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• Pöntinen, Anna Kaarina; Trung, Nguyen Vinh; Mallawaarachchi, Sudaraka; Gladstone, Rebecca Ashley; Kuronen, Juri & Samuelsen, Ørjan [Vis alle 15 forfattere av denne artikkelen] (2026). Mapping the evolutionary path towards multi-drug resistance in the pandemic Escherichia coli ST131 lineage. Microbial Genomics. 12(9). doi: 10.1099/mgen.0.001795. Fulltekst i vitenarkiv
• Gladstone, Rebecca Ashley; Pesonen, Maiju; Pöntinen, Anna Kaarina; Mäklin, Tommi; MacAlasdair, Neil Zhang Nian Zhong & Thorpe, Harry [Vis alle 17 forfattere av denne artikkelen] (2026). Identification of transporter-dependent capsular loci associated with the invasive potential of Escherichia coli. Nature Microbiology. doi: 10.1038/s41564-026-02283-w. Fulltekst i vitenarkiv Vis sammendrag

  Bacterial polysaccharide capsules contribute to antigenic diversity and immune evasion. Escherichia coli infections, including those caused by extraintestinal pathogenic E. coli (ExPEC), cause substantial antimicrobial resistance-associated morbidity and mortality. However, much-needed genotypic methods for E. coli capsule typing to aid epidemiological analysis and therapeutic design are lacking. Here we describe the curation of an in silico typing database for group 2 and 3 ATP-binding cassette transporter-dependent capsule (K) loci from 18,185 kps-positive E. coli genomes from all continents and its application to carriage and ExPEC disease cohorts. Capsules K1, K5 and K2 were the most common types in European BSIs, and together with K100 and K52 they were responsible for 58% of multidrug resistance, with differing associations with invasiveness. Homologous recombination, insertion sequences and plasmids were associated with capsular gene exchange. These findings improve understanding of capsule epidemiology and evolution to inform future diagnostic and therapeutic strategies to combat ExPEC infections.

• Xie, Ouli; Featherstone, Leo; Nguyen, An N.T.; Hayes, Andrew J.; Pitt, Miranda E. & Spring, Stephanie [Vis alle 24 forfattere av denne artikkelen] (2025). Invasive Streptococcus dysgalactiae subspecies equisimilis compared with Streptococcus pyogenes in Australia, 2011–23, and the emergence of a multi-continent stG62647 lineage: a retrospective clinical and genomic epidemiology study. Lancet Microbe. 6(10). doi: 10.1016/j.lanmic.2025.101182. Fulltekst i vitenarkiv
• Ojala, Fanni; Pesonen, Henri; Gladstone, Rebecca Ashley; Mäklin, Tommi; Tonkin-Hill, Gerry & Marttinen, Pekka [Vis alle 7 forfattere av denne artikkelen] (2025). Basic reproduction number varies markedly between closely related pandemic Escherichia coli clones. Nature Communications. 16(1). doi: 10.1038/s41467-025-65301-1. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Extra-intestinal pathogenic Escherichia coli ubiquitously colonize the human gut and represent clinically the most significant bacterial species causing urinary tract infections and bacteremia. During the last two decades clades of the ST131 lineage have spread globally, but it remains unknown how their transmission dynamics compare to the basic reproduction numbers ( R 0 ) for viral pandemics. We develop a compartmental model for asymptomatic gut colonization and onward transmission coupled with an epidemiological observation model and fit it on the major ST131 clades. Our results indicate that the ST131-A transmission potential ( R 0 = 1.47) can be comparable to pandemic influenza viruses, while the significantly lower transmissibility of ST131-C1 ( R 0 = 1.18) and ST131-C2 ( R 0 = 1.13) suggests that their dissemination has been aided by antibiotic selection pressure and healthcare facilities. Our results provide an advance in understanding the relative transmissibility of these opportunistic pathogens.

