Mutation Rate Of RNA Viruses Research Articles

Genetic and phenotypic changes to Venezuelan equine encephalitis virus following treatment with β-D-N4-hydroxycytidine, an RNA mutagen

The high mutation rate of RNA viruses provides viral populations with the ability to adapt to new environments but also makes them vulnerable to extinction due to the deleterious effects of mutations, which is the conceptual basis for the antiviral activity of RNA mutagens. However, there are still gaps in the quantitative understanding of the dynamics between the mutations induced by an RNA mutagen and its effects on viral fitness. To address this, we used Venezuelan Equine Encephalitis Virus (VEEV) and the potent RNA mutagen β-d-N4-hydroxycytidine (NHC) as a model to analyze virus replication competency and mutation frequency following treatment in the total and replication-competent viral populations separately. We found that NHC induced transition mutations in a concentration dependent manner in the total population, while the replication-competent population maintained itself within an increased, yet narrow, mutation spectrum. The incorporation of NHC mainly happened during the positive sense RNA synthesis of VEEV. A growth kinetic analysis of VEEV population treated with NHC pointed to a lower but more diverse distribution in mutational fitness, demonstrating that NHC-induced mutations negatively and broadly affect the fitness of the virus. Together, our study provides mechanistic insight into how RNA mutagens affect viral population landscape and the potential of RNA mutagens as an antiviral strategy for alphaviruses.

VIRUS: EVOLUSI, GENETIKA, DRIFT DAN SHIFT ANTIGEN

Viral evolution is a subdiscipline of evolutionary biology and virology that focuses on the evolution of viruses. Many viruses, especially RNA viruses, have relatively high mutation rates and short production durations (on the order of one point mutation or more per genome per round of replication). The rapid pace of viral mutation paired with natural selection enables viruses to rapidly adapt to changes in the host environment, despite the fact that the majority of viral mutations offer little benefit and frequently prove to be harmful. Additionally, because viruses often make several copies in an infected host, altered genes can be rapidly transmitted to a large number of offspring. The high mutation rates of RNA viruses, which are the result of an error-prone RNA-dependent RNA polymerase, make them a veritable gold mine for researchers interested in discovering evolutionary novelty and developing new methods to study evolution in action. There are two different forms of genetic changes: antigenic drift and antigenic shift. This article covers briefly the evolution of viruses in terms of genetic variation.

Effect of Genomic and Amino Acid Sequence Mutation on Virulence and Therapeutic Target of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS COV-2).

The COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). It is one of the RNA coronaviruses which share the highest mutation rates of RNA viruses when compared with that of their hosts. The collective mutation rate of RNA viruses is up to a million times higher than their hosts and is correlated with enhanced virulence of viruses. The RNA, genomic material of SARS-CoV-2, has the capacity of showing amplified fast changes as the infection spreads. These changes were frequently observed in genes for spike glycoprotein, nucleocapsid, ORF1ab, and ORF8, together with RNA dependent RNA polymerase. In contrast, genes for envelope, membrane, ORF6, ORF7a and ORF7b showed no observable changes in terms of amino acid substitutions. Mutated SARS COV-2 at these particular sites has been associated with viral infectivity, false laboratory results and viral genome mutation and interferes with therapeutic targets. Interferences with therapeutic targets is frequently observed in genes for RdRp. Additionally, mutated viral genes for RdRp render slow fidelity of RdRp protein, resulting in a high mutation rate. Such a high mutation rate might allow new virulent forms of the virus to emerge and influence the disease profile. This review aimed to elaborate on the effect of genomic and amino acid sequence mutations on the virulence and therapeutic targets of SARS COV-2. To achieve this objective, multiple literatures have been reviewed.

Quantifying the Evolutionary Constraints and Potential of Hepatitis C Virus NS5A Protein.

