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Given the extraordinarily high mutation rate of viruses, particularly those with RNA genomes, it is not surprising that new viruses are continually evolving. However, the symptomatology of old viral diseases has remained stable for centuries. The combination of genetic and ecological factors that constrain as well as facilitate the emergence of new viruses is analyzed.
Whereas most mycoviruses lead 'secret lives', some reduce the ability of their fungal hosts to cause disease in plants. This property, known as hypovirulence, has attracted attention owing to the importance of fungal diseases in agriculture and the limited strategies that are available for the control of these diseases. Using one pathogen to control another is appealing, both intellectually and ecologically. The recent development of an infectious cDNA-based reverse genetics system for members of the Hypoviridae mycovirus family has enabled the analysis of basic aspects of this fascinating virus-fungus-plant interaction, including virus-host interactions, the mechanisms underlying fungal pathogenesis, fungal signalling pathways and the evolution of RNA silencing. Such systems also provide a means for engineering mycoviruses for enhanced biocontrol potential.
Recombination in RNA viruses is considered to play a major role as a driving force in virus variability to counterbalance loss in fitness that can be due to the accumulation of detrimental mutations. Studies on mixed infections are pertinent for understanding the role of recombination in virus evolution. They also provide important baseline information for studying the biosafety of plants expressing viral sequences. To investigate the possibility of RNA recombination occurrence between two sobemoviruses under little or no selection pressure, we co-infected test plants with Cocksfoot mottle virus (CfMV) and Ryegrass mottle virus (RGMoV). CfMV and RGMoV were selected because of their overlapping host range and geographical distribution. First, symptom development of both viruses in barley (Hordeum vulgare) and oat (Avena sativa) was examined. Both viruses generated quite strong infection symptoms in oat, but synergism was not detected. RGMoV was lethal for barley, whereas CfMV infection in barley was nearly symptomless. RT-PCR analysis revealed 100% infection with both viruses in oat but not in barley. Therefore, an RNA recombination study of CfMV and RGMoV was performed in oat. 105 plants were co-inoculated with both viruses and putative recombinational hot spot regions were screened for recombination events by RT-PCR analysis at a sensitivity level down to 0.1-100 pg of viral genomic RNA. No recombination events between the two sobemoviruses were detected.
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RNA recombination, which is thought to occur due to replicase errors during viral replication, is one of the major driving forces of virus evolution. In this article, we show evidence that the replicase proteins of Cucumber necrosis virus, a tombusvirus, are directly involved in RNA recombination in vivo. Mutations within the RNA-binding domains of the replicase proteins affected the frequency of recombination observed with a prototypical defective-interfering (DI) RNA, a model template for recombination studies. Five of the 17 replicase mutants tested showed delay in the formation of recombinants when compared to the wild-type helper virus. Interestingly, two replicase mutants accelerated recombinant formation and, in addition, these mutants also increased the level of subgenomic RNA synthesis (Virology 308 (2003), 191-205). A trans-complementation system was used to demonstrate that mutation in the p33 replicase protein resulted in altered recombination rate. Isolated recombinants were mostly imprecise (nonhomologous), with the recombination sites clustered around a replication enhancer region and a putative cis-acting element, respectively. These RNA elements might facilitate the proposed template switching events by the tombusvirus replicase. Together with data in the article cited above, results presented here firmly establish that the conserved RNA-binding motif of the replicase proteins is involved in RNA replication, subgenomic RNA synthesis, and RNA recombination.
The first demonstration on the aminoacylation capacity of the RNA genome of a plant virus appeared more than 25 years ago. Shortly thereafter, aminoacylation of the RNA genome of a number of other plant viruses was observed. This led to considerable work on the tRNA-like region of these viral RNAs, and to the first demonstration of the presence of pseudoknots in their folding pattern. In spite of the vast amount of efforts put into trying to understand the reason for the aminoacylation capacity of certain viral RNA genomes, as yet no clear general conclusion emerges. It rather looks as though the reason for aminoacylation may be different for different viruses, and that aminoacylation may operate at different levels in the virus life cycle. Given that certain RNA viruses possess structures which resemble that of tRNAs at their 5'- or 3'-termini, it is most likely that convergent evolution may have dominated the appearance of such structures in the virus world.
