genomic mutational bias toward U on the negative strand manifests as A-rich coding sequences, on the positive strand. We investigated possible reasons for the advantage of A-rich sequences including weakened RNA secondary structures, codon usage bias, and selection for a particular amino acid composition, and conclude that host immune pressures may have led to similar biases in coding sequence composition across very divergent RNA viruses.

scholarly journals Marine RNA Virus Quasispecies Are Distributed throughout the Oceans

mSphere ◽  
2019 ◽  
Vol 4 (2) ◽  
Author(s):  
Marli Vlok ◽  
Andrew S. Lang ◽  
Curtis A. Suttle
Keyword(s):  
Amino Acid ◽  
Rna Viruses ◽  
Rna Virus ◽  
Purifying Selection ◽  
Amino Acid Sequences ◽  
Metagenomic Data ◽  
Spatial And Temporal Patterns ◽  
Data Set ◽  
Virus Diversity ◽  
Virus Genomes

ABSTRACTRNA viruses, particularly genetically diverse members of thePicornavirales, are widespread and abundant in the ocean. Gene surveys suggest that there are spatial and temporal patterns in the composition of RNA virus assemblages, but data on their diversity and genetic variability in different oceanographic settings are limited. Here, we show that specific RNA virus genomes have widespread geographic distributions and that the dominant genotypes are under purifying selection. Genomes from three previously unknown picorna-like viruses (BC-1, -2, and -3) assembled from a coastal site in British Columbia, Canada, as well as marine RNA viruses JP-A, JP-B, andHeterosigma akashiwoRNA virus exhibited different biogeographical patterns. Thus, biotic factors such as host specificity and viral life cycle, and not just abiotic processes such as dispersal, affect marine RNA virus distribution. Sequence differences relative to reference genomes imply that virus quasispecies are under purifying selection, with synonymous single-nucleotide variations dominating in genomes from geographically distinct regions resulting in conservation of amino acid sequences. Conversely, sequences from coastal South Africa that mapped to marine RNA virus JP-A exhibited more nonsynonymous mutations, probably representing amino acid changes that accumulated over a longer separation. This biogeographical analysis of marine RNA viruses demonstrates that purifying selection is occurring across oceanographic provinces. These data add to the spectrum of known marine RNA virus genomes, show the importance of dispersal and purifying selection for these viruses, and indicate that closely related RNA viruses are pathogens of eukaryotic microbes across oceans.IMPORTANCEVery little is known about aquatic RNA virus populations and genome evolution. This is the first study that analyzes marine environmental RNA viral assemblages in an evolutionary and broad geographical context. This study contributes the largest marine RNA virus metagenomic data set to date, substantially increasing the sequencing space for RNA viruses and also providing a baseline for comparisons of marine RNA virus diversity. The new viruses discovered in this study are representative of the most abundant family of marine RNA viruses, theMarnaviridae, and expand our view of the diversity of this important group. Overall, our data and analyses provide a foundation for interpreting marine RNA virus diversity and evolution.

scholarly journals An overview of RNA virus-encoded microRNAs

ExRNA ◽  
2019 ◽  
Vol 1 (1) ◽  
Author(s):  
Xihan Li ◽  
Xiaoping Zou
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Viral Replication ◽  
Potential Role ◽  
Rna Viruses ◽  
Rna Virus ◽  
Host Cells ◽  
Basic Pattern ◽  
Double Stranded Dna ◽  
Non Coding Rnas

Abstract MicroRNAs (miRNAs) are a number of small non-coding RNAs playing a regulatory part in gene expression. Many virus-encoded miRNAs have been found, which manifests that viruses as well apply the basic pattern of gene regulation, however, mostly in viruses transcribed from double-stranded DNA genomes. It is still in dispute if RNA viruses could encode miRNAs because the excision of miRNA might result in the cleavage of viral RNA genome. We will focus on the miRNAs encoded by RNA virus and discuss their potential role in viral replication cycle and host cells.

scholarly journals Use of Nucleotide Composition Analysis To Infer Hosts for Three Novel Picorna-Like Viruses

2010 ◽  
Vol 84 (19) ◽  
pp. 10322-10328 ◽  
Author(s):  
A. Kapoor ◽  
P. Simmonds ◽  
W. I. Lipkin ◽  
S. Zaidi ◽  
E. Delwart
Keyword(s):  
Genomic Organization ◽  
Rna Viruses ◽  
Nucleotide Composition ◽  
Training Data ◽  
Composition Analysis ◽  
Data Set ◽  
Viral Genomes ◽  
Contaminated Food ◽  
Host Origin ◽  
Human Stool

