Biology subjects

Faure, G.

Publications and source records attributed to Faure, G..

6 recordsLinked to original sources

bioRxiv2026

RNA-guided transcriptional repression by TIGR-Tas systems

Tandem interspaced guide RNA (TIGR)-TIGR-associated protein (Tas) systems are a widespread family of RNA-guided DNA-targeting proteins whose diversity has remained uncharacterized because their arrays, unlike CRISPR arrays, lack the sequence conservation required by existing annotation tools. We developed TIGRFinder, a motif-based pipeline that identified 6,685 TIGR arrays from genomic and metagenomic data. Phylogenetic and structural analysis of Tas proteins revealed clade-specific insertions in stem-loop binding Tas proteins that co-vary with features of their cognate tigRNAs. Cryo-electron microscopy structures of two stem-loop binding TasR ribonucleoprotein complexes demonstrate how these protein insertions directly accommodate extended tigRNA stems while maintaining DNA binding through catalytically inactive RuvC domains. We also show that these catalytically dead TasR proteins, along with the nuclease-lacking TasA, function as RNA-guided transcriptional repressors. These findings establish TIGR-Tas as a functionally diverse family of RNA-guided effectors, with comprehensive annotations available through TIGRSafari (https://tigr.bio) to support further exploration and engineering.

molecular biology↗

bioRxiv2022

Exaptation of inactivated host enzymes for structural roles in orthopoxviruses and novel protein folds revealed by protein structure modeling

Viruses with large double-stranded DNA genomes appear to have captured the majority of their genes from the hosts at different stages of evolution. The origin of many virus genes is readily detected through highly significant sequence similarity with cellular homologs. This is the case, in particular, for virus enzymes, such as DNA and RNA polymerases or nucleotide kinases, that retain their catalytic activity after capture by an ancestral virus. However, a large fraction of virus genes have no readily detectable cellular homologs so that their origin remains enigmatic. We sought to explore potential origins of proteins of unknown provenance encoded in the genomes of orthopoxviruses, a thoroughly studied virus genus which includes major human pathogens. To this end, we used AlphaFold2, to predict the structures of all 214 proteins encoded by orthopoxviruses. Among the proteins of unknown provenance, structure prediction yielded a clear indication of origin for 14, along with validating several inferences previously made by sequence analysis. The major trend that emerges from these findings is the exaptation of enzymes from cellular organisms for non-enzymatic, structural roles in virus reproduction which is accompanied by disruption of catalytic sites and overall drastic divergence which precludes detection of homology at the sequence level. Among the 16 orthopoxvirus proteins found to be inactivated enzyme derivatives, are the poxvirus replication processivity factor A20, an inactivated derivative of bacterial NAD-dependent DNA ligase; major core protein A3, an inactivated deubiquitinase; F11, an inactivated prolyl hydroxylase; and more similar cases. However, for nearly one third of the orthopoxvirus virion proteins, no significantly similar structures were identified, suggesting exaptation with subsequent major structural rearrangement, yielding novel protein folds.

microbiology↗

bioRxiv2021

Human pathogenic RNA viruses establish non-competing lineages by occupying independent niches