ABSTRACTRNA viruses, such as hepatitis C virus (HCV), influenza virus, and SARS-CoV-2, are notorious for their ability to evolve rapidly under selection in novel environments. It is known that the high mutation rate of RNA viruses can generate huge genetic diversity to facilitate viral adaptation. However, less attention has been paid to the underlying fitness landscape that represents the selection forces on viral genomes, especially under different selection conditions. Here, we systematically quantified the distribution of fitness effects of about 1,600 single amino acid substitutions in the drug-targeted region of NS5A protein of HCV. We found that the majority of nonsynonymous substitutions incur large fitness costs, suggesting that NS5A protein is highly optimized. The replication fitness of viruses is correlated with the pattern of sequence conservation in nature, and viral evolution is constrained by the need to maintain protein stability. We characterized the adaptive potential of HCV by subjecting the mutant viruses to selection by the antiviral drug daclatasvir at multiple concentrations. Both the relative fitness values and the number of beneficial mutations were found to increase with the increasing concentrations of daclatasvir. The changes in the spectrum of beneficial mutations in NS5A protein can be explained by a pharmacodynamics model describing viral fitness as a function of drug concentration. Overall, our results show that the distribution of fitness effects of mutations is modulated by both the constraints on the biophysical properties of proteins (i.e., selection pressure for protein stability) and the level of environmental stress (i.e., selection pressure for drug resistance).IMPORTANCE Many viruses adapt rapidly to novel selection pressures, such as antiviral drugs. Understanding how pathogens evolve under drug selection is critical for the success of antiviral therapy against human pathogens. By combining deep sequencing with selection experiments in cell culture, we have quantified the distribution of fitness effects of mutations in hepatitis C virus (HCV) NS5A protein. Our results indicate that the majority of single amino acid substitutions in NS5A protein incur large fitness costs. Simulation of protein stability suggests viral evolution is constrained by the need to maintain protein stability. By subjecting the mutant viruses to selection under an antiviral drug, we find that the adaptive potential of viral proteins in a novel environment is modulated by the level of environmental stress, which can be explained by a pharmacodynamics model. Our comprehensive characterization of the fitness landscapes of NS5A can potentially guide the design of effective strategies to limit viral evolution.

Recombination events are concentrated in the spike protein region of Betacoronaviruses.

The Betacoronaviruses comprise multiple subgenera whose members have been implicated in human disease. As with SARS, MERS and now SARS-CoV-2, the origin and emergence of new variants are often attributed to events of recombination that alter host tropism or disease severity. In most cases, recombination has been detected by searches for excessively similar genomic regions in divergent strains; however, such analyses are complicated by the high mutation rates of RNA viruses, which can produce sequence similarities in distant strains by convergent mutations. By applying a genome-wide approach that examines the source of individual polymorphisms and that can be tested against null models in which recombination is absent and homoplasies can arise only by convergent mutations, we examine the extent and limits of recombination in Betacoronaviruses. We find that recombination accounts for nearly 40% of the polymorphisms circulating in populations and that gene exchange occurs almost exclusively among strains belonging to the same subgenus. Although experimental studies have shown that recombinational exchanges occur at random along the coronaviral genome, in nature, they are vastly overrepresented in regions controlling viral interaction with host cells.

Evaluation on the use of Nanopore sequencing for direct characterization of coronaviruses from respiratory specimens, and a study on emerging missense mutations in partial RdRP gene of SARS-CoV-2

Coronavirus disease 2019 (COVID-19) pandemic has been a catastrophic burden to global healthcare systems. The fast spread of the etiologic agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), highlights the need to identify unknown coronaviruses rapidly for prompt clinical and public health decision making. Moreover, owing to the high mutation rate of RNA viruses, periodic surveillance on emerging variants of key virus components is essential for evaluating the efficacy of antiviral drugs, diagnostic assays and vaccines. These 2 knowledge gaps formed the basis of this study. In the first place, we evaluated the feasibility of characterizing coronaviruses directly from respiratory specimens. We amplified partial RdRP gene, a stable genetic marker of coronaviruses, from a collection of 57 clinical specimens positive for SARS-CoV-2 or other human coronaviruses, and sequenced the amplicons with Nanopore Flongle and MinION, the fastest and the most scalable massively-parallel sequencing platforms to-date. Partial RdRP sequences were successfully amplified and sequenced from 82.46% (47/57) of specimens, ranging from 75 to 100% by virus type, with consensus accuracy of 100% compared with Sanger sequences available (n = 40). In the second part, we further compared 19 SARS-CoV-2 RdRP sequences collected from the first to third waves of COVID-19 outbreak in Hong Kong with 22,173 genomes from GISAID EpiCoV™ database. No single nucleotide variants (SNVs) were found in our sequences, and 125 SNVs were observed from global data, with 56.8% being low-frequency (n = 1–47) missense mutations affecting the rear part of RNA polymerase. Among the 9 SNVs found on 4 conserved domains, the frequency of 15438G > T was highest (n = 34) and was predominantly found in Europe. Our data provided a glimpse into the sequence diversity of a primary antiviral drug and diagnostic target. Further studies are warranted to investigate the significance of these mutations.

Why can COVID-19 fatality in space be significantly higher than on Earth?