ABSTRACT Nearly complete genome sequences of three novel RNA viruses were acquired from the stool of an Afghan child. Phylogenetic analysis indicated that these viruses belong to the picorna-like virus superfamily. Because of their unique genomic organization and deep phylogenetic roots, we propose these viruses, provisionally named calhevirus, tetnovirus-1, and tetnovirus-2, as prototypes of new viral families. A newly developed nucleotide composition analysis (NCA) method was used to compare mononucleotide and dinucleotide frequencies for RNA viruses infecting mammals, plants, or insects. Using a large training data set of 284 representative picornavirus-like genomic sequences with defined host origins, NCA correctly identified the kingdom or phylum of the viral host for >95% of picorna-like viruses. NCA predicted an insect host origin for the 3 novel picorna-like viruses. Their presence in human stool therefore likely reflects ingestion of insect-contaminated food. As metagenomic analyses of different environments and organisms continue to yield highly divergent viral genomes NCA provides a rapid and robust method to identify their likely cellular hosts.

scholarly journals A speed-fidelity trade-off determines the mutation rate and virulence of an RNA virus

2018 ◽  
Author(s):  
William Fitzsimmons ◽  
Robert J. Woods ◽  
John T. McCrone ◽  
Andrew Woodman ◽  
Jamie J. Arnold ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Experimental Evolution ◽  
Rna Viruses ◽  
Fundamental Problem ◽  
Rna Virus ◽  
Mutation Rates ◽  
Direct Selection ◽  
Growth Defect ◽  
Infection Model ◽  
Selection For

AbstractMutation rates can evolve through genetic drift, indirect selection due to genetic hitchhiking, or direct selection on the physicochemical cost of high fidelity. However, for many systems, it has been difficult to disentangle the relative impact of these forces empirically. In RNA viruses, an observed correlation between mutation rate and virulence has led many to argue that their extremely high mutation rates are advantageous, because they may allow for increased adaptability. This argument has profound implications, as it suggests that pathogenesis in many viral infections depends on rare orde novomutations. Here we present data for an alternative model whereby RNA viruses evolve high mutation rates as a byproduct of selection for increased replicative speed. We find that a poliovirus antimutator, 3DG64S, has a significant replication defect and that wild type and 3DG64Spopulations have similar adaptability in two distinct cellular environments. Experimental evolution of 3DG64Sunder r-selection led to reversion and compensation of the fidelity phenotype. Mice infected with 3DG64Sexhibited delayed morbidity at doses well above the LD50, consistent with attenuation by slower growth as opposed to reduced mutational supply. Furthermore, compensation of the 3DG64Sgrowth defect restored virulence, while compensation of the fidelity phenotype did not. Our data are consistent with the kinetic proofreading model for biosynthetic reactions and suggest that speed is more important than accuracy. In contrast to what has been suggested for many RNA viruses, we find that within host spread is associated with viral replicative speed and not standing genetic diversity.Author SummaryMutation rate evolution has long been a fundamental problem in evolutionary biology. The polymerases of RNA viruses generally lack proofreading activity and exhibit extremely high mutation rates. Since most mutations are deleterious and mutation rates are tuned by natural selection, we asked why hasn’t the virus evolved to have a lower mutation rate? We used experimental evolution and a murine infection model to show that RNA virus mutation rates may actually be too high and are not necessarily adaptive. Rather, our data indicate that viral mutation rates are driven higher as a result of selection for viruses with faster replication kinetics. We suggest that viruses have high mutation rates, not because they facilitate adaption, but because it is hard to be both fast and accurate.

scholarly journals Berbamine inhibits the infection of SARS-CoV-2 and flaviviruses by compromising TPRMLs-mediated endolysosomal trafficking of viral receptors

2020 ◽  
Author(s):  
Lihong Huang ◽  
Huanan Li ◽  
Terrence Tsz-Tai Yuen ◽  
Zuodong Ye ◽  
Qiang Fu ◽  
...  
Keyword(s):  
Viral Entry ◽  
Rna Viruses ◽  
Rna Virus ◽  
Antiviral Agents ◽  
Host Cells ◽  
Lethal Challenge ◽  
Benzylisoquinoline Alkaloids ◽  
The World ◽  
Positive Sense ◽  
Viral Receptors