Many pathogenic viruses are endemic among human populations and can cause a broad variety of diseases, some potentially leading to devastating pandemics. How virus populations maintain diversity and what selective pressures drive population turnover, is not thoroughly understood. We conducted a large-scale phylodynamic analysis of 27 human pathogenic RNA viruses spanning diverse life history traits in search of unifying trends that shape virus evolution. For most virus species, we identify multiple, co-circulating lineages with low turnover rates. These lineages appear to be largely noncompeting and likely occupy semi-independent epidemiological niches that are not regionally or seasonally defined. Typically, intra-lineage mutational signatures are similar to inter-lineage signatures. The principal exception are members of the family Picornaviridae, for which mutations in capsid protein genes are primarily lineage-defining. The persistence of virus lineages appears to stem from limited outbreaks within small communities so that only a minor fraction of the global susceptible population is infected at any time. As disparate communities become increasingly connected through globalization, interaction and competition between lineages might increase as well, which could result in changing selective pressures and increased diversification and/or pathogenicity. Thus, in addition to zoonotic events, ongoing surveillance of familiar, endemic viruses appears to merit global attention with respect to the prevention or mitigation of future pandemics. SignificanceNumerous pathogenic viruses are endemic in humans and cause a broad variety of diseases, but what is their potential of causing new pandemics? We show that most human pathogenic RNA viruses form multiple, co-circulating lineages with low turnover rates. These lineages appear to be largely noncompeting and occupy distinct epidemiological niches that are not regionally or seasonally defined, and their persistence appears to stem from limited outbreaks in small communities so that a minor fraction of the global susceptible population is infected at any time. However, due to globalization, interaction and competition between lineages might increase, potentially leading to increased diversification and pathogenicity. Thus, endemic viruses appear to merit global attention with respect to the prevention of future pandemics.

evolutionary biology↗

bioRxiv2021

Epistasis at the SARS-CoV-2 RBD Interface and the Propitiously Boring Implications for Vaccine Escape

At the time of this writing, December 2021, potential emergence of vaccine escape variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a grave global concern. The interface between the receptor-binding domain (RBD) of SARS-CoV-2 spike (S) protein and the host receptor (ACE2) overlap with the binding site of principal neutralizing antibodies (NAb), limiting the repertoire of viable mutations. Nonetheless, variants with multiple mutations in the RBD have rose to dominance. Non-additive, epistatic relationships among RBD mutations are apparent, and assessing the impact of such epistasis on the mutational landscape is crucial. Epistasis can substantially increase the risk of vaccine escape and cannot be completely characterized through the study of the wild type (WT) alone. We employed protein structure modeling using Rosetta to compare the effects of all single mutants at the RBD-NAb and RBD-ACE2 interfaces for the WT, Delta, Gamma, and Omicron variants. Overall, epistasis at the RBD interface appears to be limited and the effects of most multiple mutations are additive. Epistasis at the Delta variant interface weakly stabilizes NAb interaction relative to ACE2 interaction, whereas in the Gamma variant, epistasis more substantially destabilizes NAb interaction. Although a small, systematic trend towards NAb destabilization not observed for Delta or Gamma was detected for Omicron, and despite bearing significantly more RBD mutations, the epistatic landscape of the Omicron variant closely resembles that of Gamma. These results suggest that, although Omicron poses new risks not observed with Delta, structural constraints on the RBD hamper continued evolution towards more complete vaccine escape. The modest ensemble of mutations relative to the WT that are currently known to reduce vaccine efficacy is likely to comprise the majority of all possible escape mutations for future variants, predicting continued efficacy of the existing vaccines. SignificanceEmergence of vaccine escape variants of SARS-CoV-2 is arguably the most pressing problem during the COVID-19 pandemic as vaccines are distributed worldwide. We employed a computational approach to assess the risk of antibody escape resulting from mutations in the receptor-binding domain of the spike protein of the wild type SARS-CoV-2 virus as well as the Delta, Gamma, and Omicron variants. At the time of writing, December, 2021, Omicron is poised to replace Delta as the dominant variant worldwide. The efficacy of the existing vaccines against Omicron could be substantially reduced relative to the WT and the potential for vaccine escape is of grave concern. Our results suggest that although Omicron poses new evolutionary risks not observed for the Delta variant, structural constraints on the RBD make continued evolution towards more complete vaccine escape unlikely. The modest set of escape-enhancing mutations already identified for the wild type likely include the majority of all possible mutations with this effect.

microbiology↗

bioRxiv2021

Cargo genes of Tn7-like transposons comprise an enormous diversity of defense systems, mobile genetic elements and antibiotic resistance genes

