Biology subjects

Didelot, X.

Publications and source records attributed to Didelot, X..

At least 37 records · Page 2Linked to original sources

bioRxiv2022

The bounded coalescent model: conditioning a genealogy on a minimum root date

The coalescent model represents how individuals sampled from a population may have originated from a last common ancestor. The bounded coalescent model is obtained by conditioning the coalescent model such that the last common ancestor must have existed after a certain date. This conditioned model arises in a variety of applications, such as speciation, horizontal gene transfer or transmission analysis, and yet the bounded coalescent model has not been previously analysed in detail. Here we describe a new algorithm to simulate from this model directly, without resorting to rejection sampling. We show that this direct simulation algorithm is more computationally efficient than the rejection sampling approach. We also show how to calculate the probability of the last common ancestor occurring after a given date, which is required to compute the probability of realisations under the bounded coalescent model. Our results are applicable in both the isochronous (when all samples have the same date) and heterochronous (where samples can have different dates) settings. We explore the effect of setting a bound on the date of the last common ancestor, and show that it affects a number of properties of the resulting phylogenies. All our methods are implemented in a new R package called BoundedCoalescent which is freely available online.

evolutionary biology↗

bioRxiv2021

A scalable analytical approach from bacterial genomes to epidemiology

Recent years have seen a remarkable increase in the practicality of sequencing whole genomes from large numbers of bacterial isolates. The availability of this data has huge potential to deliver new insights into the evolution and epidemiology of bacterial pathogens, but the scalability of the analytical methodology has been lagging behind that of the sequencing technology. Here we present a step-by-step approach for such large-scale genomic epidemiology analyses, from bacterial genomes to epidemiological interpretations. A central component of this approach is the dated phylogeny, which is a phylogenetic tree with branch lengths measured in units of time. The construction of dated phylogenies from bacterial genomic data needs to account for the disruptive effect of recombination on phylogenetic relationships, and we describe how this can be achieved. Dated phylogenies can then be used to perform fine-scale or large-scale epidemiological analyses, depending on the proportion of cases for which genomes are available. A key feature of this approach is computational scalability, and in particular the ability to process hundreds or thousands of genomes within a matter of hours. This is a clear advantage of the step-by-step approach described here. We discuss other advantages and disadvantages of the approach, as well as potential improvements and avenues for future research.

microbiology↗

bioRxiv2021

Bayesian inference of clonal expansions in a dated phylogeny

Microbial population genetics models often assume that all lineages are constrained by the same population size dynamics over time. However, many neutral and selective events can invalidate this assumption, and can contribute to the clonal expansion of a specific lineage relative to the rest of the population. Such differential phylodynamic properties between lineages result in asymmetries and imbalances in phylogenetic trees that are sometimes described informally but which are difficult to analyse formally. To this end, we developed a model of how clonal expansions occur and affect the branching patterns of a phylogeny. We show how the parameters of this model can be inferred from a given dated phylogeny using Bayesian statistics, which allows us to assess the probability that one or more clonal expansion events occurred. For each putative clonal expansion event we estimate their date of emergence and subsequent phylodynamic trajectories, including their long-term evolutionary potential which is important to determine how much effort should be placed on specific control measures. We demonstrate the applicability of our methodology on simulated and real datasets.