Astronauts are exposed to a wide variety of stressors ranging from radiation and microgravity to persistent fluids shifts, circadian shifts and the psychological stress of prolonged isolation and confinement. On deep space missions, beyond the range of the Earth's magnetosphere, ionizing radiation may increase oxidative stress and DNA damage, immune system dysregulation and alter the effectiveness of the cellular defense mechanisms. By reviewing the health problems reported by astronauts participated in previous space missions, it is evident that viral infections are not rare in space. Recent reports suggest that COVID-19 can last for a long time in communities. Although NASA implements countermeasures designed to limit crew illness during space missions such as a pre-flight quarantine, it is not clear whether an outbreak can be prevented. Currently, it is not likely that astronauts could get a viral infection, but the consequences of potential lifethreatening viral diseases such as COVID-19 should be better characterized. In this paper we discuss why COVID-19 fatality in space might be significantly higher than on the Earth. The reasons for such an increased risk include 1) uselessness of social distancing due to microgravity 2) immune system dysregulation 3) possibly higher mutation rates of RNA viruses such as the novel coronavirus (SARS-CoV-2) 4) existence of strong selective pressure and 5) decreased maximum oxygen uptake. Given these considerations, the combined effects of microgravity, space radiation (and possibly other major space stressors) on the immune system of astronauts exposed to SARS-CoV-2 and possible interactions of the virus, space stressors and host should be carefully investigated.

Why are RNA virus mutation rates so damn high?

The high mutation rate of RNA viruses is credited with their evolvability and virulence. This Primer, however, discusses recent evidence that this is, in part, a byproduct of selection for faster genomic replication.

The not-so-infinite malleability of RNA viruses: Viral and cellular determinants of RNA virus mutation rates.

The not-so-infinite malleability of RNA viruses: Viral and cellular determinants of RNA virus mutation rates.

Ultra-deep sequencing of VHSV isolates contributes to understanding the role of viral quasispecies.

The high mutation rate of RNA viruses enables the generation of a genetically diverse viral population, termed a quasispecies, within a single infected host. This high in-host genetic diversity enables an RNA virus to adapt to a diverse array of selective pressures such as host immune response and switching between host species. The negative-sense, single-stranded RNA virus, viral haemorrhagic septicaemia virus (VHSV), was originally considered an epidemic virus of cultured rainbow trout in Europe, but was later proved to be endemic among a range of marine fish species in the Northern hemisphere. To better understand the nature of a virus quasispecies related to the evolutionary potential of VHSV, a deep-sequencing protocol specific to VHSV was established and applied to 4 VHSV isolates, 2 originating from rainbow trout and 2 from Atlantic herring. Each isolate was subjected to Illumina paired end shotgun sequencing after PCR amplification and the 11.1 kb genome was successfully sequenced with an average coverage of 0.5–1.9 × 106 sequenced copies. Differences in single nucleotide polymorphism (SNP) frequency were detected both within and between isolates, possibly related to their stage of adaptation to host species and host immune reactions. The N, M, P and Nv genes appeared nearly fixed, while genetic variation in the G and L genes demonstrated presence of diverse genetic populations particularly in two isolates. The results demonstrate that deep sequencing and analysis methodologies can be useful for future in vivo host adaption studies of VHSV.

One-step real-time RT-PCR assays for serotyping dengue virus in clinical samples.

BackgroundDengue is one of the leading causes of morbidity in tropical and subtropical regions and infection with any of the four dengue virus serotypes (DENV1-4) result in a wide range of clinical manifestations. Given the geographic expansion of DENV1-4, assays for serotyping are needed to be able to perform surveillance and epidemiological studies. In this study, we describe the design and validation of one-step real-time serotype-specific DENV RT-PCR assays.MethodsThe DENV1, DENV2, DENV3, and DENV4 RT-PCR assays were designed using all available whole genome DENV sequences in the NCBI nucleotide collection. Because of the high mutation rates of RNA viruses, the assays were performed in singleplex format to enable quick modifications to the primer and probe sequences when new genetic variants emerge. The analytical performance of the RT-PCR assays were evaluated using in vitro transcribed RNA and their specificity was determined by testing 24 DENV isolates, external DENV control panels and RNA preparation of non-DENV flaviviruses and non-dengue clinical samples. Additionally, the clinical performance of the serotype-specific DENV RT-PCR were compared to that of the CDC DENV-1-4 RT-PCR using 85 clinical samples collected from patients presenting with acute dengue.ResultsThe RT-PCR assays were found to be specific for their respective serotype and did not cross-react with other flaviviruses or human mRNA. All assays had a linear dynamic range of 102 to 106 copies/reaction with detection limits between 12 and 44 copies/reaction. When testing sera from 85 confirmed acute dengue cases, the serotype-specific DENV RT-PCR assays had 100 % positive agreement with the FDA-approved CDC DENV-1-4 RT-PCR assay performed in a singleplex format. Additionally 15 samples that tested negative in the CDC DENV-1-4- RT-PCR assay were found positive using the serotype-specific DENV RT-PCR assays.ConclusionsOur results suggest that these RT-PCR assays are useful alternatives to existing methods for serotyping DENV in clinical sera.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-015-1226-z) contains supplementary material, which is available to authorized users.

