[POSSIBLE PATHWAYS OF CHEMICAL EVOLUTION OF VIRUSES AND NUCLEIC ACIDS].
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Biological Evolution↗
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Evolution of sex and the molecular clock in RNA viruses.
Although there exist many hypotheses for the advantage of sexual reproduction, Muller's ratchet is one that has received recent attention as an explanation for the evolution of sex in RNA viruses. Muller's ratchet provides for an advantage of sex when the rate of deleterious mutations is high and population size is small. A small population size intensifies genetic drift, which can lead to the random loss of genomes that are free of deleterious mutations. Sex becomes advantageous because it can re-create, through genetic exchange, genomes with fewer or no mutations. RNA viruses may be subject to Muller's ratchet because they have very high mutation rates and they may experience genetic drift if their populations are forced through small bottlenecks during infection. This review discusses the results of laboratory studies examining the possibility of an advantage of sex through Muller's ratchet in RNA viruses. Data from studies of wild populations of RNA viruses are also considered, and a model is presented for how an observed pattern of molecular evolution (or the molecular clock) in wild populations may be explained by Muller's ratchet (or a similar process) and the addition of compensatory mutations to Ohta's model of evolution by slightly deleterious mutations.
Evolution, Molecular↗
Secondary structure-dependent evolution of Cymbidium ringspot virus defective interfering RNA.
Mutational analysis of defective interfering (DI) RNAs of Cymbidium ringspot virus (CymRSV) was used to study the mechanism of DI RNA evolution. It was shown that a highly base-paired structure in the 3' region of the longer DI RNA directed the formation of smaller DI RNA molecules. Mutations which increased the stability of the computer-predicted, highly structured 3' region of the longest DI RNA of CymRSV significantly enhanced the generation and accumulation of the smaller derivatives. Sequence analysis of smaller progeny molecules revealed that the highly base-paired region was deleted from the precursor DI RNA. Moreover, sites of recombination were found in other regions of the DI RNA progenies due to transposition of the highly base-paired structure. It is likely that the deletion event was structure- and not sequence-specific, and operated when a foreign sequence containing a 37-nt-long base-paired stem was inserted at the appropriate position of DI RNA.
Base Sequence↗
[Variability and development of viral populations: assessment and implications].
RNA virus populations consist of complex distributions of closely related but not identical genomes known as viral quasi-species. The quasi-species concept describes the dynamics of these genomes subjected to a continuous process of variation, competition, and selection. Quasi-species dynamics has broad implications not only in the understanding of the molecular mechanisms underlying adaptation of RNA viruses but also in the design of strategies for control and prevention of viral disease. Viral load and genetic heterogeneity have a determinant influence on the adaptation of RNA virus to their environment. Vaccines designed to control diseases caused by highly variable viruses must contain several B and T epitopes to provide an ample and diversified immune response. Similarly, antiviral drugs should be used in combination therapy to minimize selection of resistant viruses. The theoretical model of quasi-species has opened the way for new antiviral therapies based on augmentation of the mutation rate during replication of viral RNA. Finally the quasi-species concept provides the basis for defining the selective factors that could influence the evolution of RNA virus and promote the emergence or reemergence of viral diseases.
Antibiosis↗
Viral mutation accelerated by nitric oxide production during infection in vivo.
Nitric oxide (NO), superoxide (O(2)(-)), and their reaction product peroxynitrite (ONOO(-)) are generated in excess during a host's response against viral infection, and contribute to viral pathogenesis by promoting oxidative stress and tissue injury. Here we demonstrate that NO and peroxynitrite greatly accelerates the mutation of Sendai virus (SeV), a nonsegmented negative-strand RNA virus, by using green fluorescent protein (GFP) inserted into and expressed by a recombinant SeV (GFP-SeV) as an indicator for mutation. GFP-SeV mutation frequencies were much higher in the wild-type mice than in those lacking inducible NO synthase, suggesting that mutation of the virus in vivo is NO dependent. High levels of NO and NO-mediated oxidative stress were induced by GFP-SeV infection in the lung of the wild-type mice, but not in the iNOS-deficient mice, as evidenced by electron spin resonance spectroscopy and immunohistochemical analysis for nitrotyrosine formation as well as histopathological examination. Furthermore, peroxynitrite, an NO-derived reactive nitrogen intermediate, enhanced viral mutation in vitro. These results indicate that the oxidative stress induced by NO produced during the natural course of viral infection increases mutation, expands the quasispecies spectrum, and facilitates evolution of RNA viruses.
Animals↗
Characterization of new recombinant noroviruses.