evolutionary biology↗

bioRxiv2021

Cross-species evolutionary rewiring in the enteric bacterium Campylobacter

Significance StatementGenetic exchange among bacteria shapes the microbial world. From the acquisition of antimicrobial resistance genes to fundamental questions about the nature of bacterial species, this powerful evolutionary force has preoccupied scientists for decades. However, the mixing of genes between species rests on a paradox. On one hand, promoting adaptation by conferring novel functionality, on the other potentially introducing disharmonious gene combinations (negative epistasis) that will be selected against. Taking an interdisciplinary approach to analyse natural populations of the enteric bacteria Campylobacter, an ideal example of long-range admixture, we demonstrate that genes can independently transfer across species boundaries and rejoin in epistasis in a recipient genome. This challenges conventional ideas and highlights the possibility of single step evolution by saltation. AbstractRecombination of short DNA fragments via horizontal gene transfer (HGT) can both introduce beneficial alleles and create genomic disharmony through negative epistasis. For non-core (accessory) genes, the negative epistatic cost is likely to be minimal because the incoming genes have not co-evolved with the recipient genome. By contrast, for the core genome, interspecific recombination is expected to be rare because disruptive allelic replacement is likely to introduce negative epistasis. Why then is homologous recombination common in the core of bacterial genomes? To understand this enigma we take advantage of an exceptional model system, the common enteric pathogens Campylobacter jejuni and Campylobacter coli, that are known for very high magnitude interspecies gene flow in the core genome. As expected, HGT does indeed disrupt co-adapted allele pairings (negative epistasis). However, multiple HGT events enable recovery of the genomes co-adaption between introgressing alleles, even in core metabolism genes (e.g., formate dehydrogenase). These findings demonstrate that, even for complex traits, genetic coalitions can be decoupled, transferred and independently reinstated in a new genetic background - facilitating transition between fitness peaks. In this example, the two-step recombinational process is associated with C. coli that are adapted to the agricultural niche.

microbiology↗

bioRxiv2021

Maximum likelihood inference of pathogen population size history from a phylogeny

Inference of effective population size from genomic data can provide unique information about demographic history, and when applied to pathogen genetic data can also provide insights into epidemiological dynamics. The combination of non-parametric models for population dynamics with molecular clock models which relate genetic data to time has enabled phylodynamic inference based on large sets of time-stamped genetic sequence data. The methodology for non-parametric inference of effective population size is well-developed in the Bayesian setting, but here we develop a frequentist approach based on non-parametric latent process models of population size dynamics. We appeal to statistical principles based on out-of-sample prediction accuracy in order to optimize parameters that control shape and smoothness of the population size over time. We demonstrate the flexibility and speed of this approach in a series of simulation experiments, and apply the methodology to reconstruct the previously described waves in the seventh pandemic of cholera. We also estimate the impact of non-pharmaceutical interventions for COVID-19 in England using thousands of SARS-CoV-2 sequences. By incorporating a measure of the strength of these interventions over time within the phylodynamic model, we estimate the impact of the first national lockdown in the UK on the epidemic reproduction number.

bioinformatics↗

bioRxiv2020

Detection of a bedaquiline / clofazimine resistance reservoir in Mycobacterium tuberculosis predating the antibiotic era

Drug resistance in tuberculosis (TB) poses a major ongoing challenge to public health. The recent inclusion of bedaquiline into TB drug regimens has improved treatment outcomes, but this advance is threatened by the emergence of strains of Mycobacterium tuberculosis (Mtb) resistant to bedaquiline. Clinical bedaquiline resistance is most frequently conferred by off-target resistance-associated variants (RAVs) in the mmpR5 gene (Rv0678), the regulator of an efflux pump, which can also confer cross-resistance to clofazimine, another TB drug. We compiled a dataset of 3,682 Mtb genomes, including 150 carrying variants in mmpR5 that have been associated to borderline (henceforth intermediate) or confirmed resistance to bedaquiline. We identified eight cases where RAVs were present in the genomes of strains collected prior to the use of bedaquiline in TB treatment regimes. Phylogenetic reconstruction points to multiple emergence events and circulation of RAVs in mmpR5, some estimated to predate the introduction of bedaquiline. However, epistatic interactions can complicate bedaquiline drug-susceptibility prediction from genetic sequence data. Indeed, in one clade of isolates where the RAV Ile67fs is estimated to have emerged prior to the antibiotic era, co-occurrence of mutations in mmpL5 are found to neutralise bedaquiline resistance. The presence of a pre-existing reservoir of Mtb strains carrying bedaquiline RAVs prior to its clinical use augments the need for rapid drug susceptibility testing and individualised regimen selection to safeguard the use of bedaquiline in TB care and control.

genomics↗

bioRxiv2020

The Clostridioides difficile species problem: global phylogenomic analysis uncovers three ancient, toxigenic, genomospecies