Introduction of RNA virus evolution

Lots of viruses, in particular RNA viruses, have high mutation rates and relatively short generation times. Particle stability during infection in nature or in laboratory triggers the evolutionary event toward different mechanisms such as genome segmentation, point mutation and recombination. The frequency of mutant genomes increase and modify the previous distribution, which, consequently, lead to emergence of a new infectious particle. Mutation and selection are the most fundamental processes in evolution. High mutation rate of RNA viruses has an important role in viral fitness. Therefore, it increase our understanding about molecular biology of viral infections and their evolution by selection, mutation could reliably determine our ability to challenge destructive viruses. This review focuses on existing impressions of genetic organization and mechanisms of RNA viruses evolution.

Emergence and transmission of arbovirus evolutionary intermediates with epidemic potential.

The high replication and mutation rates of RNA viruses can result in the emergence of new epidemic variants. Thus, the ability to follow host-specific evolutionary trajectories of viruses is essential to predict and prevent epidemics. By studying the spatial and temporal evolution of chikungunya virus during natural transmission between mosquitoes and mammals, we have identified viral evolutionary intermediates prior to emergence. Analysis of virus populations at anatomical barriers revealed that the mosquito midgut and salivary gland pose population bottlenecks. By focusing on virus subpopulations in the saliva of multiple mosquito strains, we recapitulated the emergence of a recent epidemic strain of chikungunya and identified E1 glycoprotein mutations with potential to emerge in the future. These mutations confer fitness advantages in mosquito and mammalian hosts by altering virion stability and fusogenic activity. Thus, virus evolutionary trajectories can be predicted and studied in the short term before new variants displace currently circulating strains.

Variability in the Mutation Rates of RNA Viruses

ABSTRACT: It is well established that RNA viruses show extremely high mutation rates, but less attention has been paid to the fact that their mutation rates also vary strongly, from 10-6 to 10-4 substitutions per nucleotide per cell infection. The causes explaining this variability are still poorly understood, but candidate factors are the viral genome size and polarity, host-specific gene expression patterns, or the intracellular environment. Differences between animal and plant viruses, or between arthropod-borne and directly transmitted viruses have also been postulated. Finally, RNA viruses may be able to regulate the rate at which new mutations spread in the population by modifying features of the viral infection cycle, such as lysis time.

Benzophenone C-glucosides and gallotannins from mango tree stem bark with broad-spectrum anti-viral activity

The high mutation rate of RNA viruses has resulted in limitation of vaccine effectiveness and increased emergence of drug-resistant viruses. New effective antivirals are therefore needed to control of the highly mutative RNA viruses. The n-butanol fraction of the stem bark of Mangifera indica exhibited inhibitory activity against influenza neuraminidase (NA) and coxsackie virus 3C protease. Bioassay guided phytochemical study of M. indica stem bark afforded two new compounds including one benzophenone C-glycoside (4) and one xanthone dimer (7), together with eleven known compounds. The structures of these isolated compounds were elucidated on the basis of spectroscopic evidences and correlated with known compounds. Anti-influenza and anti-coxsackie virus activities were evaluated by determining the inhibition of anti-influenza neuraminidase (NA) from pandemic A/RI/5+/1957 H2N2 influenza A virus and inhibition of coxsackie B3 virus 3C protease, respectively. The highest anti-influenza activity was observed for compounds 8 and 9 with IC50 values of 11.9 and 9.2μM, respectively. Compounds 8 and 9 were even more potent against coxsackie B3 virus 3C protease, with IC50 values of 1.1 and 2.0μM, respectively. Compounds 8 and 9 showed weak cytotoxic effect against human hepatocellular carcinoma and human epithelial carcinoma cell lines through MTT assay.