Noroviruses are important etiologic agents of acute gastroenteritis and show great genetic diversity. To characterize more fully previously detected strains that could not be assigned unequivocally to one particular genotype based on the RNA polymerase, we have sequenced a region in the capsid gene and, in some cases, in the junction between open reading frame 1 (ORF 1) and ORF 2. The results allowed us to identify several recombinant noroviruses: GGIIb viruses were detected for the first time in France in August 2000 and then spread through France and to Europe during the following winter. Here we present the characterization of three other probable GII recombinants which showed different phylogenetic positions depending on their ORF 1 and ORF 2 sequences. Analysis of the region located between ORF 1 and ORF 2 by a nucleotide identity window search showed a sudden shift in similarities. Moreover, recombination breakpoints were identified upstream and downstream of the beginning of ORF 2 by using a statistical test, thus confirming the involvement of this region in recombination. Unlike GGIIb, the three recombinants described here do not seem to have diffused widely in the community: one was found in a waterborne outbreak, and the other two were found in sporadic cases. Recombination is important for the evolution of RNA viruses and has already been described for noroviruses. Our results suggest that recombination is not a rare phenomenon among noroviruses, but not all these presumed recombinants that formed during RNA replication are able to spread widely.
Base Sequence↗
The evolution of morbilliviruses: a comparison of nucleocapsid gene sequences including a porpoise morbillivirus.
Sequence data for the nucleocapsid protein (N) gene of the porpoise morbillivirus including the very conserved middle section of the protein and the hypervariable C terminus are reported. Analysis of dissimilarity indices based on an alignment of the N proteins of various morbilliviruses identifies a variable region of the N protein from amino acids residues 121 to 145 and a hypervariable part from amino acids 400 to 517. This type of analysis can be usefully applied when protein sequences of five or more morbillivirus species are available. Regions of variability between species identified by this index also represent regions of variation within one species e.g. measles virus (MV). Hence, comparative analysis of different morbilliviruses provides an insight into the potentially variable parts of viral proteins. From the great and unexplained nucleotide sequence conservation observed within MV, it would appear that the various morbilliviruses have diverged from each other a very long time ago. However, the data do not yet allow us to estimate the time span of these divergences. The relatedness and the number of different morbillivirus species provides a unique database for study of the evolution of RNA viruses.
Amino Acid Sequence↗
RNA recombination in vivo in the absence of viral replication.
To study fundamental aspects of RNA recombination, an in vivo RNA recombination system was established. This system allowed the efficient generation of recombinant cytopathogenic pestiviruses after transfection of synthetic, nonreplicatable, subgenomic transcripts in cells infected with a replicating noncytopathogenic virus. Studies addressing the interplay between RNA recombination and replication revealed that cotransfection of noninfected cells with various pairs of nonreplicatable RNA derivatives also led to the emergence of recombinant viral genomes. Remarkably, homologous and nonhomologous recombination occurred between two overlapping transcripts, each lacking different essential parts of the viral RNA-dependent RNA polymerase (RdRp) gene. Apart from the generally accepted viral replicative copy choice recombination, our results prove the existence of a viral RdRp-independent mechanism of RNA recombination that occurs in vivo. It appears likely that such a mechanism not only contributes to the evolution of RNA viruses but also leads to the generation of recombinant cellular RNAs.
Amino Acid Sequence↗
Homologous sequences in non-structural proteins from cowpea mosaic virus and picornaviruses.
Computer analyses have revealed sequence homology between two non-structural proteins encoded by cowpea mosaic virus (CPMV), and corresponding proteins encoded by two picornaviruses, poliovirus and foot-and-mouth disease virus. A region of 535 amino acids in the 87-K polypeptide from CPMV was found to be homologous to the RNA-dependent RNA polymerases from both picornaviruses, the best matches being found where the picornaviral proteins most resemble each other. Additionally, the 58-K polypeptide from CPMV and polypeptide P2-X from poliovirus contain a conserved region of 143 amino acids. Based on the homology observed, a genetic map of the CPMV genome has been constructed in which the 87-K polypeptide represents the core polymerase domain of the CPMV replicase. These results have implications for the evolution of RNA viruses, and mechanisms are discussed which may explain the existence of homology between picornaviruses (animal viruses with single genomic RNAs) and comoviruses (plant viruses with two genomic RNAs).
Journal Article↗
Role of recombination in the evolution of natural populations of Cucumber mosaic virus, a tripartite RNA plant virus.
The role of recombination in the evolution of Cucumber mosaic virus (CMV) was analyzed in a collection of Spanish isolates from 1989 to 2002. Isolates were characterized by ribonuclease protection assay using six RNA probes, two for each of the three genomic RNAs, which allowed the identification of the analyzed regions as belonging to CMV isolates in subgroups IA, IB, and II. Most isolates belonged to subgroups IA (64%) and IB (12%), 5% were reassortants among subgroups IA, IB, or II, and 17% were recombinants between these groups. Recombinants at RNA3 were significantly more frequent than recombinants at RNAs 1 and 2. One IB-IA recombinant RNA3 was as frequent in central Spain as the IA RNA3. The genetic structure of the virus population suggested that reassortants and most recombinant genotypes were selected against and was consistent with a higher biological cost of reassortment than recombination. Data also suggest that recombinants that encode hybrid proteins are at a higher disadvantage than recombinants that exchange whole ORFs.