Clostridioides difficile infection (CDI) remains an urgent global One Health threat. The genetic heterogeneity seen across C. difficile underscores its wide ecological versatility and has driven the significant changes in CDI epidemiology seen in the last 20 years. We analysed an international collection of over 12,000 C. difficile genomes spanning the eight currently defined phylogenetic clades. Through whole-genome average nucleotide identity, pangenomic and Bayesian analyses, we identified major taxonomic incoherence with clear species boundaries for each of the recently described cryptic clades CI-III. The emergence of these three novel genomospecies predates clades C1-5 by millions of years, rewriting the global population structure of C. difficile specifically and taxonomy of the Peptostreptococcaceae in general. These genomospecies all show unique and highly divergent toxin gene architecture, advancing our understanding of the evolution of C. difficile and close relatives. Beyond the taxonomic ramifications, this work impacts the diagnosis of CDI worldwide.

microbiology↗

bioRxiv2020

Hospital outbreak of carbapenem-resistant Enterobacteriales associated with an OXA-48 plasmid carried mostly by Escherichia coli ST399

A hospital outbreak of carbapenem-resistant Enterobacteriales was detected by routine surveillance. Whole genome sequencing and subsequent analysis revealed a conserved promiscuous OXA-48 carrying plasmid as the defining factor within this outbreak. Four different species of Enterobacteriales were involved in the outbreak. Escherichia coli ST399 accounted for 20/55 of all the isolates. Comparative genomics with publicly available E. coli ST399 sequence data showed that the outbreak isolates formed a unique clade. The OXA-48 plasmid identified in the outbreak differed from other known plasmids by an estimated five homologous recombination events. We estimated a lower bound to the plasmid conjugation rate to be 0.23 conjugation events per lineage per year. Our analysis suggests co-evolution between the plasmid and its main bacterial host to be a key driver of the outbreak. This is the first study to report carbapenem-resistant E. coli ST399 carrying OXA48 as the main cause of a plasmid-borne outbreak within a hospital setting. This study supports complementary roles for both plasmid conjugation and clonal expansion in the emergence of this outbreak.

evolutionary biology↗

bioRxiv2020

Population genomics and antimicrobial resistance in Corynebacterium diphtheriae

Corynebacterium diphtheriae, the agent of diphtheria, is a genetically diverse bacterial species. Although antimicrobial resistance has emerged against several drugs including first-line penicillin, the genomic determinants and population dynamics of resistance are largely unknown for this neglected human pathogen. Here we analyzed the associations of antimicrobial susceptibility phenotypes, diphtheria toxin production and genomic features in C. diphtheriae. We used 247 strains collected over several decades in multiple world regions, including the 163 clinical isolates collected prospectively from 2008 to 2017 in France mainland and overseas territories. Phylogenetic analysis revealed multiple deep-branching sublineages, grouped into a Mitis lineage strongly associated with diphtheria toxin production, and a tox-negative Gravis lineage with few tox+ exceptions including the 1990s ex-Soviet Union outbreak strain. The distribution of susceptibility phenotypes allowed proposing ecological cutoffs for most of the 19 agents tested, thereby defining acquired antimicrobial resistance. Penicillin resistance was found in 17.2% of prospective isolates. Four isolates were multidrug resistant (>8 agents), including to penicillin and macrolides. Homologous recombination was frequent (r/m = 5) and horizontal gene transfer contributed to the emergence of antimicrobial resistance in multiple sublineages. Genome-wide association mapping uncovered genetic factors of resistance, including an accessory penicillin-binding protein (PBP2m) located in diverse genomic contexts. Gene pbp2m is widespread in other Corynebacterium species and its expression in C. glutamicum demonstrated its effect against several beta-lactams. A novel 73-kb C. diphtheriae multi-resistance plasmid was discovered. This work uncovers the dynamics of antimicrobial resistance in C. diphtheriae in the context of phylogenetic structure, biovar and diphtheria toxin production, and provides a blueprint to analyze re-emerging diphtheria.

