Examination of this region revealed two differential properties. To more directly test the effect of RNA structure on HIV-1 RT fidelity, we used in vitro polymerization assays with two different templates: a random sequence and RNA from potato spindle tuber viroid, which shows a marked, stem-like secondary structure [ ].
Using a conceptually similar approach, we recently characterized the accumulation of mutations along the HCV genome under weak or no selection using a bicistronic replicon by cloning HCV sequences at a site commonly used for inserting reporter genes Fig.
This revealed extreme mutation rate variations across individual nucleotide sites of the viral genome, with differences of orders of magnitude even between adjacent sites [ ]. In that system, we found little or no effect of RNA structure on mutation rate, but a more significant effect of base identity, such that A and U bases were more prone to mutation than G and C. The finding that HIV-1 has a reduced mutation rate in the genome region encoding the outermost domains of the gp envelope protein reveals an uncoupling between mutation rate and genetic diversity, as these domains are the most variable regions of the HIV-1 genome, mainly as a consequence of immune pressure [ ].
This indicates that HIV-1 has not evolved the ability to target mutation to regions wherein they are more likely to be needed for adaptation. Similarly, strong selection at the protein level may have favored amino acid replacements within this region even at the cost of disrupting pre-existing RNA secondary structures and, as a consequence, these RNA structural changes would have modified replication fidelity [ 99 ].
In HCV, we found no significant differences in mutation rate across genes [ ], as opposed to genetic variation, which concentrates in specific genomes regions including external domains of the E2 envelope protein [ ].
This again supports the view that RNA viruses cannot target mutations to specific genomes regions to improve their adaptability. This contrasts with bacteria and DNA viruses, in which mechanisms of error-prone replication have evolved at specific loci involved in host-pathogen interactions [ — ]. A well-characterized system of mutation targeting, called diversity-generating retro-elements DGRs , is found in large DNA bacteriophages [ ]. DGRs are typically located in genes involved in host attachment, a step of the infection cycle that is subject to rapid changes depending on host species availability.
The cDNA is then transferred to the VR, producing a large number of variants of the mtd gene capable of interacting with new host ligands [ ]. DGRs have also been described in plasmids, bacterial and archaeal chromosomes, and archaeal viruses [ — ]. It therefore appears that at least some prokaryotic DNA viruses have evolved the ability to target mutations to specific regions, as opposed to RNA viruses.
Diversity-generating retro-elements have not been described in eukaryotic viruses, but these viruses can use other mechanisms of mutational targeting that involve recombination. The inverted terminal repeats of vaccinia virus contain 10— base repeated sequence motifs known to experience frequent unequal crossover events and rapid changes in copy number [ , ]. Recombination has been shown to promote the rapid production of genetic diversity in other genome regions of the vaccinia virus involved in immune escape and the colonization of novel hosts.
Protein kinase R PKR is a central effector of innate antiviral immunity that induces translational shutoff, modifies protein phosphorylation status, alters mRNA stability, and induces apoptosis [ ]. Poxvirus proteins K3L and E3L block PKR and have evolved as antagonists of innate immune responses in a host-specific manner [ , ].
Experimental deletion of E3L renders vaccinia virus more susceptible to host antiviral responses, imposing a strong selection pressure in the other PKR suppressor K3L to increase its function [ ]. Serial transfers of E3L-deleted vaccinia virus led to an elevated K3L copy number, a recombination-driven process that allowed the virus to overexpress this gene. This gain-of-function mutation had a direct fitness benefit, but also increased the number of available targets for the appearance of subsequent selectively advantageous point mutations in K3L.
Remarkably, upon selection of these mutants K3L copy numbers were again reduced. Hence, recombination led to an evolutionary process characterized by expansion and contraction of a specific genome region. These so-called genomic accordions have been posited to mediate adaptive duplications in other poxviruses such as myxoma virus [ ]. Interesting interplays between recombination and mutation rates have also been recently found in RNA viruses.
These two processes are primarily controlled by the viral polymerase since, in RNA viruses, recombination takes place when the viral polymerase switches between different template genomes present in the same cell [ ]. The estimated recombination rates of different riboviruses and retroviruses correlate positively with estimated mutation rates [ ]. High mutation rates confer viruses the ability to rapidly produce advantageous mutations, but also inflate the genetic load of the population.
In turn, frequent recombination allows beneficial mutations to unlink from deleterious genetic backgrounds, as well different beneficial mutations to be combined into the same genome. As such, recombination is expected to enhance adaptation when a large number of alleles coexist in the same population, a scenario that typically takes place at high mutation rates [ ].