We have identified a cDNA clone that encodes a protein with high sequence homology to Argonaute proteins of mammals and Drosophila melanogaster. The cDNA of Penaeus monodon (Pm Ago) consisted of 3178 nucleotides encoding 939-amino acid residues with a calculated molecular weight of 104 kDa. The primary structure of Pm Ago showed the presence of two signature domains, PAZ and PIWI domains that exhibit highest homology to their counterparts in D. melanogaster. The inferred protein sequence of Pm Ago was 80.8% identical with D. melanogaster and 82.1% identical with Anopheles gambiae Ago proteins. Phylogenetic analysis of Pm Ago with other invertebrate and vertebrate Argonaute proteins suggested that Pm Ago belongs to the Ago1 subfamily that plays crucial roles in stem cell differentiation or RNA interference (RNAi). Semi-quantitative RT-PCR analysis showed that the gene is highly expressed in the lymphoid organ and moderately expressed in intestine, muscle, pleopods and hemocytes. The expression of Pm Ago1 mRNA was 2-3-fold increased during the early period of viral infection but declined rapidly at 30 hour post infection. By contrast, infection of shrimp by a bacterial pathogen, Vibrio harveyi did not induce a reduction of Pm Ago1 mRNA suggesting that its expression is associated with virus infection.
Viruses have served as excellent model systems in which to study biological self-organization. Purified virion structural constituents have been shown to self-assemble into particles that can initiate a productive infection in the host cell resulting in the release of progeny virions. Accumulating information on virus structures and assembly principles has revealed unexpected similarities between viruses that infect hosts as diverse as bacteria and humans, suggesting that these viruses had an early common ancestor. I will describe, in more detail, the assembly pathway of a complex double-stranded RNA bacterial virus. In this system, infectious viral particles are produced starting from purified protein and nucleic acid constituents through an elaborate self-assembly, RNA-packaging and synthesis pathway.
The great adaptability shown by RNA viruses is a consequence of their high mutation rates. Here we investigate the kinetics of virus fitness gains during repeated transfers of large virus populations in cell culture. Results always show that fitness increases exponentially. Low fitness clones exhibit regular increases observed as biphasic periods of exponential evolutionary improvement, while neutral clones show monophasic kinetics. These results are significant for RNA virus epidemiology, optimal handling of attenuated live virus vaccines, and routine laboratory procedures.
The main tenet of the neutral theory is that the great majority of evolutionary changes at the molecular level are caused not by Darwinian selection but by random fixation of selectively neutral (or very nearly neutral) alleles through random sampling drift under continued mutation pressure. The theory also asserts that the majority of protein and DNA polymorphisms are selectively neutral, and that they are maintained in the species by mutational input balanced by random extinction rather than by "balancing selection." The neutral theory is based on simple assumptions. This enabled us to develop mathematical theories (using the diffusion equation method) that can treat these phenomena in quantitative terms and that permit theory to be tested against actual observations. Although the neutral theory has been severely criticized by the neo-Darwinian establishment, supporting evidence has accumulated over the last 20 years. In particular, the recent burst of DNA sequence data helped to strengthen the theory a great deal. I believe that the neutral theory triggered reexamination of the traditional "synthetic theory of evolution." In this paper, I review the present status of the neutral theory, including discussions of such topics as "molecular evolutionary clock," very high evolutionary rates observed in RNA viruses, a deviant coding system found in Mycoplasm together with the concept of mutation-driven neutral evolution, and the origin of life. I also present a worldview based on the conception of what I call "survival of the luckiest."
This paper describes various hypotheses for the origin of viruses, prerequisites for the introduction of a virus into a host population, and the concerted evolution of virus and host. In general, viruses evolve through mutations and genetic recombinations. Selection pressure is exerted by various host defence mechanisms and possible ways of virus transmission. The virus variants showing a high reproduction rate without killing their host are most likely to be selected for. In addition, the viral infection vice versa exert a selection pressure on the host population resulting in the elimination of highly susceptible individuals and an increased number of resistant individuals. The apparent consequence is a tendency for the virus to be less virulent and the host to be more resistant.