Cucumovirus↗
Two domains distantly related to protein-tyrosine kinases in the vesicular stomatitis virus polymerase.
We have carried out an exhaustive search for amino acid sequence similarities between vesicular stomatitis virus (VSV) proteins and database entries. Unexpectedly, we found that the L polymerase protein contains two blocks of sequence (residues 725-1102 and 1291-1671) with distant but statistically significant similarity to the catalytic domain of tyrosine-specific protein kinases. The first kinase-like region is most similar to members of the Abl subfamily, Fes and Fps (26.6% and 27.3% identity, respectively), whereas the second region is closest to members of the platelet-derived growth factor receptor (PDGFR) subfamily, PDGFR and Kit (30.4% and 25.9% identity, respectively). Multiple alignment of the catalytic domain of these kinases to all three rhabdovirus L protein sequences available (VSV Indiana, VSV New Jersey, and rabies) revealed that the polymerases contain many but not all residues well conserved in the protein kinase family. Similarity was highest for VSV Indiana and lowest for rabies. We conclude that the kinase-like regions in the rhabdoviral L proteins are probably very distantly related to the protein kinase family. The similarities could either reflect contemporary protein kinase activity or represent some other function(s) associated with these large multifunctional polymerase proteins. Our findings also shed new light on questions of the origins and evolution of RNA viruses.
Amino Acid Sequence↗
3'-terminal sequence of the plum pox virus PS and ŏ6 isolates: evidence for RNA recombination within the potyvirus group.
The sequence of the 3'-terminal 1768 nucleotides of the PS and ŏ6 isolates of plum pox virus (PPV) has been determined and compared with that of the equivalent regions of other PPV isolates sequenced previously. The sequenced region is part of the PPV open reading frame encoding the last 186 amino acids of the NIb protein and the coat protein (CP, 330 amino acids), followed by a non-coding region of 220 nucleotides and a poly(A) tail. PPV-PS and PPV(-)ŏ6, just like PPV-El Amar, show rather high levels of nucleotide diversity in the sequence encoding the C-terminal region of the NIb protein (19.4 to 31%) and the N terminus of CP (22.8 to 41.1%) when compared with PPV-Rankovic, PPV-D and PPV-NAT, whereas the level of diversity in the rest of the CP sequence and the 3' non-coding region is low (8 to 10.8% and 5.5 to 7.7%, respectively). However, the first 429 sequenced nucleotides of PPV(-)ŏ6 are very similar to those of the PPV-Rankovic, PPV-D and PPV-NAT isolates, whereas the rest of the sequence clearly resembles PPV-PS. Thus, PPV(-)ŏ6 seems to be the result of a natural recombination event between two wild strains of PPV. To our knowledge this is the first evidence of homologous RNA recombination (a process which could play an important role in the evolution of RNA viruses) within the potyvirus group.
Amino Acid Sequence↗
[Quasispecies and molecular evolution of viruses].
Ribonucleic acid (RNA) viruses evolve as complex distributions of genetically different but closely related variants termed viral quasispecies. The precise genome of a quasispecies cannot be defined, since the consensus genome is an average of many variants. The dynamics of quasispecies has considerable implications for the understanding of the adaptability and pathogenic potential of viruses, and in addition, for the design of preventive and therapeutic measures for the diseases caused by these viruses. The authors summarise current knowledge on the structure of quasispecies, and the biological implications of this structure.
Adaptation, Biological↗
Evolution by small steps and rugged landscapes in the RNA virus phi6.
Fisher's geometric model of adaptive evolution argues that adaptive evolution should generally result from the substitution of many mutations of small effect because advantageous mutations of small effect should be more common than those of large effect. However, evidence for both evolution by small steps and for Fisher's model has been mixed. Here we report supporting results from a new experimental test of the model. We subjected the bacteriophage phi6 to intensified genetic drift in small populations and caused viral fitness to decline through the accumulation of a deleterious mutation. We then propagated the mutated virus at a range of larger population sizes and allowed fitness to recover by natural selection. Although fitness declined in one large step, it was usually recovered in smaller steps. More importantly, step size during recovery was smaller with decreasing size of the recovery population. These results confirm Fisher's main prediction that advantageous mutations of small effect should be more common. We also show that the advantageous mutations of small effect are compensatory mutations whose advantage is conditional (epistatic) on the presence of the deleterious mutation, in which case the adaptive landscape of phi6 is likely to be very rugged.