Correlation Between Mutation Rate and Genome Size in Riboviruses: Mutation Rate of Bacteriophage Qβ

Genome sizes and mutation rates covary across all domains of life. In unicellular organisms and DNA viruses, they show an inverse relationship known as Drake’s rule. However, it is still unclear whether a similar relationship exists between genome sizes and mutation rates in RNA genomes. Coronaviruses, the RNA viruses with the largest genomes (∼30 kb), encode a proofreading 3′ exonuclease that allows them to increase replication fidelity. However, it is unknown whether, conversely, the RNA viruses with the smallest genomes tend to show particularly high mutation rates. To test this, we measured the mutation rate of bacteriophage Qβ, a 4.2-kb levivirus. Amber reversion-based Luria–Delbrück fluctuation tests combined with mutant sequencing gave an estimate of 1.4 × 10−4 substitutions per nucleotide per round of copying, the highest mutation rate reported for any virus using this method. This estimate was confirmed using a direct plaque sequencing approach and after reanalysis of previously published estimates for this phage. Comparison with other riboviruses (all RNA viruses except retroviruses) provided statistical support for a negative correlation between mutation rates and genome sizes. We suggest that the mutation rates of RNA viruses might be optimized for maximal adaptability and that the value of this optimum may in turn depend inversely on genome size.

The Role of Viral Population Diversity in Adaptation of Bovine Coronavirus to New Host Environments

The high mutation rate of RNA viruses enables a diverse genetic population of viral genotypes to exist within a single infected host. In-host genetic diversity could better position the virus population to respond and adapt to a diverse array of selective pressures such as host-switching events. Multiple new coronaviruses, including SARS, have been identified in human samples just within the last ten years, demonstrating the potential of coronaviruses as emergent human pathogens. Deep sequencing was used to characterize genomic changes in coronavirus quasispecies during simulated host-switching. Three bovine nasal samples infected with bovine coronavirus were used to infect human and bovine macrophage and lung cell lines. The virus reproduced relatively well in macrophages, but the lung cell lines were not infected efficiently enough to allow passage of non lab-adapted samples. Approximately 12 kb of the genome was amplified before and after passage and sequenced at average coverages of nearly 950×(454 sequencing) and 38,000×(Illumina). The consensus sequence of many of the passaged samples had a 12 nucleotide insert in the consensus sequence of the spike gene, and multiple point mutations were associated with the presence of the insert. Deep sequencing revealed that the insert was present but very rare in the unpassaged samples and could quickly shift to dominate the population when placed in a different environment. The insert coded for three arginine residues, occurred in a region associated with fusion entry into host cells, and may allow infection of new cell types via heparin sulfate binding. Analysis of the deep sequencing data indicated that two distinct genotypes circulated at different frequency levels in each sample, and support the hypothesis that the mutations present in passaged strains were “selected” from a pre-existing pool rather than through de novo mutation and subsequent population fixation.

Molecular epidemiology and genetic analysis of HCV infection in Cyprus within an intravenous drug user study cohort

The HCV genome is highly heterogeneous, owing to the high mutation rate of RNA viruses. There are seven HCV genotypes, with numerous subtypes and viral quasispecies. The prevalence and distribution of HCV genotypes varies globally, and strains show highly variable sensitivity to available therapeutics. Thus, genetic and epidemiological studies of hepatitis C infection are significant, especially within high-risk cohorts where viral evolution can be rapid and unpredictable.