Experimental evidence supporting the joint effects of recombination and mutation rates in viral adaptability has been recently obtained using poliovirus polymerase mutants that individually alter replication fidelity or recombination rate [ ]. In another recent work, a low-fidelity variant of Sindbis virus was found to exhibit increased recombination [ ].
This variant showed low fitness and a greater tendency to accumulate defective interfering particles i. Therefore, it appears that high mutation and recombination rates enhance viral adaptability, but only up to a certain point, beyond which both processes contribute to the accumulation of deleterious alleles in the population.
Some of these processes underlie large-scale patterns of variation among viruses, such as differences between RNA and DNA viruses, between viruses with small and large genomes, and between single-strand and double-strand viruses, but important mechanistic aspects behind these differences still remain uncharacterized. Furthermore, mutation rates are not static and can evolve in response to selective pressures, as exemplified by fidelity variants selected under mutagenic conditions in a variety of viruses.
In addition to polymerase fidelity, other mutation rate-determinants such as access to DNA repair may have also changed in response to selective pressures during viral evolution.
In RNA viruses, both low- and high-fidelity polymerase variants tend to have a negative impact in viral fitness in complex environments, suggesting that RNA virus mutation rates have been evolutionarily optimized. It appears that large DNA viruses have adopted a different and more elaborate strategy consisting of targeting mutations to specific genome regions subject to rapidly varying selective pressures, such as genes encoding attachment proteins or inhibitors of innate immunity responses.
Mutation targeting mechanisms such as DGRs and recombination-driven gene copy amplification are probably not accessible to small DNA viruses with compact genomes. Furthermore, mutation rate evolution in small DNA viruses is further constrained by the fact they do not encode autonomous replication systems. Therefore, small DNA viruses should rely on repair avoidance and on use of host-encoded error-prone DNA polymerases to elevate their mutation rates and achieve faster adaptation.
Elucidating the mutational mechanisms of small DNA viruses is a current challenge in virus molecular biology and evolution. Other exciting unresolved questions include unveiling the interplays between mutation and recombination, the roles played by viral accessory proteins in determining mutation rates, the effects of host-encoding enzymes on viral diversity and evolution, whether mutation accumulation can be evolutionary adjusted by modifying viral replication modes, and how template sequences regulate viral mutation rates.
National Center for Biotechnology Information , U. Cell Mol Life Sci. Published online Jul 8. Author information Article notes Copyright and License information Disclaimer. Corresponding author.
This article has been cited by other articles in PMC. Abstract The remarkable capacity of some viruses to adapt to new hosts and environments is highly dependent on their ability to generate de novo diversity in a short period of time. Introduction The mutation rate of an organism is defined as the probability that a change in genetic information is passed to the next generation. Open in a separate window. RNA viruses versus DNA viruses The Baltimore classification of viruses establishes the following categories according to the genetic material contained in the virion: positive-strand RNA viruses e.
Table 1 Summary of viral mutation rates. Single-strand viruses show higher mutation rates than double-strand viruses Single-strand DNA viruses tend to mutate faster than double-strand DNA viruses, although this difference is based on work with bacteriophages, as no mutation rate estimates have been obtained for eukaryotic single-strand DNA viruses [ 1 ].
Viruses with smaller genomes tend to mutate faster A general inverse correlation between genome size and mutation rate applies to DNA-based microorganisms including viruses, bacteria and unicellular eukaryotes [ 28 ]. Polymerase fidelity variants Intrinsic polymerase fidelity i. Host-encoded mutation rate modifiers in RNA and reverse-transcribing viruses Whereas post-replicative repair probably plays a role in determining DNA virus mutation rates as discussed above , RNA virus mutation rates are strongly influenced by other host-encoded factors.
Mutation accumulation is determined by replication mode In contrast to cells, viruses can adopt a variety of replication modes. Lysis time as a regulator of mutational output Changes in lysis time can be thought of as another mechanism for regulating the production of mutations in viral populations. Template-dependent effects on mutation rate The fidelity of a given polymerase varies according to certain template properties.
Targeted hyper-mutation in viruses The finding that HIV-1 has a reduced mutation rate in the genome region encoding the outermost domains of the gp envelope protein reveals an uncoupling between mutation rate and genetic diversity, as these domains are the most variable regions of the HIV-1 genome, mainly as a consequence of immune pressure [ ].
