Predicting the Stability of Homologous Gene Duplications in a Plant RNA Virus

One of the striking features of many eukaryotes is the apparent amount of redundancy in coding and non-coding elements of their genomes. Despite the possible evolutionary advantages, there are fewer examples of redundant sequences in viral genomes, particularly those with RNA genomes. The factors constraining the maintenance of redundant sequences in present-day RNA virus genomes are not well known. Here, we use Tobacco etch virus, a plant RNA virus, to investigate the stability of genetically redundant sequences by generating viruses with potentially beneficial gene duplications. Subsequently, we tested the viability of these viruses and performed experimental evolution. We found that all gene duplication events resulted in a loss of viability or in a significant reduction in viralfitness. Moreover,uponanalyzing thegenomesof theevolved viruses,wealways observedthedeletionof the duplicated gene copy andmaintenance of the ancestral copy. Interestingly, there were clear differences in the deletion dynamics of the duplicated gene associated with the passage duration and the size and position of the duplicated copy. Based on the experimental data,wedeveloped a mathematical model to characterize the stability of genetically redundant sequences, and showed that fitness effects are not enough to predict genomic stability.Acontext-dependent recombination rate is also required, with the context being the duplicated gene and its position. Our results therefore demonstrate experimentally the deleterious nature of gene duplications in RNA viruses. Beside previously described constraints on genome size, we identified additional factors that reduce the likelihood of the maintenance of duplicated genes.We thank Francisca de la Iglesia and Paula Agudo for excellent technical assistance. This work was supported by the John Templeton Foundation [grant number 22371 to S.F.E.]; the European Commission 7th Framework Program EvoEvo Project [grant number ICT-610427 to S.F.E.]; the Spanish Ministerio de Economia y Competitividad (MINECO) [grant numbers BFU2012-30805 and BFU2015-65037-P to S.F.E.]; the Botin Foundation from Banco Santander through its Santander Universities Global Division [J.S.]; the Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement de la Generalitat de Catalunya [J.S.]; and the European Molecular Biology Organization [grant number ASTF 625-2015 to A.W]. The opinions expressed in this publication are those of the authors and do not necessarily reflect the views of the John Templeton Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Willemsen, A.; Zwart, MP.; Higueras, P.; Sardanyes Cayuela, J.; Elena Fito, SF. (2016). Predicting the Stability of Homologous Gene Duplications in a Plant RNA Virus. Genome Biology and Evolution. 8(9):3065-3082. https://doi.org/10.1093/gbe/evw219S306530828

Viral genome size distribution does not correlate with the antiquity of the host lineages

It has been suggested that RNA viruses and other subcellular entities endowed with RNA genomes are relicts from an ancient RNA/protein World which is believed to have preceded extant DNA/RNA/protein-based cells. According to their proponents, this possibility is supported by the small-genome sizes of RNA viruses and their manifold replication strategies, which have been interpreted as the result of an evolutionary exploration of different alternative genome organizations and replication strategies during early evolutionary stages. At the other extreme are the giant DNA viruses, whose genome sizes can be as large as those of some prokaryotes, and which have been grouped by some authors into a fourth domain of life. As argued here, the comparative analysis of the chemical nature and sizes of the viral genomes reported in GenBank does not reveal any obvious correlation with the phylogenetic history of their hosts. Accordingly, it is somewhat difficult to reconcile the proposal of the putative pre-DNA antiquity of RNA viruses, with their extraordinary diversity in plant hosts and their apparent absence among the Archaea. Other issues related to the genome size of all known viruses and subviral agents and the relationship with their hosts are discussed

Sofosbuvir as a potential alternative to treat the SARS-CoV-2 epidemic

Abstract As of today, there is no antiviral for the treatment of the SARS-CoV-2 infection, and the development of a vaccine might take several months or even years. The structural superposition of the hepatitis C virus polymerase bound to sofosbuvir, a nucleoside analog antiviral approved for hepatitis C virus infections, with the SARS-CoV polymerase shows that the residues that bind to the drug are present in the latter. Moreover, a multiple alignment of several SARS-CoV-2, SARS and MERS-related coronaviruses polymerases shows that these residues are conserved in all these viruses, opening the possibility to use sofosbuvir against these highly infectious pathogens

Structural analysis of viral ExoN domains reveals polyphyletic hijacking events.

Nidoviruses and arenaviruses are the only known RNA viruses encoding a 3'-5' exonuclease domain (ExoN). The proofreading activity of the ExoN domain has played a key role in the growth of nidoviral genomes, while in arenaviruses this domain partakes in the suppression of the host innate immune signaling. Sequence and structural homology analyses suggest that these proteins have been hijacked from cellular hosts many times. Analysis of the available nidoviral ExoN sequences reveals a high conservation level comparable to that of the viral RNA-dependent RNA polymerases (RdRp), which are the most conserved viral proteins. Two highly preserved zinc fingers are present in all nidoviral exonucleases, while in the arenaviral protein only one zinc finger can be identified. This is in sharp contrast with the reported lack of zinc fingers in cellular ExoNs, and opens the possibility of therapeutic strategies in the struggle against COVID-19

Two short low complexity regions (LCRs) are hallmark sequences of the Delta SARS-CoV-2 variant spike protein

Low complexity regions (LCRs) are protein sequences formed by a set of compositionally biased residues. LCRs are extremely abundant in cellular proteins and have also been reported in viruses, where they may partake in evasion of the host immune system. Analyses of 28,231 SARS-CoV-2 whole proteomes and of 261,051 spike protein sequences revealed the presence of four extremely conserved LCRs in the spike protein of several SARS-CoV-2 variants. With the exception of Iota, where it is absent, the Spike LCR-1 is present in the signal peptide of 80.57% of the Delta variant sequences, and in other variants of concern and interest. The Spike LCR-2 is highly prevalent (79.87%) in Iota. Two distinctive LCRs are present in the Delta spike protein. The Delta Spike LCR-3 is present in 99.19% of the analyzed sequences, and the Delta Spike LCR-4 in 98.3% of the same set of proteins. These two LCRs are located in the furin cleavage site and HR1 domain, respectively, and may be considered hallmark traits of the Delta variant. The presence of the medically-important point mutations P681R and D950N in these LCRs, combined with the ubiquity of these regions in the highly contagious Delta variant opens the possibility that they may play a role in its rapid spread

Discovery and analysis of RNA viruses in insects

Abstract Viruses are the most abundant pathogens on Earth infecting all cellular life forms. Only in recent years have we started to gain knowledge on insect viromes, thanks to the development of sequencing technologies. The discovery and characterization of insect viruses is important for understanding insect-virus interactions, coevolution, and insect immune defenses. We describe here a bioinformatic pipeline for the discovery of RNA viruses from insects based on RNA sequence data and the analysis of insect antiviral immune response against the discovered viruses by using small RNA sequence data