Transposition is a major mechanism of horizontal gene mobility in prokaryotes. However, exploration of the genes mobilized by transposons (cargo) is hampered by the difficulty in delineating integrated transposons from their surrounding genetic context. Here, we present a computational approach that allowed us to identify the boundaries of 6,549 Tn7-like transposons at base pair resolution. We found that 96% of these transposons carry at least one cargo gene. Delineation of distinct communities in a gene-sharing network demonstrates how transposons function as a conduit of genes between phylogenetically distant hosts. Comparative analysis of the cargo genes reveals significant enrichment of mobile genetic elements (MGEs) nested within Tn7-like transposons, such as insertion sequences and toxin-antitoxin modules, genes involved in recombination and anti-MGE defense, and in antibiotic resistance. More unexpectedly, cargo also includes genes encoding central carbon metabolism enzymes. Twenty- two Tn7-like transposons carry both an anti-MGE defense system and antibiotic resistance genes, illustrating how bacteria can overcome these combined pressures upon acquisition of a single transposon. This work substantially expands the distribution of Tn7-like transposons, defines their evolutionary relationships and provides a large-scale functional classification of prokaryotic genes mobilized by transposition. SignificanceTransposons are major vehicles of horizontal gene transfer that, in addition to genes directly involved in transposition, carry cargo genes. However, characterization of these genes is hampered by the difficulty of identification of transposon boundaries. We developed a computational approach for detecting transposon ends and applied it to perform a comprehensive census of the cargo genes of Tn7-like transposons, a large class of bacterial mobile genetic elements (MGE), many of which employ a unique, CRISPR-mediated mechanism of site- specific transposition. The cargo genes encompass a striking diversity of MGE, defense and antibiotic resistance systems. Unexpectedly, we also identified cargo genes encoding metabolic enzymes. Thus, Tn7-like transposons mobilize a vast repertoire of genes that can have multiple effects on the host bacteria.

genomics↗

bioRxiv2020

Ongoing Adaptive Evolution and Globalization of Sars-Cov-2

Understanding the trends in SARS-CoV-2 evolution is paramount to control the COVID- 19 pandemic. We analyzed more than 300,000 high quality genome sequences of SARS-CoV-2 variants available as of January 2021. The results show that the ongoing evolution of SARS-CoV-2 during the pandemic is characterized primarily by purifying selection, but a small set of sites appear to evolve under positive selection. The receptor-binding domain of the spike protein and the nuclear localization signal (NLS) associated region of the nucleocapsid protein are enriched with positively selected amino acid replacements. These replacements form a strongly connected network of apparent epistatic interactions and are signatures of major partitions in the SARS-CoV-2 phylogeny. Virus diversity within each geographic region has been steadily growing for the entirety of the pandemic, but analysis of the phylogenetic distances between pairs of regions reveals four distinct periods based on global partitioning of the tree and the emergence of key mutations. The initial period of rapid diversification into region- specific phylogenies that ended in February 2020 was followed by a major extinction event and global homogenization concomitant with the spread of D614G in the spike protein, ending in March 2020. The NLS associated variants across multiple partitions rose to global prominence in March-July, during a period of stasis in terms of inter- regional diversity. Finally, beginning July 2020, multiple mutations, some of which have since been demonstrated to enable antibody evasion, began to emerge associated with ongoing regional diversification, which might be indicative of speciation. SignificanceUnderstanding the ongoing evolution of SARS-CoV-2 is essential to control and ultimately end the pandemic. We analyzed more than 300,000 SARS-CoV-2 genomes available as of January 2021 and demonstrate adaptive evolution of the virus that affects, primarily, multiple sites in the spike and nucleocapsid protein. Selection appears to act on combinations of mutations in these and other SARS-CoV-2 genes. Evolution of the virus is accompanied by ongoing adaptive diversification within and between geographic regions. This diversification could substantially prolong the pandemic and the vaccination campaign, in which variant-specific vaccines are likely to be required.

microbiology↗