Interplays between mutation and recombination Diversity-generating retro-elements have not been described in eukaryotic viruses, but these viruses can use other mechanisms of mutational targeting that involve recombination. Table 2 Molecular determinants of viral mutation rates. References 1. Viral mutation rates. J Virol. Rates of evolutionary change in viruses: patterns and determinants. Nat Rev Genet. From molecular genetics to phylodynamics: evolutionary relevance of mutation rates across viruses.
PLoS Pathog. Perelson AS. Modelling viral and immune system dynamics. Nat Rev Immunol. Pawlotsky JM. Hepatitis C virus resistance to direct-acting antiviral drugs in interferon-fee regimens. Clin Res Hepatol Gastroenterol. Clinical significance of hepatitis B surface antigen mutants. World J Hepatol. Influenza vaccines: a moving interdisciplinary field. The accuracy of reverse transcriptase from HIV Lack of evidence for proofreading mechanisms associated with an RNA virus polymerase.
Thinking outside the triangle: replication fidelity of the largest RNA viruses. Annu Rev Virol. J Biochem Mol Biol. Mutation rates and intrinsic fidelity of retroviral reverse transcriptases. Measurably evolving pathogens in the genomic era.
Trends Ecol Evol. High rate of viral evolution associated with the emergence of carnivore parvovirus. Phylogenetic evidence for the rapid evolution of human B19 erythrovirus. Duffy S, Holmes EC. Phylogenetic evidence for rapid rates of molecular evolution in the single-stranded DNA begomovirus tomato yellow leaf curl virus.
Mutability dynamics of an emergent single stranded DNA virus in a naive host. PLoS One. Comprehensive phylogenetic reconstructions of African swine fever virus: proposal for a new classification and molecular dating of the virus. Limits and patterns of cytomegalovirus genomic diversity in humans. Ethanol and reactive species increase basal sequence heterogeneity of hepatitis C virus and produce variants with reduced susceptibility to antivirals. Jiricny J. Postreplicative mismatch repair.
Cold Spring Harb Perspect Biol. Deschavanne P, Radman M. Counterselection of GATC sequences in enterobacteriophages by the components of the methyl-directed mismatch repair system. J Mol Evol. Luftig MA. Viruses and the DNA damage response: activation and antagonism. Genomes in conflict: maintaining genome integrity during virus infection. Annu Rev Microbiol.
Lynch M. Evolution of the mutation rate. Trends Genet. Induction and utilization of an ATM signaling pathway by polyomavirus. Human papillomaviruses recruit cellular DNA repair and homologous recombination factors to viral replication centers. Luo Y, Qiu J. Parvovirus infection-induced DNA damage response. Future Virol.
Deletion of the E4 region of the genome produces adenovirus DNA concatemers. Ciccia A, Elledge SJ. The DNA damage response: making it safe to play with knives. Mol Cell. Fidelity variants and RNA quasispecies. Curr Top Microbiol Immunol. Pfeiffer JK, Kirkegaard K. A single mutation in poliovirus RNA-dependent RNA polymerase confers resistance to mutagenic nucleotide analogs via increased fidelity.
Ribavirin-resistant mutants of human enterovirus 71 express a high replication fidelity phenotype during growth in cell culture. Meng T, Kwang J. Attenuation of human enterovirus 71 high-replication-fidelity variants in AG mice. Arbovirus high fidelity variant loses fitness in mosquitoes and mice. Generation and characterization of influenza A viruses with altered polymerase fidelity. Nat Commun. Sequence-specific fidelity alterations associated with West Nile virus attenuation in mosquitoes.
Gong P, Peersen OB. Structure-function relationships of the viral RNA-dependent RNA polymerase: fidelity, replication speed, and initiation mechanism determined by a residue in the ribose-binding pocket. J Biol Chem. Viral polymerase-helicase complexes regulate replication fidelity to overcome intracellular nucleotide depletion.
Virus mutators and antimutators: roles in evolution, pathogenesis and emergence. Mufti S. Mutator effects of alleles of phage T4 genes 32, 41, 44, and 45 in the presence of an antimutator polymerase.
Effects of mutations in the Exo III motif of the herpes simplex virus DNA polymerase gene on enzyme activities, viral replication, and replication fidelity. Finger domain mutation affects enzyme activity, DNA replication efficiency, and fidelity of an exonuclease-deficient DNA polymerase of herpes simplex virus type 1.