microbiology↗

bioRxiv2020

Emerging phylogenetic structure of the SARS-CoV-2 pandemic

Since spilling over into humans, SARS-CoV-2 has rapidly spread across the globe, accumulating significant genetic diversity. The structure of this genetic diversity, and whether it reveals epidemiological insights, are fundamental questions for understanding the evolutionary trajectory of this virus. Here we use a recently developed phylodynamic approach to uncover phylogenetic structures underlying the SARS-CoV-2 pandemic. We find support for three SARS-CoV-2 lineages co-circulating, each with significantly different demographic dynamics concordant with known epidemiological factors. For example, Lineage C emerged in Europe with a high growth rate in late February, just prior to the exponential increase in cases in several European countries. Mutations that characterize Lineage C in particular are non-synonymous and occur in functionally important gene regions responsible for viral replication and cell entry. Even though Lineages A and B had distinct demographic patterns, they were much more difficult to distinguish. Continuous application of phylogenetic approaches to track the evolutionary epidemiology of SARS-CoV-2 lineages will be increasingly important to validate the efficacy of control efforts and monitor significant evolutionary events in the future.

genetics↗

bioRxiv2020

Speeding up Inference of Homologous Recombination in Bacteria

Bacteria reproduce clonally but most species recombine frequently, so that the ancestral process is best captured using an ancestral recombination graph. This graph model is often too complex to be used in an inferential setup, but it can be approximated for example by the ClonalOrigin model. Inference in the ClonalOrigin model is performed via a Reversible-Jump Markov Chain Monte Carlo algorithm, which attempts to jointly explore: the recombination rate, the number of recombination events, the departure and arrival points on the clonal genealogy for each recombination event, and the range of genomic sites affected by each recombination event. However, the Reversible-Jump algorithm usually performs poorly due to the complexity of the target distribution since it needs to explore spaces of different dimensions. Recent developments in Bayesian computation methodology have provided ways to improve existing methods and code, but are not well-known outside the statistics community. We show how exploiting one of these new computational methods can lead to faster inference under the ClonalOrigin model.

evolutionary biology↗

bioRxiv2020

The sudden emergence of a Neisseria gonorrhoeae strain with reduced susceptibility to extended-spectrum cephalosporins, Norway

The Neisseria gonorrhoeae multilocus sequence type (ST) 7827 emerged in dramatic fashion in Norway in the period 2016-2018. Here, we aim to determine what enabled it to establish and spread so quickly. In Norway, ST-7827 isolates were almost exclusively isolated from men. Phylogeographic analyses demonstrated an Asian origin of the ST with multiple importation events to Europe. The ST was uniformly resistant to fluoroquinolones and associated with reduced susceptibility to both azithromycin and the extended-spectrum cephalosporins (ESC) cefixime and ceftriaxone. We identified additional independent events of acquisition of penA and porB alleles in Europe, associated with further reduction in cefixime and ceftriaxone susceptibility, respectively. Transmission of the ST was largely curbed in Norway in 2019, but our results indicate the existence of a reservoir in Europe. The worrisome drug resistance profile and rapid emergence of ST-7827 calls for close monitoring of the situation.

genomics↗

bioRxiv2019

Identification of hidden population structure in time-scaled phylogenies

Population structure influences genealogical patterns, however data pertaining to how populations are structured are often unavailable or not directly observable. Inference of population structure is highly important in molecular epidemiology where pathogen phylogenetics is increasingly used to infer transmission patterns and detect outbreaks. Discrepancies between observed and idealised genealogies, such as those generated by the coalescent process, can be quantified, and where significant differences occur, may reveal the action of natural selection, host population structure, or other demographic and epidemiological heterogeneities. We have developed a fast non-parametric statistical test for detection of cryptic population structure in time-scaled phylogenetic trees. The test is based on contrasting estimated phylogenies with the theoretically expected phylodynamic ordering of common ancestors in two clades within a coalescent framework. These statistical tests have also motivated the development of algorithms which can be used to quickly screen a phylogenetic tree for clades which are likely to share a distinct demographic or epidemiological history. Epidemiological applications include identification of outbreaks in vulnerable host populations or rapid expansion of genotypes with a fitness advantage. To demonstrate the utility of these methods for outbreak detection, we applied the new methods to large phylogenies reconstructed from thousands of HIV-1 partial pol sequences. This revealed the presence of clades which had grown rapidly in the recent past, and was significantly concentrated in young men, suggesting recent and rapid transmission in that group. Furthermore, to demonstrate the utility of these methods for the study of antimicrobial resistance, we applied the new methods to a large phylogeny reconstructed from whole genome Neisseria gonorrhoeae sequences. We find that population structure detected using these methods closely overlaps with the appearance and expansion of mutations conferring antimicrobial resistance.