The family Filoviridae contains extremely pathogenic human viruses causing a fulminating, febrile hemorrhagic disease. Filoviruses are enveloped, filamentous particles with a nonsegmented negative-strand RNA genome showing the gene arrangement 3'-NP-VP35-VP40-GP-VP30-VP24-L-5'. Genes are flanked by highly conserved transcriptional signals and are generally separated by variable intergenic regions. They are transcribed into monocistronic polyadenylated messenger RNAs which contain relatively long 5' and 3' untranslated regions. Seven structural proteins are encoded by the genome of which four form the helical nucleocapsid (NP-VP35-VP30-L), two are membrane-associated (VP40-VP24), and one is a transmembrane glycoprotein (GP). Comparison of filovirus genomes with those of other nonsegmented negative-strand RNA viruses suggest comparable mechanisms of transcription and replication and a common evolutionary lineage for all these viruses. Sequence analyses of single genes, however, showed that filoviruses are more closely related to paramyxoviruses, particularly human respiratory syncytial virus. These data support the concept of the taxonomic order Mononegavirales for all nonsegmented negative-strand RNA viruses and the classification of Marburg virus, Ebola virus, and Reston virus in the family Filoviridae, separate from the families Paramyxoviridae and Rhabdoviridae.
Evolution of viruses in the eastern equine encephalomyelitis (EEE) complex was studied by analyzing RNA sequences and oligonucleotide fingerprints from isolates representing the North and South American antigenic varieties. By using homologous sequences of Venezuelan equine encephalomyelitis virus as an outgroup, phylogenetic trees revealed three main EEE virus monophyletic groups. A North American variety group included all isolates from North America and the Caribbean. One South American variety group included isolates from the Amazon basin in Brazil and Peru, while the other included strains from Argentina, Guyana, Ecuador, Panama, Trinidad, and Venezuela. No evidence of heterologous recombination was obtained when three separate regions of the EEE virus genome were analyzed independently. Estimates of the overall rate of EEE virus evolution (nucleotide substitution) were 1.6 x 10(-4) substitution per nucleotide per year for the North American group and 4.3 x 10(-4) for the Argentina-Panama South American group. Evolutionary rate estimates for the North American group increased over 10-fold (from about 2 x 10(-5) to 4 x 10(-4)) concurrent with divergence of two monophyletic groups during the early 1970s. The North and South American antigenic varieties diverged roughly 1,000 years ago, while the two main South American groups diverged about 450 years ago. Analysis of multiple strains isolated from an upstate New York transmission focus during the same years suggested that, in certain locations, EEE virus may be relatively isolated for short time periods.
Here we explore the adaptation of vesicular stomatitis RNA virus to different population densities and the existence of a trade-off between r- and K-selection. Increasing population density represents a challenging special situation for viruses, since different selective pressures arise depending upon the number of available host cells per virus. Adaptation to low density represents a prototypical case of r-selection, where the optimal evolutionary solution should be a high replication rate. Adaptation to high density represents a case of K-selection. In this case, genotypes optimally exploiting the resources, instead of faster replicating ones, should be selected. Five independent populations were maintained in two environments, called r and K, for 100 generations. In the r environment, effective population size was small. In contrast, the effective population size in the K environment was large. Our results support the existence of the expected trade-offs between these two types of selections. Viral populations evolved at low density performed worse as population density increased. Similarly, viral populations evolved at high density showed reduced fitness at low density. Finally, we compare our results with those obtained for other RNA viruses.
The nucleotide sequences of RNA segment 5 of an avian influenza A virus, A/Mallard/NY/6750/78 (H2N2), and a human influenza A virus, A/Udorn/307/72 (H3N2), were determined and the deduced amino acid sequences of the nucleoprotein (NP) of these viruses were compared to two other avian and two other human influenza A NP sequences. The results indicated that there are separate classes of avian and human influenza A NP genes that can be distinguished on the basis of sites containing amino acids specific for avian and human influenza viruses and also by amino acid composition. The human influenza A virus NP genes appear to follow a linear pathway of evolution with the greatest homology (96.9%) between A/NT/60/68 (H3N2) and A/Udorn/72, isolated only 4 years apart, and the least homology (91.1%) between A/PR/8/34 (H1N1) and A/Udorn/72, isolated 38 years apart. Furthermore, 84% of the nucleotide substitutions between A/PR/8/34 and A/NT/60/68 are preserved in the NP gene of the A/Udorn/72 strain. In contrast, a distinct linear pathway is not present in the avian influenza NP genes since the homology (90.3%) between the two avian influenza viruses A/Parrot/Ulster/73 (H7N1) and A/Mallard/78 isolated only 5 years apart is not significantly greater than the homology (90.1%) between strains A/FPV/Rostock/34 and A/Mallard/78 isolated 44 years apart and only 49% of the nucleotide substitutions between A/FPV/34 and A/Parrot/73 are found in A/Mallard/78. A determination of the rate of evolution of the human influenza A virus NP genes suggested that there were a greater number of nucleotide substitutions per year during the first several years immediately following the emergence of a new subtype in 1968.