Coronaviruses lacking exoribonuclease activity are susceptible to lethal mutagenesis: evidence for proofreading and potential therapeutics. Andino R, Domingo E. Viral quasispecies. BMC Evol Biol. DNA deamination mediates innate immunity to retroviral infection. J Mol Biol. Nucleic Acids Res. Extremely high mutation rate of HIV-1 in vivo. PLoS Biol. ADARs and the balance game between virus infection and innate immune cell response. Unlike influenza, however, coronaviruses possess no physical segmentation to undergo reassortment.
Coronaviruses can experience some shifts in function through a process known as recombination, when segments of one viral genome are spliced onto another by the enzyme making the viral copy. Understanding these evolutionary dynamics of SARS-CoV-2 is vital to ensure that treatments and vaccines keep pace with the virus. For now, the available vaccines are effective in preventing severe disease from all the viral variants.
Filling in these blanks could help us learn how to protect ourselves in the future. All rights reserved. The pace of evolution Mutations may happen randomly, but the rate at which they occur depends on the virus. The wide world of viruses Mutations drive evolution, but they are not the only way that a virus can change over time.
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But alarm spread fast across the media. The word was scrubbed from the peer-reviewed version of the paper, published in Cell in July 2. The work sparked a frenzy of interest in DG. Some experiments suggest that viruses carrying the variant infect cells more easily. But many scientists say there remains no solid proof that DG has a significant effect on the spread of the virus, or that a process of natural selection explains its rise.
Researchers still have more questions than answers about coronavirus mutations, and no one has yet found any change in SARS-CoV-2 that should raise public-health concerns, Sheahan, Grubaugh and others say.
But studying mutations in detail could be important for controlling the pandemic. It might also help to pre-empt the most worrying of mutations: those that could help the virus to evade immune systems, vaccines or antibody therapies. Mutations — most of them single-letter alterations between viruses from different people — allowed researchers to track the spread by linking closely related viruses, and to estimate when SARS-CoV-2 started infecting humans.
After the severe acute respiratory syndrome SARS virus began circulating in humans, for instance, it developed a kind of mutation called a deletion that might have slowed its spread 4. A typical SARS-CoV-2 virus accumulates only two single-letter mutations per month in its genome — a rate of change about half that of influenza and one-quarter that of HIV, says Emma Hodcroft, a molecular epidemiologist at the University of Basel, Switzerland.
Other genome data have emphasized this stability — more than 90, isolates have been sequenced and made public see www. Two SARS-CoV-2 viruses collected from anywhere in the world differ by an average of just 10 RNA letters out of 29,, says Lucy Van Dorp, a computational geneticist at University College London, who is tracking the differences for signs that they confer an evolutionary advantage. But scientists can spot mutations faster than they can make sense of them. Sources: L. Van Dorp et al.
Young et al. Lancet , — Many researchers suspect that if a mutation did help the virus to spread faster, it probably happened earlier, when the virus first jumped into humans or acquired the ability to move efficiently from one person to another. At a time when nearly everyone on the planet is susceptible, there is likely to be little evolutionary pressure on the virus to spread better, so even potentially beneficial mutations might not flourish.
When Korber saw the rapid spread of DG, she thought she might have found an example of meaningful natural selection. And viruses with the mutation were also rising in frequency in more than one part of the world. DG was first spotted in viruses collected in China and Germany in late January; most scientists suspect the mutation arose in China.
In March, G viruses rose in frequency across the continent, and by April they were dominant, reported Korber, Montefiori and their team 1 , 2. At this time, viruses with the DG mutation were spreading across Europe. The European dominance of G variants could be simply down to chance — if, for instance, the mutation happened to be slightly more common in the viruses that arrived in Europe.
Korber and her colleagues tried to rule out a founder effect, by showing in their April preprint 1 that DG rose to dominance quickly in Canada, Australia and parts of the United States an exception was Iceland, where G viruses present early in its outbreak were overtaken by D viruses. Analysing hospitalization data from Sheffield, UK, the team found no evidence that viruses carrying the mutation made people any sicker. But those infected with G viruses seemed to have slightly higher levels of viral RNA in their noses and mouths than did those with D viruses.
To examine further whether DG made the virus more transmissible, Montefiori gauged its effects under laboratory conditions. Credit: Jeremy Luban. The teams used different pseudovirus systems and tested them on various kinds of cell, but the experiments pointed to the same conclusion: viruses carrying the G mutation infected cells much more ably than did D viruses — up to ten times more efficiently, in some cases.
But these studies come with many caveats — and their relevance to human infections is unclear. The pseudoviruses carry only the coronavirus spike protein, in most cases, and so the experiments measure only the ability of these particles to enter cells, not aspects of their effects inside cells, let alone on an organism.
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