evolutionary biology↗

bioRxiv2019

Vaccination against antibiotic resistant gonorrhoea for men who have sex with men in England: a modelling study

BackgroundGonorrhoea incidence is increasing rapidly: diagnoses in men who have sex with men (MSM) in England increased eight-fold 2008-2017. Concurrently, antibiotic resistance is making treatment more difficult, leading to renewed interest in a gonococcal vaccine. The MeNZB meningococcal B vaccine is partially protective, and several other candidates are in development. We modelled realistic vaccination strategies under various scenarios of antibiotic resistance and vaccine protection level and duration, to assess the impact of vaccination and examine the feasibility of the WHOs target of reducing gonorrhoea incidence by 90% between 2016 and 2030.\n\nMethodsWe fitted a stochastic transmission-dynamic model, incorporating asymptomatic and symptomatic infection and heterogeneous sexual behaviour, to gonorrhoea incidence in MSM in England, 2008-17, using particle Markov Chain Monte Carlo methods. Bayesian forecasting was used to examine future scenarios, including emergence of extensively antibiotic-resistant (ABR) gonorrhoea.\n\nFindingsEven in the worst-case scenario of untreatable infection emerging, the WHO target could be met by vaccinating all MSM attending sexual health clinics with a 53%-protective vaccine lasting for >6 years, or a 70%-protective vaccine lasting >3 years. A vaccine like MeNZB, conferring 30% protection for 2-4 years, could reduce incidence in 2030 by 45% in the worst-case scenario, and by 75% if >70% of ABR gonorrhoea is treatable.\n\nInterpretationOur statistically-rigorous assessment shows that even a partially-protective vaccine, delivered through a practical targeting strategy, could have substantial benefit in reducing gonorrhoea incidence in the context of an epidemic with rising antibiotic resistance.

microbiology↗

bioRxiv2019

Phylogenomic analysis reveals the basis of adaptation of Pseudorhizobium species to extreme environments

The family Rhizobiaceae includes many genera of soil bacteria, often isolated for their association with plants. Herein, we investigate the genomic diversity of a group of Rhizobium species and unclassified strains isolated from atypical environments, including seawater, rock matrix or polluted soil. Based on whole-genome similarity and core genome phylogeny, we show that this group corresponds to the genus Pseudorhizobium. We thus reclassify Rhizobium halotolerans, R. marinum, R. flavum and R. endolithicum as P. halotolerans comb. nov., P. marinum comb. nov., P. flavum comb. nov. and R. endolithicum comb. nov., respectively, and show that P. pelagicum is a synonym of P. marinum. We also delineate a new chemolithoautotroph species, P. banfieldiae sp. nov., whose type strain is NT-26T (= DSM 106348T = CFBP 8663T). This genome-based classification was supported by a chemotaxonomic comparison, with gradual taxonomic resolution provided by fatty acid, protein and metabolic profiles. In addition, we used a phylogenetic approach to infer scenarios of duplication, horizontal transfer and loss for all genes in the Pseudorhizobium pangenome. We thus identify the key functions associated with the diversification of each species and higher clades, shedding light on the mechanisms of adaptation to their respective ecological niches. Respiratory proteins acquired at the origin of Pseudorhizobium are combined with clade-specific genes to encode different strategies for detoxification and nutrition in harsh, nutrient-poor environments. Finally, we predict diagnostic phenotypes for the distinction of P. banfieldiae from other Pseudorhizobium species, including autotrophy and sensitivity to the azo dye Congo Red, which we experimentally validated.