Abstract Positive-sense single-stranded ((+)ss) RNA viruses are among the leading causes of human and animal infectious diseases in the world, but so far, no effective antiviral agents are available to treat these infections. Here we found that several bis- benzylisoquinoline alkaloids (e.g. berbamine), potently inhibited the infection of coronaviruses (e.g. SARS-CoV-2 and MERS-CoV), flaviviruses (e.g. JEV, ZIKV and DENV), and enteroviruses (e.g. EV-A71) in host cells. Moreover, berbamine protected mice from lethal challenge of JEV. We also found that berbamine inhibited TRPMLs (Ca2+ permeable non-selective cation channels in endosomes and lysosomes), which compromised the endolysosomal trafficking of viral receptors, such as ACE2 and DPP4. This led to the increased secretion of these receptors via extracellular vesicles and the concomitant decrease in their levels at the plasma membrane, thereby preventing (+)ss RNA viruses from entering the host cells. In summary, these results indicate that bis- benzylisoquinoline alkaloids such as berbamine, can act as a pan-anti-(+)ss RNA virus drug by inhibiting TPRMLs to prevent viral entry.

scholarly journals Rapid protein sequence evolution via compensatory frameshift is widespread in RNA virus genomes

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Dongbin Park ◽  
Yoonsoo Hahn
Keyword(s):  
Amino Acid ◽  
Large Scale ◽  
Rna Viruses ◽  
Rna Virus ◽  
Phylogenetic Analyses ◽  
Sequence Evolution ◽  
Protein Coding ◽  
Coding Sequences ◽  
Reading Frame ◽  
Nucleotide Insertions

Abstract Background RNA viruses possess remarkable evolutionary versatility driven by the high mutability of their genomes. Frameshifting nucleotide insertions or deletions (indels), which cause the premature termination of proteins, are frequently observed in the coding sequences of various viral genomes. When a secondary indel occurs near the primary indel site, the open reading frame can be restored to produce functional proteins, a phenomenon known as the compensatory frameshift. Results In this study, we systematically analyzed publicly available viral genome sequences and identified compensatory frameshift events in hundreds of viral protein-coding sequences. Compensatory frameshift events resulted in large-scale amino acid differences between the compensatory frameshift form and the wild type even though their nucleotide sequences were almost identical. Phylogenetic analyses revealed that the evolutionary distance between proteins with and without a compensatory frameshift were significantly overestimated because amino acid mismatches caused by compensatory frameshifts were counted as substitutions. Further, this could cause compensatory frameshift forms to branch in different locations in the protein and nucleotide trees, which may obscure the correct interpretation of phylogenetic relationships between variant viruses. Conclusions Our results imply that the compensatory frameshift is one of the mechanisms driving the rapid protein evolution of RNA viruses and potentially assisting their host-range expansion and adaptation.

scholarly journals Viral cross-linking and solid-phase purification enables discovery of ribonucleoprotein complexes on incoming RNA virus genomes

2020 ◽  
Author(s):  
Byungil Kim ◽  
Sarah Arcos ◽  
Katherine Rothamel ◽  
Manuel Ascano
Keyword(s):  
Protein Interactions ◽  
Rna Viruses ◽  
Solid Phase ◽  
Rna Virus ◽  
Host Protein ◽  
Host Cells ◽  
Cross Linking ◽  
Viral Genomes ◽  
Ribonucleoprotein Complexes ◽  
Virus Genomes

AbstractThe initial interactions between incoming, pre-replicated RNA virus genomes and host protein factors are important in infection and immunity. Yet there are no current methods to study these crucial events. We established VIR-CLASP (VIRal Cross-Linking And Solid-phase Purification) to identify the primary viral RNA-host protein interactions. First, host cells are infected with 4SU-labeled RNA viruses and irradiated with 365 nm light to crosslink 4SU-labeled viral genomes and interacting proteins from host or virus. The cross-linked RBPs are purified by solid-phase reversible immobilization (SPRI) beads with protein denaturing buffers, and then identified by proteomics. With VIR-CLASP, only the incoming viral genomes are labeled with 4SU, so cross-linking events specifically occur between proteins and pre-replicated viral genomic RNA. Since solid-phase purification under protein-denaturing conditions is used to pull-down total RNA and cross-linked RBPs, this facilitates investigation of potentially all RNA viruses, regardless of RNA sequence. Preparation of 4SU-labeled virus takes ∼7 days and VIR-CLASP takes 1 day.