• Tonkin-Hill, Gerry; Ruis, Christopher; Bentley, Stephen D.; Lythgoe, Katrina A. & Bryant, Josephine M. (2025). Within-host bacterial evolution and the emergence of pathogenicity. Nature Microbiology. doi: 10.1038/s41564-025-02036-1. Fulltekst i vitenarkiv
• Alonso, Sergio Arredondo; Pöntinen, Anna Kaarina; Gama, João Alves; Gladstone, Rebecca Ashley; Harms, Klaus & Tonkin-Hill, Gerry [Vis alle 23 forfattere av denne artikkelen] (2025). Plasmid-driven strategies for clone success in Escherichia coli. Nature Communications. 16, s. 1–15. doi: 10.1038/s41467-025-57940-1. Fulltekst i vitenarkiv
• Xie, Ouli; Morris, Jacqueline M.; Hayes, Andrew J.; Towers, Rebecca J.; Jespersen, Magnus G. & Lees, John A. [Vis alle 32 forfattere av denne artikkelen] (2024). Inter-species gene flow drives ongoing evolution of Streptococcus pyogenes and Streptococcus dysgalactiae subsp. equisimilis. Nature Communications. 15(1). doi: 10.1038/s41467-024-46530-2. Fulltekst i vitenarkiv Vis sammendrag

  Streptococcus dysgalactiae subsp. equisimilis (SDSE) is an emerging cause of human infection with invasive disease incidence and clinical manifestations comparable to the closely related species, Streptococcus pyogenes. Through systematic genomic analyses of 501 disseminated SDSE strains, we demonstrate extensive overlap between the genomes of SDSE and S. pyogenes. More than 75% of core genes are shared between the two species with one third demonstrating evidence of cross-species recombination. Twenty-five percent of mobile genetic element (MGE) clusters and 16 of 55 SDSE MGE insertion regions were shared across species. Assessing potential cross-protection from leading S. pyogenes vaccine candidates on SDSE, 12/34 preclinical vaccine antigen genes were shown to be present in >99% of isolates of both species. Relevant to possible vaccine evasion, six vaccine candidate genes demonstrated evidence of inter-species recombination. These findings demonstrate previously unappreciated levels of genomic overlap between these closely related pathogens with implications for streptococcal pathobiology, disease surveillance and prevention.

• Hackman, Jada; Hibberd, Martin L.; Swarthout, Todd D.; Hinds, Jason; Ashall, James & Sheppard, Carmen [Vis alle 18 forfattere av denne artikkelen] (2024). Evaluating methods for identifying and quantifying Streptococcus pneumoniae co-colonization using next-generation sequencing data. Microbiology spectrum. 12(12). doi: 10.1128/spectrum.03643-23. Fulltekst i vitenarkiv Vis sammendrag

  Detection of multiple pneumococcal serotype carriage can enhance monitoring of pneumococcal vaccine impact, particularly among high-burden childhood populations. We assessed methods for identifying co-carriage of pneumococcal serotypes from whole-genome sequences. Twenty-four nasopharyngeal samples were collected during community carriage surveillance from healthy children in Blantyre, Malawi, which were then serotyped by microarray. Pneumococcal DNA from culture plate sweeps were sequenced using Illumina MiSeq, and genomic serotyping was carried out using SeroCall and PneumoKITy. Their sensitivity was calculated in reference to the microarray data. Local maxima in the single-nucleotide polymorphism (SNP) density distributions were assessed for their correspondence to the relative abundance of serotypes. Across the 24 individuals, the microarray detected 77 non-unique serotypes, of which 42 occurred at high relative abundance (>10%) (per individual, median, 3; range, 1–6 serotypes). The average sequencing depth was 57X (range: 21X–88X). The sensitivity of SeroCall for identifying high-abundance serotypes was 98% (95% CI, 0.87–1.00), 20% (0.08–0.36) for low abundance (<10%), and 62% (0.50–0.72) overall. PneumoKITy’s sensitivity was 86% (0.72–0.95), 20% (0.06–0.32), and 56% (0.42–0.65), respectively. Local maxima in the SNP frequency distribution were highly correlated with the relative abundance of high-abundance serotypes. Six samples were resequenced, and the pooled runs had an average fourfold increase in sequencing depth. This allowed genomic serotyping of two of the previously undetectable seven low-abundance serotypes. Genomic serotyping is highly sensitive for the detection of high-abundance serotypes in samples with co-carriage. Serotype-associated reads may be identified through SNP frequency, and increased read depth can increase sensitivity for low-abundance serotype detection.