Bacteriophage phi 6↗
Influenza A virus evolution: complete sequences of influenza A/NT/60/68 RNA segment 3 and its predicted acidic P polypeptide compared with those of influenza A/PR/8/34.
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Amino Acid Sequence↗
Viral evolution and interferon resistance of hepatitis C virus RNA replication in a cell culture model.
Hepatitis C virus (HCV) replicates through an error-prone process that may support the evolution of genetic variants resistant to the host cell antiviral response and interferon (IFN)-based therapy. We evaluated HCV-IFN interactions within a long-term culture system of Huh7 cell lines harboring different variants of an HCV type 1b subgenomic RNA replicon that differed at only two sites within the NS5A-encoding region. A replicon with a K insertion at HCV codon 2040 replicated efficiently and exhibited sequence stability in the absence of host antiviral pressure. In contrast, a replicon with an L2198S point mutation replicated poorly and triggered a cellular response characterized by IFN-beta production and low-level IFN-stimulated gene (ISG) expression. When maintained in long term-culture, the L2198S RNA evolved into a stable high-passage (HP) variant with six additional point mutations throughout the HCV protein-encoding region that enhanced viral replication. The HP RNA transduced Huh7 cells with more than 1,000-fold greater efficiency than its L2198S progenitor or the K2040 sequence. Replication of the HP RNA resisted suppression by IFN-alpha treatment and was associated with virus-directed reduction in host cell expression of ISG56, an antagonist of HCV RNA translation. Accordingly, the HP RNA was retained within polyribosome complexes in vivo that were refractory to IFN-induced disassembly. These results identify ISG56 as a translational control effector of the host response to HCV and provide direct evidence to link this response to viral sequence evolution, ISG regulation, and selection of the IFN-resistant viral phenotype.
Biological Evolution↗
Sequence of the genome RNA of rubella virus: evidence for genetic rearrangement during togavirus evolution.
The nucleotide sequence of the rubella virus (RUB) genomic RNA was determined. The RUB genomic RNA is 9757 nucleotides in length [excluding the poly(A) tail] and has a G/C content of 69.5%, the highest of any RNA virus sequenced to data. The RUB genomic RNA contains two long open reading frames (ORFs), a 5'-proximal ORF of 6656 nucleotides and a 3'-proximal ORF of 3189 nucleotides which encodes the structural proteins. Thus, the genomic organization of RUB is similar to that of alphaviruses, the other genus of the Togavirus family, and the 5'-proximal ORF of RUB therefore putatively codes for the nonstructural proteins. Sequences homologous to three regions of nucleotide sequence highly conserved among alphaviruses (a stem-and-loop structure at the 5' end of the genome, a 51-nucleotide conserved sequence near the 5' end of the genome, and a 20-nucleotide conserved sequence at the subgenomic RNA start site) were found in the RUB genomic RNA. Amino acid sequence comparisons between the nonstructural ORF of RUB and alphaviruses revealed only one short (122 amino acids) region of significant homology, indicating that these viruses are only distantly related. This region of homology is located at the NH2 terminus of nsP3 in the alphavirus genome. The RUB nonstructural protein ORF contains two global amino acid motifs conserved in a large number of positive-polarity RNA viruses, a motif indicative of helicase activity and a motif indicative of replicase activity. The order of the helicase motif and the nsP3 homology region in the RUB genome is reversed with respect to the alphavirus genome indicating that a genetic rearrangement has occurred during the evolution of these viruses.
Amino Acid Sequence↗
A positive-sense single-stranded RNA virus acquired a negative-sense open reading frame through recombination.
Although positive- and negative-sense single-stranded RNA viruses are ubiquitous in nature, there is currently no evidence of recombination or reassortment between viruses with these two major forms of genome organization. Here, we describe the discovery of brine shrimp virga-like virus 1 (BSVV1), a novel positive-sense single-stranded RNA virus with a recombinant genome structure derived from two viral phyla with differing genome organizations. The genome of BSVV1 comprises three open reading frames (ORFs). ORF1 resembles the RNA-dependent RNA polymerase of Ips virga-like virus 1 (a positive-sense RNA virus), while ORF2, transcribed in the positive orientation, is related to the glycoprotein of Hubei bunya-like virus 10 and other negative-sense RNA viruses. The predicted ORF3 was unique to BSVV1 without known homologs identified. The presence of the three protein products was verified by mass spectrometry. Notably, our analysis also revealed that BSVV1 is geographically widespread and found in brine shrimp from at least eight countries on four continents. In addition, BSVV1 was successfully cultured and proliferated to high viral loads during brine shrimp development. In sum, we provide compelling evidence of an ancient recombination event between negative- and positive-sense single-stranded RNA viruses, enriching our understanding of the evolution of genome structures in RNA viruses.
Open Reading Frames↗