50 Years Ago in The Journal of Pediatrics: Nutrition and Infection

Dubos RJ, Schaedler RW. J Pediatr 1959;55:1-14This lucid, seminal work triggered research that defined the interactions between infection, nutritional status, and host defenses. Observations in India, Africa, and Central America illustrated that when infected, children ate less, lost more nutrients via urine/stools, and stopped growing. The nutrition/infection relationship was conceptualized as a triangle in which diet and infection defined nutritional status, whereas nutrition affected case fatality from infection. The effects of retinol, ascorbate, tocopherol, iron, zinc, copper, and other essential nutrients on innate and acquired defense systems were soon recognized. The epidemiologic and laboratory work of Scrimshaw and Mata in Central America, Chandra in India, and Beisel and Good in the United States, among other researchers, established the critical role of protein-energy malnutrition in defining cellular and humoral immune function as well as nonspecific defenses. Methodological advances facilitated the study of cellular and molecular mechanisms underlying the initial observations in malnourished infants. Thus, the relationship between nutrition and infection expanded to include immunity and the myriad of effects mediated by tissue and circulating cytokines, setting the stage for new layers of complexity in this interaction. Traditional essential nutrients such as tocopherol, retinol, and zinc serve as key regulators of inflammation; arachidonic and eicosapentaenoic acids derived from essential fatty acids were found to mediate immunity, inflammation, and cell injury responses by generating eicosanoids and docosanoids.The chain of interactive events presently includes nutrition, infection, immunity, inflammation, and cell injury. We now acknowledge that nutrient excess as well as deficit can interfere with normal host defense systems. When given in excess, α-tocopherol, a key antioxidant required for normal host defenses, interferes with superoxide production, compromising leukocyte-killing capacity and leading to increased mortality from necrotizing enterocolitis in neonates and pneumonia in older age groups. The role of nutrients in modifying pathogens such as viral agents is also recognized; for example, tocopherol and selenium deficiency in the host increases mutation rates of RNA viruses, leading to progressive increases in virulence of the virus and lethality of subjects further along the expansion of the infection.1Solomons N.W. Malnutrition and infection: an update.Br J Nutr. 2007; 98: S5-S10Crossref PubMed Scopus (53) Google Scholar, 2Katona R. Katona-Apte J. The interaction between nutrition and infection.Clin Infect Dis. 2005; 46: 1582-1588Crossref Scopus (480) Google Scholar More is yet to come in the next 50 years… Dubos RJ, Schaedler RW. J Pediatr 1959;55:1-14 This lucid, seminal work triggered research that defined the interactions between infection, nutritional status, and host defenses. Observations in India, Africa, and Central America illustrated that when infected, children ate less, lost more nutrients via urine/stools, and stopped growing. The nutrition/infection relationship was conceptualized as a triangle in which diet and infection defined nutritional status, whereas nutrition affected case fatality from infection. The effects of retinol, ascorbate, tocopherol, iron, zinc, copper, and other essential nutrients on innate and acquired defense systems were soon recognized. The epidemiologic and laboratory work of Scrimshaw and Mata in Central America, Chandra in India, and Beisel and Good in the United States, among other researchers, established the critical role of protein-energy malnutrition in defining cellular and humoral immune function as well as nonspecific defenses. Methodological advances facilitated the study of cellular and molecular mechanisms underlying the initial observations in malnourished infants. Thus, the relationship between nutrition and infection expanded to include immunity and the myriad of effects mediated by tissue and circulating cytokines, setting the stage for new layers of complexity in this interaction. Traditional essential nutrients such as tocopherol, retinol, and zinc serve as key regulators of inflammation; arachidonic and eicosapentaenoic acids derived from essential fatty acids were found to mediate immunity, inflammation, and cell injury responses by generating eicosanoids and docosanoids. The chain of interactive events presently includes nutrition, infection, immunity, inflammation, and cell injury. We now acknowledge that nutrient excess as well as deficit can interfere with normal host defense systems. When given in excess, α-tocopherol, a key antioxidant required for normal host defenses, interferes with superoxide production, compromising leukocyte-killing capacity and leading to increased mortality from necrotizing enterocolitis in neonates and pneumonia in older age groups. The role of nutrients in modifying pathogens such as viral agents is also recognized; for example, tocopherol and selenium deficiency in the host increases mutation rates of RNA viruses, leading to progressive increases in virulence of the virus and lethality of subjects further along the expansion of the infection.1Solomons N.W. Malnutrition and infection: an update.Br J Nutr. 2007; 98: S5-S10Crossref PubMed Scopus (53) Google Scholar, 2Katona R. Katona-Apte J. The interaction between nutrition and infection.Clin Infect Dis. 2005; 46: 1582-1588Crossref Scopus (480) Google Scholar More is yet to come in the next 50 years…

Upper-limit mutation rate estimation for a plant RNA virus

It is generally accepted that mutation rates of RNA viruses are inherently high due to the lack of proofreading mechanisms. However, direct estimates of mutation rate are surprisingly scarce, in particular for plant viruses. Here, based on the analysis of in vivo mutation frequencies in tobacco etch virus, we calculate an upper-bound mutation rate estimation of 3x10(-5) per site and per round of replication; a value which turns out to be undistinguishable from the methodological error. Nonetheless, the value is barely on the lower side of the range accepted for RNA viruses, although in good agreement with the only direct estimate obtained for other plant viruses. These observations suggest that, perhaps, differences in the selective pressures operating during plant virus evolution may have driven their mutation rates towards values lower than those characteristic of other RNA viruses infecting bacteria or animals.