• Kuronen, Juri; Horsfield, Samuel T.; Pöntinen, Anna Kaarina; Mallawaarachchi, Sudaraka; Alonso, Sergio Arredondo & Thorpe, Harry [Vis alle 14 forfattere av denne artikkelen] (2024). Pangenome-spanning epistasis and coselection analysis via de Bruijn graphs. Genome Research. ISSN 1088-9051. 34(7), s. 1081–1088. doi: 10.1101/gr.278485.123. Fulltekst i vitenarkiv Vis sammendrag

  Studies of bacterial adaptation and evolution are hampered by the difficulty of measuring traits such as virulence, drug resistance, and transmissibility in large populations. In contrast, it is now feasible to obtain high-quality complete assemblies of many bacterial genomes thanks to scalable high-accuracy long-read sequencing technologies. To exploit this opportunity, we introduce a phenotype- and alignment-free method for discovering coselected and epistatically interacting genomic variation from genome assemblies covering both core and accessory parts of genomes. Our approach uses a compact colored de Bruijn graph to approximate the intragenome distances between pairs of loci for a collection of bacterial genomes to account for the impacts of linkage disequilibrium (LD). We demonstrate the versatility of our approach to efficiently identify associations between loci linked with drug resistance and adaptation to the hospital niche in the major human bacterial pathogens Streptococcus pneumoniae and Enterococcus faecalis.

• Arachchi, Sudaraka Mallawa; Tonkin-Hill, Gerry; Pöntinen, Anna Kaarina; Calland, Jessica Kate; Gladstone, Rebecca Ashley & Alonso, Sergio Arredondo [Vis alle 13 forfattere av denne artikkelen] (2024). Detecting co-selection through excess linkage disequilibrium in bacterial genomes. NAR Genomics and Bioinformatics. 6(2). doi: 10.1093/nargab/lqae061. Fulltekst i vitenarkiv Vis sammendrag

  Population genomics has revolutionized our ability to study bacterial evolution by enabling data-driven discovery of the genetic architecture of trait variation. Genome-wide association studies (GWAS) have more recently become accompanied by genome-wide epistasis and co-selection (GWES) analysis, which offers a phenotype-free approach to generating hypotheses about selective processes that simultaneously impact multiple loci across the genome. However, existing GWES methods only consider associations between distant pairs of loci within the genome due to the strong impact of linkage-disequilibrium (LD) over short distances. Based on the general functional organisation of genomes it is nevertheless expected that majority of co-selection and epistasis will act within relatively short genomic proximity, on co-variation occurring within genes and their promoter regions, and within operons. Here, we introduce LDWeaver, which enables an exhaustive GWES across both short- and long-range LD, to disentangle likely neutral co-variation from selection. We demonstrate the ability of LDWeaver to efficiently generate hypotheses about co-selection using large genomic surveys of multiple major human bacterial pathogen species and validate several findings using functional annotation and phenotypic measurements. Our approach will facilitate the study of bacterial evolution in the light of rapidly expanding population genomic data.

• Belman, Sophie; Lefrancq, Noémie; Nzenze, Susan; Downs, Sarah; Plessis, Mignon du & Lo, Stephanie W. [Vis alle 97 forfattere av denne artikkelen] (2024). Geographical migration and fitness dynamics of Streptococcus pneumoniae. Nature. ISSN 0028-0836. 631, s. 386–392. doi: 10.1038/s41586-024-07626-3. Fulltekst i vitenarkiv Vis sammendrag

  Streptococcus pneumoniae is a leading cause of pneumonia and meningitis worldwide. Many different serotypes co-circulate endemically in any one location1,2. The extent and mechanisms of spread and vaccine-driven changes in fitness and antimicrobial resistance remain largely unquantified. Here using geolocated genome sequences from South Africa (n = 6,910, collected from 2000 to 2014), we developed models to reconstruct spread, pairing detailed human mobility data and genomic data. Separately, we estimated the population-level changes in fitness of strains that are included (vaccine type (VT)) and not included (non-vaccine type (NVT)) in pneumococcal conjugate vaccines, first implemented in South Africa in 2009. Differences in strain fitness between those that are and are not resistant to penicillin were also evaluated. We found that pneumococci only become homogenously mixed across South Africa after 50 years of transmission, with the slow spread driven by the focal nature of human mobility. Furthermore, in the years following vaccine implementation, the relative fitness of NVT compared with VT strains increased (relative risk of 1.68; 95% confidence interval of 1.59–1.77), with an increasing proportion of these NVT strains becoming resistant to penicillin. Our findings point to highly entrenched, slow transmission and indicate that initial vaccine-linked decreases in antimicrobial resistance may be transient.