The monopartite genome of Nudaurelia beta virus, the type species of the Betatetravirus genus of the family Tetraviridae, consists of a single-stranded positive-sense RNA (ss+RNA) of 6625 nucleotides containing two open reading frames (ORFs). The 5' proximal ORF of 5778 nucleotides encodes a protein of 215 kDa containing three functional domains characteristic of RNA-dependent RNA polymerases of ss+RNA viruses. The 3' proximal ORF of 1836 nucleotides, which encodes the 66-kDa capsid precursor protein, overlaps the replicase gene by more than 99% (1827 nucleotides) and is in the +1 reading frame relative to the replicase reading frame. This capsid precursor is expressed via a 2656-nucleotide subgenomic RNA. The 3' terminus of the genome can be folded into a tRNA-like secondary structure that has a valine anticodon; the tRNA-like structure lacks a pseudoknot in the aminoacyl stem, a feature common to both genera of tetraviruses. Comparison of the sequences of Nudaurelia beta virus and another member of the Tetraviridae, Helicoverpa armigera stunt virus, which is in the genus Omegatetravirus, shows identities of 31.6% for the replicase and 24.5% for the capsid protein. The viruses in the genera Betatetravirus and Omegatetravirus of the Tetraviridae are clearly related but show significant differences in their genome organization. It is concluded that the ancestral virus with a bipartite genome, as found in the genus Omegatetravirus, likely evolved from a virus with an unsegmented genome, as found in the genus Betatetravirus, through evolution of the subgenomic RNA into a separate genomic component, with the accompanying loss of the capsid gene from the longer genomic RNA.
The division of the living world into three cellular domains, Archaea, Bacteria, and Eukarya, is now generally accepted. However, there is no consensus about the evolutionary relationships among these domains, because all of the proposed models have a number of more or less severe pitfalls. Another drawback of current models for the universal tree of life is the exclusion of viruses, otherwise a major component of the biosphere. Recently, it was suggested that the transition from RNA to DNA genomes occurred in the viral world, and that cellular DNA and its replication machineries originated via transfers from DNA viruses to RNA cells. Here, I explore the possibility that three such independent transfers were at the origin of Archaea, Bacteria, and Eukarya, respectively. The reduction of evolutionary rates following the transition from RNA to DNA genomes would have stabilized the three canonical versions of proteins involved in translation, whereas the existence of three different founder DNA viruses explains why each domain has its specific DNA replication apparatus. In that model, plasmids can be viewed as transitional forms between DNA viruses and cellular chromosomes, and the formation of different levels of cellular organization (prokaryote or eukaryote) could be traced back to the nature of the founder DNA viruses and RNA cells.
Evolution guides biological systems to populate ecological niches, with viruses among the most successful examples of this principle. Viruses evolved over billions of years to efficiently transfer genetic information. Although viruses are highly diverse, most have converged towards remarkable similarity in the size and shape of their capsids1,2. By contrast, generative models for protein design enable the creation of protein architectures that are absent from nature3-5. Here we investigate whether protein assemblies designed by artificial intelligence can be functionalized to construct nucleic acid transport vehicles that are independent of evolutionary trajectories. By combining natural protein domains with synthetic protein assemblies, we create more than 100 bottom-up RNA transfer vehicles with unique sizes and shapes. These vehicles surpass the RNA transfer efficiency of widely used delivery vehicles by several orders of magnitude. In addition, we demonstrate that their tropism can be programmed by incorporation of computationally designed peptide binders and use them to deliver therapeutically relevant cargo RNAs into a wide range of cellular models. We show the in vivo biodistribution of one of these vehicles in a mouse at near-single-cell resolution, confirm its safety, and use it to perform a gene-editing treatment strategy for Duchenne muscular dystrophy in patient-derived cells and a pig. Our work demonstrates how proteins created by generative artificial intelligence can be harnessed for the rational engineering of RNA transport systems with the desired properties by overcoming the limitations of natural protein diversity.