microbiology↗

bioRxiv2019

The speciation and hybridization history of the genus Salmonella

Bacteria and archaea make up most of natural diversity but the mechanisms that underlie the origin and maintenance of prokaryotic species are poorly understood. We investigated the speciation history of the genus Salmonella, an ecologically diverse bacterial lineage, within which S. enterica subsp. enterica is responsible for important human food-borne infections. We performed a survey of diversity across a large reference collection using multilocus sequence typing, followed by genome sequencing of distinct lineages. We identified eleven distinct phylogroups, three of which were previously undescribed. Strains assigned to S. enterica subsp. salamae are polyphyletic, with two distinct lineages that we designate Salamae A and Salamae B. Strains of subspecies houtenae are subdivided into two groups, Houtenae A and B and are both related to Selanders group VII. A phylogroup we designate VIII was previously unknown. A simple binary fission model of speciation cannot explain observed patterns of sequence diversity. In the recent past, there have been large scale hybridization events involving an unsampled ancestral lineage and three distantly related lineages of the genus that have given rise to Houtenae A, Houtenae B and VII. We found no evidence for ongoing hybridization in the other eight lineages but detected more subtle signals of ancient recombination events. We are unable to fully resolve the speciation history of the genus, which might have involved additional speciation-by-hybridization or multi-way speciation events. Our results imply that traditional models of speciation by binary fission and divergence may not apply in Salmonella.\n\nData summaryIllumina sequence data were submitted to the European Nucleotide Archive under project number PRJEB2099 and are available from INSDC (NCBI/ENA/DDBJ) under accession numbers ERS011101 to ERS011146. The MLST sequence and profile data generated in this study have been publicly available on the Salmonella MLST web site between 2010 and the migration of the Salmonella MLST website to EnteroBase (https://enterobase.warwick.ac.uk/), and subsequently from there.

microbiology↗

bioRxiv2019

Automated reconstruction of all gene histories in large bacterial pangenome datasets and search for co-evolved gene modules with Pantagruel

The availability of bacterial pangenome data grows exponentially, requiring efficient new methods of analysis. Currently popular approaches for the fast comparison of genomes have the drawback of not being based on explicit evolutionary models of diversification. Making sense of bacterial genome evolution, and notably in the accessory genome, requires however to take into account the complex processes by which the genomes evolve. Here we present the Pantagruel bioinformatic software pipeline, which enables the construction of a complete bacterial pangenome database geared towards the inference of gene evolution scenarios using gene tree/species tree reconciliation. Pantagruel is a modular pipeline that combines state-of-the-art external software with unique new methods. It can be executed with no supervision to perform a standard pangenome analysis, or be configured by advanced users to integrate methods of choice. A relational database underlies its data structure, allowing efficient retrieval of the large-scale data generated by integrative analyses of pangenome evolutionary history. From the reconstructed gene evolution scenarios, two main outputs are derived: firstly the gene tree-aware assignation of orthology, allowing the fine analysis of gene gain and loss history over the species phylogeny, and secondly a network of gene-to-gene association based on correlated events in scenarios of gene evolution, leading to the definition of co-evolved gene modules. Pantagruel is available as an open source software package at https://github.com/flass/pantagruel.

bioinformatics↗

bioRxiv2018

Why panmictic bacteria are rare

BackgroundBacteria typically have more structured populations than higher eukaryotes, but this difference is surprising given high recombination rates, enormous population sizes and effective geographical dispersal in many bacterial species.\n\nResultsWe estimated the recombination scaled effective population size Ner in 21 bacterial species and find that it does not correlate with synonymous nucleotide diversity as would be expected under neutral models of evolution. Only two species have estimates substantially over 100, consistent with approximate panmixia, namely Helicobacter pylori and Vibrio parahaemolyticus. Both species are far from demographic equilibrium, with diversity predicted to increase more than 30 fold in V. parahaemolyticus if the current value of Ner were maintained, to values much higher than found in any species. We propose that panmixia is unstable in bacteria, and that persistent environmental species are likely to evolve barriers to genetic exchange, which act to prevent a continuous increase in diversity by enhancing genetic drift.\n\nConclusionsOur results highlight the dynamic nature of bacterial population structures and imply that overall diversity levels found within a species are poor indicators of its size.

microbiology↗