• Thorpe, Harry; Pesonen, Maiju; Corbella, Marta; Pesonen, Henri; Gaiarsa, Stefano & Boinett, Christine J [Vis alle 28 forfattere av denne artikkelen] (2024). Pan-pathogen deep sequencing of nosocomial bacterial pathogens in Italy in spring 2020: a prospective cohort study. Lancet Microbe. 5(10). doi: 10.1016/S2666-5247(24)00113-7. Fulltekst i vitenarkiv Vis sammendrag

  Background Nosocomial infections pose a considerable risk to patients who are susceptible, and this is particularly acute in intensive care units when hospital-associated bacteria are endemic. During the first wave of the COVID-19 pandemic, the surge of patients presented a significant obstacle to the effectiveness of infection control measures. We aimed to assess the risks and extent of nosocomial pathogen transmission under a high patient burden by designing a novel bacterial pan-pathogen deep-sequencing approach that could be integrated with standard clinical surveillance and diagnostics workflows. Methods We did a prospective cohort study in a region of northern Italy that was severely affected by the first wave of the COVID-19 pandemic. Inpatients on both ordinary and intensive care unit (ICU) wards at the San Matteo hospital, Pavia were sampled on multiple occasions to identify bacterial pathogens from respiratory, nasal, and rectal samples. Diagnostic samples collected between April 7 and May 10, 2020 were cultured on six different selective media designed to enrich for Acinetobacter baumannii, Escherichia coli, Enterococcus faecium, Enterococcus faecalis, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae, and DNA from each plate with positive growth was deep sequenced en masse. We used mSWEEP and mGEMS to bin sequencing reads by sequence cluster for each species, followed by mapping with snippy to generate high quality alignments. Antimicrobial resistance genes were detected by use of ARIBA and CARD. Estimates of hospital transmission were obtained from pairwise bacterial single nucleotide polymorphism distances, partitioned by within-patient and between-patient samples. Finally, we compared the accuracy of our binned Acinetobacter baumannii genomes with those obtained by single colony whole-genome sequencing of isolates from the same hospital. Findings We recruited patients from March 1 to May 7, 2020. The pathogen population among the patients was large and diverse, with 2148 species detections overall among the 2418 sequenced samples from the 256 patients. In total, 55 sequence clusters from key pathogen species were detected at least five times. The antimicrobial resistance gene prevalence was correspondingly high, with key carbapenemase and extended spectrum ß-lactamase genes detected in at least 50 (40%) of 125 patients in ICUs. Using high-resolution mapping to infer transmission, we established that hospital transmission was likely to be a significant mode of acquisition for each of the pathogen species. Finally, comparison with single colony Acinetobacter baumannii genomes showed that the resolution offered by deep sequencing was equivalent to single-colony sequencing, with the additional benefit of detection of co-colonisation of highly similar strains. Interpretation Our study shows that a culture-based deep-sequencing approach is a possible route towards improving future pathogen surveillance and infection control at hospitals. Future studies should be designed to directly compare the accuracy, cost, and feasibility of culture-based deep sequencing with single colony whole-genome sequencing on a range of bacterial species. Funding Wellcome Trust, European Research Council, Academy of Finland Flagship program, Trond Mohn Foundation, and Research Council of Norway.