scholarly journals Host proteostasis modulates influenza evolution

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Angela M Phillips ◽  
Luna O Gonzalez ◽  
Emmanuel E Nekongo ◽  
Anna I Ponomarenko ◽  
Sean M McHugh ◽  
...  
Keyword(s):  
Rna Viruses ◽  
Rna Virus ◽  
Viral Evolution ◽  
Virus Evolution ◽  
Critical Force ◽  
Host Cells ◽  
Mutation Rates ◽  
Biophysical Properties ◽  
And Function ◽  
Protein Variants

Predicting and constraining RNA virus evolution require understanding the molecular factors that define the mutational landscape accessible to these pathogens. RNA viruses typically have high mutation rates, resulting in frequent production of protein variants with compromised biophysical properties. Their evolution is necessarily constrained by the consequent challenge to protein folding and function. We hypothesized that host proteostasis mechanisms may be significant determinants of the fitness of viral protein variants, serving as a critical force shaping viral evolution. Here, we test that hypothesis by propagating influenza in host cells displaying chemically-controlled, divergent proteostasis environments. We find that both the nature of selection on the influenza genome and the accessibility of specific mutational trajectories are significantly impacted by host proteostasis. These findings provide new insights into features of host–pathogen interactions that shape viral evolution, and into the potential design of host proteostasis-targeted antiviral therapeutics that are refractory to resistance.

scholarly journals How do we transition from non-coding to coding?

2017 ◽  
Author(s):  
Jorge Ruiz-Orera ◽  
José Luis Villanueva-Cañas ◽  
William Blevins ◽  
M.Mar Albà
Keyword(s):  
De Novo ◽  
Gene Evolution ◽  
Purifying Selection ◽  
Neutral Evolution ◽  
Functional Protein ◽  
Protein Coding ◽  
Coding Sequences ◽  
Sequence Composition ◽  
Protein Coding Genes ◽  
Small Proteins

Recent years have witnessed the discovery of protein–coding genes which appear to have evolved de novo from previously non-coding sequences. This has changed the long-standing view that coding sequences can only evolve from other coding sequences. However, there are still many open questions regarding how new protein-coding sequences can arise from non-genic DNA. Two prerequisites for the birth of a new functional protein-coding gene are that the corresponding DNA fragment is transcribed and that it is also translated. Transcription is known to be pervasive in the genome, producing a large number of transcripts that do not correspond to conserved protein-coding genes, and which are usually annotated as long non-coding RNAs (lncRNA). Recently, sequencing of ribosome protected fragments (Ribo-Seq) has provided evidence that many of these transcripts actually translate small proteins. We have used mouse non-synonymous and synonymous variation data to estimate the strength of purifying selection acting on the translated open reading frames (ORFs). Whereas a subset of the lncRNAs are likely to actually be true protein-coding genes (and thus previously misclassified), the bulk of lncRNAs code for proteins which show variation patterns consistent with neutral evolution. We also show that the ORFs that have a more favorable, coding-like, sequence composition are more likely to be translated than other ORFs in lncRNAs. This study provides strong evidence that there is a large and ever-changing reservoir of lowly abundant proteins; some of these peptides may become useful and act as seeds for de novo gene evolution.

scholarly journals Non-neutral processes drive the nucleotide composition of non-coding sequences in Drosophila

2008 ◽  
Vol 4 (4) ◽  
pp. 438-441 ◽  
Author(s):  
Penelope R Haddrill ◽  
Brian Charlesworth
Keyword(s):  
Gene Conversion ◽  
X Chromosome ◽  
Base Composition ◽  
Gc Content ◽  
Nucleotide Composition ◽  
Mutational Bias ◽  
Base Pairs ◽  
Coding Sequences ◽  
Biased Gene Conversion ◽  
Gc Contents

The nature of the forces affecting base composition is a key question in genome evolution. There is uncertainty as to whether differences in the GC contents of non-coding sequences reflect differences in mutational bias, or in the intensity of selection or biased gene conversion. We have used a polymorphism dataset for non-coding sequences on the X chromosome of Drosophila simulans to examine this question. The proportion of GC→AT versus AT→GC polymorphic mutations in a locus is correlated with its GC content. This implies the action of forces that favour GC over AT base pairs, which are apparently strongest in GC-rich sequences.

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