• Xie, Ouli; Zachreson, Cameron; Tonkin-Hill, Gerry; Price, David J.; Lacey, Jake A. & Morris, Jacqueline M. [Vis alle 15 forfattere av denne artikkelen] (2024). Overlapping Streptococcus pyogenes and Streptococcus dysgalactiae subspecies equisimilis household transmission and mobile genetic element exchange. Nature Communications. 15(1). doi: 10.1038/s41467-024-47816-1. Fulltekst i vitenarkiv Vis sammendrag

  Streptococcus dysgalactiae subspecies equisimilis (SDSE) and Streptococcus pyogenes share skin and throat niches with extensive genomic homology and horizontal gene transfer (HGT) possibly underlying shared disease phenotypes. It is unknown if cross-species transmission interaction occurs. Here, we conduct a genomic analysis of a longitudinal household survey in remote Australian First Nations communities for patterns of cross-species transmission interaction and HGT. Collected from 4547 person-consultations, we analyse 294 SDSE and 315 S. pyogenes genomes. We find SDSE and S. pyogenes transmission intersects extensively among households and show that patterns of co-occurrence and transmission links are consistent with independent transmission without inter-species interference. We identify at least one of three near-identical cross-species mobile genetic elements (MGEs) carrying antimicrobial resistance or streptodornase virulence genes in 55 (19%) SDSE and 23 (7%) S. pyogenes isolates. These findings demonstrate co-circulation of both pathogens and HGT in communities with a high burden of streptococcal disease, supporting a need to integrate SDSE and S. pyogenes surveillance and control efforts.

• Alonso, Sergio Arredondo; Gladstone, Rebecca Ashley; Pöntinen, Anna Kaarina; Gama, João Alves; Schürch, Anita C. & Lanza, Val F. [Vis alle 10 forfattere av denne artikkelen] (2023). Mge-cluster: a reference-free approach for typing bacterial plasmids. NAR Genomics and Bioinformatics. 5(3). doi: 10.1093/nargab/lqad066. Fulltekst i vitenarkiv Vis sammendrag

  Extrachromosomal elements of bacterial cells such as plasmids are notorious for their importance in evolution and adaptation to changing ecology. However, high-resolution population-wide analysis of plasmids has only become accessible recently with the advent of scalable long-read sequencing technology. Current typing methods for the classification of plasmids remain limited in their scope which motivated us to develop a computationally efficient approach to simultaneously recognize novel types and classify plasmids into previously identified groups. Here, we introduce mge-cluster that can easily handle thousands of input sequences which are compressed using a unitig representation in a de Bruijn graph. Our approach offers a faster runtime than existing algorithms, with moderate memory usage, and enables an intuitive visualization, classification and clustering scheme that users can explore interactively within a single framework. Mge-cluster platform for plasmid analysis can be easily distributed and replicated, enabling a consistent labelling of plasmids across past, present, and future sequence collections. We underscore the advantages of our approach by analysing a population-wide plasmid data set obtained from the opportunistic pathogen Escherichia coli, studying the prevalence of the colistin resistance gene mcr-1.1 within the plasmid population, and describing an instance of resistance plasmid transmission within a hospital environment.

• Horsfield, Samuel T.; Tonkin-Hill, Gerry; Croucher, Nicholas J. & Lees, John A. (2023). Accurate and fast graph-based pangenome annotation and clustering with ggCaller. Genome Research. ISSN 1088-9051. 33(9), s. 1622–1637. doi: 10.1101/gr.277733.123. Fulltekst i vitenarkiv Vis sammendrag

  Bacterial genomes differ in both gene content and sequence mutations, which underlie extensive phenotypic diversity, including variation in susceptibility to antimicrobials or vaccine-induced immunity. To identify and quantify important variants, all genes within a population must be predicted, functionally annotated, and clustered, representing the “pangenome.” Despite the volume of genome data available, gene prediction and annotation are currently conducted in isolation on individual genomes, which is computationally inefficient and frequently inconsistent across genomes. Here, we introduce the open-source software graph-gene-caller (ggCaller). ggCaller combines gene prediction, functional annotation, and clustering into a single workflow using population-wide de Bruijn graphs, removing redundancy in gene annotation and resulting in more accurate gene predictions and orthologue clustering. We applied ggCaller to simulated and real-world bacterial data sets containing hundreds or thousands of genomes, comparing it to current state-of-the-art tools. ggCaller has considerable speed-ups with equivalent or greater accuracy, particularly with data sets containing complex sources of error, such as assembly contamination or fragmentation. ggCaller is also an important extension to bacterial genome-wide association studies, enabling querying of annotated graphs for functional analyses. We highlight this application by functionally annotating DNA sequences with significant associations to tetracycline and macrolide resistance in Streptococcus pneumoniae , identifying key resistance determinants that were missed when using only a single reference genome. ggCaller is a novel bacterial genome analysis tool with applications in bacterial evolution and epidemiology.

• Tonkin-Hill, Gerry; Corander, Jukka & Parkhill, Julian (2023). Challenges in prokaryote pangenomics. Microbial Genomics. 9(5). doi: 10.1099/mgen.0.001021. Fulltekst i vitenarkiv Vis sammendrag

  Horizontal gene transfer (HGT) and the resulting patterns of gene gain and loss are a fundamental part of bacterial evolution. Investigating these patterns can help us to understand the role of selection in the evolution of bacterial pangenomes and how bacteria adapt to a new niche. Predicting the presence or absence of genes can be a highly error-prone process that can confound efforts to understand the dynamics of horizontal gene transfer. This review discusses both the challenges in accurately constructing a pangenome and the potential consequences errors can have on downstream analyses. We hope that by summarizing these issues researchers will be able to avoid potential pitfalls, leading to improved bacterial pangenome analyses.

• Tonkin-Hill, Gerry; Gladstone, Rebecca Ashley; Pöntinen, Anna Kaarina; Alonso, Sergio Arredondo; Bentley, Stephen D. & Corander, Jukka (2023). Robust analysis of prokaryotic pangenome gene gain and loss rates with Panstripe. Genome Research. ISSN 1088-9051. 33(1), s. 129–140. doi: 10.1101/gr.277340.122. Fulltekst i vitenarkiv Vis sammendrag

  Horizontal gene transfer (HGT) plays a critical role in the evolution and diversification of many microbial species. The resulting dynamics of gene gain and loss can have important implications for the development of antibiotic resistance and the design of vaccine and drug interventions. Methods for the analysis of gene presence/absence patterns typically do not account for errors introduced in the automated annotation and clustering of gene sequences. In particular, methods adapted from ecological studies, including the pangenome gene accumulation curve, can be misleading as they may reflect the underlying diversity in the temporal sampling of genomes rather than a difference in the dynamics of HGT. Here, we introduce Panstripe, a method based on generalized linear regression that is robust to population structure, sampling bias, and errors in the predicted presence/absence of genes. We show using simulations that Panstripe can effectively identify differences in the rate and number of genes involved in HGT events, and illustrate its capability by analyzing several diverse bacterial genome data sets representing major human pathogens.

• Ruis, Christopher; Weimann, Aaron; Tonkin-Hill, Gerry; Pandurangan, Arun Prasad; Matuszewska, Marta & Murray, Gemma G. R. [Vis alle 10 forfattere av denne artikkelen] (2023). Mutational spectra are associated with bacterial niche. Nature Communications. 14(1). doi: 10.1038/s41467-023-42916-w. Fulltekst i vitenarkiv Vis sammendrag

  Abstract As observed in cancers, individual mutagens and defects in DNA repair create distinctive mutational signatures that combine to form context-specific spectra within cells. We reasoned that similar processes must occur in bacterial lineages, potentially allowing decomposition analysis to detect both disruption of DNA repair processes and exposure to niche-specific mutagens. Here we reconstruct mutational spectra for 84 clades from 31 diverse bacterial species and find distinct mutational patterns. We extract signatures driven by specific DNA repair defects using hypermutator lineages, and further deconvolute the spectra into multiple signatures operating within different clades. We show that these signatures are explained by both bacterial phylogeny and replication niche. By comparing mutational spectra of clades from different environmental and biological locations, we identify niche-associated mutational signatures, and then employ these signatures to infer the predominant replication niches for several clades where this was previously obscure. Our results show that mutational spectra may be associated with sites of bacterial replication when mutagen exposures differ, and can be used in these cases to infer transmission routes for established and emergent human bacterial pathogens.

• Chaguza, Chrispin; Ebruke, Chinelo; Senghore, Madikay; Lo, Stephanie W.; Tientcheu, Peggy-Estelle & Gladstone, Rebecca Ashley [Vis alle 21 forfattere av denne artikkelen] (2022). Comparative Genomics of Disease and Carriage Serotype 1 Pneumococci. Genome Biology and Evolution (GBE). 14(4). doi: 10.1093/gbe/evac052. Fulltekst i vitenarkiv Vis sammendrag

  Abstract The isolation of Streptococcus pneumoniae serotypes in systemic tissues of patients with invasive disease versus the nasopharynx of healthy individuals with asymptomatic carriage varies widely. Some serotypes are hyper-invasive, particularly serotype 1, but the underlying genetics remain poorly understood due to the rarity of carriage isolates, reducing the power of comparison with invasive isolates. Here, we use a well-controlled genome-wide association study to search for genetic variation associated with invasiveness of serotype 1 pneumococci from a serotype 1 endemic setting in Africa. We found no consensus evidence that certain genomic variation is overrepresented among isolates from patients with invasive disease than asymptomatic carriage. Overall, the genomic variation explained negligible phenotypic variability, suggesting a minimal effect on the disease status. Furthermore, changes in lineage distribution were seen with lineages replacing each other over time, highlighting the importance of continued pathogen surveillance. Our findings suggest that the hyper-invasiveness is an intrinsic property of the serotype 1 strains, not specific for a “disease-associated” subpopulation disproportionately harboring unique genomic variation.

• Lees, John A.; Tonkin-Hill, Gerry; Yang, Zhirong & Corander, Jukka (2022). Mandrake: visualizing microbial population structure by embedding millions of genomes into a low-dimensional representation. Philosophical Transactions of the Royal Society of London. Biological Sciences. ISSN 0962-8436. 377(1861). doi: 10.1098/rstb.2021.0237. Fulltekst i vitenarkiv Vis sammendrag

  In less than a decade, population genomics of microbes has progressed fromthe effort of sequencing dozens of strains to thousands, or even tens of thou-sands of strains in a single study. There are now hundreds of thousands ofgenomes available even for a single bacterial species, and the number of gen-omes is expected to continue to increase at an accelerated pace given theadvances in sequencing technology and widespread genomic surveillanceinitiatives. This explosion of data calls for innovative methods to enablerapid exploration of the structure of a population based on different datamodalities, such as multiple sequence alignments, assemblies and estimatesof gene content across different genomes. Here, we present Mandrake, anefficient implementation of a dimensional reduction method tailored forthe needs of large-scale population genomics. Mandrake is capable of visua-lizing population structure from millions of whole genomes, and weillustrate its usefulness with several datasets representing major pathogens.Our method is freely available both as an analysis pipeline (https://github.com/johnlees/mandrake) and as a browser-based interactive application(https://gtonkinhill.github.io/mandrake-web/).This article is part of a discussion meeting issue‘Genomic populationstructures of microbial pathogens’.1. IntroductionAdvances in DNA sequencing technology have recently made whole-genomesequencing both affordable and scalable enough for routine use in pathogensurveillance by research organizations and public health agencies around theworld [1,2]. A striking example of this is genomic surveillance of the SARS-CoV-2 virus for which over one million genome sequences became availablein just 15 months after its initial discovery [3]. To shed light on population geno-mic data at this scale calls for new tools that can be used for rapid exploration ofthe structure among the samples, with particular emphasis on detecting clustersof similar sequences [4,5]. In this paper, we explore and extend a class ofmethods that aims to reduce the dimensionality of such data to only two dimen-sions, in a manner that supports ready visualization and identification ofclusters.© 2022 The Authors. Published by the Royal Society under the terms of the Creative Commons AttributionLicense http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the originalauthor and source are credited.

• Tonkin-Hill, Gerry; Ling, Clare; Chaguza, Chrispin; Salter, Susannah J.; Hinfonthong, Pattaraporn & Nikolaou, Elissavet [Vis alle 15 forfattere av denne artikkelen] (2022). Pneumococcal within-host diversity during colonization, transmission and treatment. Nature Microbiology. 7(11), s. 1791–1804. doi: 10.1038/s41564-022-01238-1. Fulltekst i vitenarkiv Vis sammendrag

  Characterizing the genetic diversity of pathogens within the host promises to greatly improve surveillance and reconstruction of transmission chains. For bacteria, it also informs our understanding of inter-strain competition and how this shapes the distribution of resistant and sensitive bacteria. Here we study the genetic diversity of Streptococcus pneumoniae within 468 infants and 145 of their mothers by deep sequencing whole pneumococcal populations from 3,761 longitudinal nasopharyngeal samples. We demonstrate that deep sequencing has unsurpassed sensitivity for detecting multiple colonization, doubling the rate at which highly invasive serotype 1 bacteria were detected in carriage compared with gold-standard methods. The greater resolution identified an elevated rate of transmission from mothers to their children in the first year of the child’s life. Comprehensive treatment data demonstrated that infants were at an elevated risk of both the acquisition and persistent colonization of a multidrug-resistant bacterium following antimicrobial treatment. Some alleles were enriched after antimicrobial treatment, suggesting that they aided persistence, but generally purifying selection dominated within-host evolution. Rates of co-colonization imply that in the absence of treatment, susceptible lineages outcompeted resistant lineages within the host. These results demonstrate the many benefits of deep sequencing for the genomic surveillance of bacterial pathogens.

• Feng, Qiang; Tiedje, Kathryn; Ruybal-Pesántez, Shazia; Tonkin-Hill, Gerry; Duffy, Michael & Day, Karen [Vis alle 8 forfattere av denne artikkelen] (2022). An accurate method for identifying recent recombinants from unaligned sequences. Bioinformatics. ISSN 1367-4803. 38(7), s. 1823–1829. doi: 10.1093/bioinformatics/btac012. Fulltekst i vitenarkiv
• Pöntinen, Anna Kaarina; Top, Janetta; Alonso, Sergio Arredondo; Tonkin-Hill, Gerry; Freitas, Ana R. & Novais, Carla [Vis alle 21 forfattere av denne artikkelen] (2021). Apparent nosocomial adaptation of Enterococcus faecalis predates the modern hospital era. Nature Communications. 12. doi: 10.1038/s41467-021-21749-5. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Enterococcus faecalis is a commensal and nosocomial pathogen, which is also ubiquitous in animals and insects, representing a classical generalist microorganism. Here, we study E. faecalis isolates ranging from the pre-antibiotic era in 1936 up to 2018, covering a large set of host species including wild birds, mammals, healthy humans, and hospitalised patients. We sequence the bacterial genomes using short- and long-read techniques, and identify multiple extant hospital-associated lineages, with last common ancestors dating back as far as the 19th century. We find a population cohesively connected through homologous recombination, a metabolic flexibility despite a small genome size, and a stable large core genome. Our findings indicate that the apparent hospital adaptations found in hospital-associated E. faecalis lineages likely predate the “modern hospital” era, suggesting selection in another niche, and underlining the generalist nature of this nosocomial pathogen.

• Horesh, Gal; Blackwell, Grace A.; Tonkin-Hill, Gerry; Corander, Jukka; Heinz, Eva & Thomson, Nicholas R. (2021). A comprehensive and high-quality collection of escherichia coli genomes and their genes. Microbial Genomics. 7(2), s. 1–15. doi: 10.1099/mgen.0.000499. Fulltekst i vitenarkiv Vis sammendrag

  Escherichia coli is a highly diverse organism that includes a range of commensal and pathogenic variants found across a range of niches and worldwide. In addition to causing severe intestinal and extraintestinal disease, E. coli is considered a priority pathogen due to high levels of observed drug resistance. The diversity in the E. coli population is driven by high genome plasticity and a very large gene pool. All these have made E. coli one of the most well-studied organisms, as well as a commonly used laboratory strain. Today, there are thousands of sequenced E. coli genomes stored in public databases. While data is widely available, accessing the information in order to perform analyses can still be a challenge. Collecting relevant available data requires accessing different sources, where data may be stored in a range of formats, and often requires further manipulation and processing to apply various analyses and extract useful information. In this study, we collated and intensely curated a collection of over 10 000 E. coli and Shigella genomes to provide a single, uniform, high-quality dataset. Shigella were included as they are considered specialized pathovars of E. coli . We provide these data in a number of easily accessible formats that can be used as the foundation for future studies addressing the biological differences between E. coli lineages and the distribution and flow of genes in the E. coli population at a high resolution. The analysis we present emphasizes our lack of understanding of the true diversity of the E. coli species, and the biased nature of our current understanding of the genetic diversity of such a key pathogen.

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