Vegard Eldholm

Norwegian Institute of Public Health

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Ola Brynildsrud

Norwegian Institute of Public Health

Kristian Alfsnes

Norwegian Institute of Public Health

François Balloux

University College London

Dominique A. Caugant

University of Oslo

Jon Bohlin

Norwegian Institute of Public Health

Magnus N Osnes

Norwegian Institute of Public Health

John H.‐O. Pettersson

Public Health Agency of Sweden

Xavier Didelot

University of Warwick

Lucy van Dorp

University College London

Yonatan H. Grad

Brigham and Women's Hospital

Cooperative Institutions

Norwegian Institute of Public Health

University of Oslo

Oslo University Hospital

University of Oxford

University College London

Fundação Oswaldo Cruz

London School of Hygiene & Tropical Medicine

Imperial College London

Nasjonalforeningen for Folkehelsen

Norwegian University of Life Sciences

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Additional file 6: of The nucleotide composition of microbial genomes indicates differential patterns of selection on core and accessory genomes

Figshare (2017)

Jon Bohlin Vegard Eldholm John H.‐O. Pettersson Ola Brynildsrud Lars Snipen

Dataset containing all data used in the statistical models together with the strains IDâ s and accession numbers. (XLSX 196Â kb)

10.6084/m9.figshare.c.3689179_d7

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Citations (0)

Comparing phylogenetic trees according to tip label categories

bioRxiv (Cold Spring Harbor Laboratory) (2018)

Michelle Kendall Vegard Eldholm Caroline Colijn

Abstract Trees that illustrate patterns of ancestry and evolution are a central tool in many areas of biology. Comparing evolutionary trees to each other has widespread applications in comparing the evolutionary stories told by different sources of data, assessing the quality of inference methods, and highlighting areas where patterns of ancestry are uncertain. While these tasks are complicated by the fact that trees are high-dimensional structures encoding a large amount of information, there are a number of metrics suitable for comparing evolutionary trees whose tips have the same set of unique labels. There are also metrics for comparing trees where there is no relationship between their labels: in ‘unlabelled’ tree metrics the tree shapes are compared without reference to the tip labels. In many interesting applications, however, the taxa present in two or more trees are related but not identical, and it is informative to compare the trees whilst retaining information about their tips’ relationships. We present methods for comparing trees whose labels belong to a pre-defined set of categories. The methods include a measure of distance between two such trees, and a measure of concordance between one such tree and a hierarchical classification tree of the unique categories. We demonstrate the intuition of our methods with some toy examples before presenting an analysis of Mycobacterium tuberculosis trees, in which we use our methods to quantify the differences between trees built from typing versus sequence data.

Tree (set theory)

Tree rearrangement

10.1101/251710

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Citations (14)

Evolution and emergence of multidrug-resistant Mycobacterium tuberculosis in Chisinau, Moldova

Microbial Genomics (2021)

Tyler S. Brown Vegard Eldholm Ola Brynildsrud Magnus N Osnes Natalie S. Levy

The evolution and emergence of drug-resistant tuberculosis (TB) has been studied extensively in some contexts, but the ecological drivers of these two processes remain poorly understood. This study sought to describe the joint evolutionary and epidemiological histories of a novel multidrug-resistant Mycobacterium tuberculosis strain recently identified in the capital city of the Republic of Moldova (MDR Ural/4.2), where genomic surveillance of drug-resistant M. tuberculosis has been limited thus far. Using whole genome sequence data and Bayesian phylogenomic methods, we reconstruct the stepwise acquisition of drug resistance mutations in the MDR Ural/4.2 strain, estimate its historical bacterial population size over time, and infer the migration history of this strain between Eastern European countries. We infer that MDR Ural/4.2 likely evolved (via acquisition of rpoB S450L, which confers resistance to rifampin) in the early 1990s, during a period of social turmoil following Moldovan independence from the Soviet Union. This strain subsequently underwent substantial population size expansion in the early 2000s, at a time when national guidelines encouraged inpatient treatment of TB patients. We infer exportation of this strain and its isoniazid-resistant ancestral precursor from Moldova to neighbouring countries starting as early as 1985. Our findings suggest temporal and ecological associations between specific public health practices, including inpatient hospitalization of drug-resistant TB cases from the early 2000s until 2013, and the evolution of drug-resistant M. tuberculosis in Moldova. These findings underscore the need for regional coordination in TB control and expanded genomic surveillance efforts across Eastern Europe.

Mycobacterium tuberculosis complex

10.1099/mgen.0.000620

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Citations (11)

Detection of a historic reservoir of bedaquiline / clofazimine resistance associated variants inMycobacterium tuberculosis

bioRxiv (Cold Spring Harbor Laboratory) (2020)

Camus Nimmo Arturo Torres Ortiz Juanita Pang Mislav Acman Cedric C.S. Tan

Abstract 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.

Bedaquiline

Clofazimine

Efflux

10.1101/2020.10.06.328799

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Re-visiting the evolution, dispersal and epidemiology of Zika virus in Asia

Figshare (2019)

John H.‐O. Pettersson Jon Bohlin Myrielle Dupont‐Rouzeyrol Ola Brynildsrud Kristian Alfsnes

Based on serological evidence and viral isolation, Zika virus (ZIKV) has circulated for many years relatively benignly in a sylvatic cycle in Africa and an urban cycle in South East Asia (SEA). With the recent availability of limited but novel Indian ZIKV sequences to add to the plethora of SEA sequences, we traced the phylogenetic history and spatio-temporal dispersal pattern of ZIKV in Asia prior to its explosive emergence in the Pacific region and the Americas. These analyses demonstrated that the introduction and dispersal of ZIKV on the Pacific islands were preceded by an extended period of relatively silent transmission in SEA, enabling the virus to expand geographically and evolve adaptively before its unanticipated introduction to immunologically naive populations on the Pacific islands and in the Americas. Our findings reveal new features of the evolution and dispersal of this intriguing virus and may benefit future disease control strategies.

Zika Virus

10.6084/m9.figshare.7936829

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Global expansion of Mycobacterium tuberculosis lineage 4 shaped by colonial migration and local adaptation

Science Advances (2018)

Ola Brynildsrud Caitlin S. Pepperell Philip Noël Suffys Louis Grandjean Johana Monteserin

On the basis of population genomic and phylogeographic analyses of 1669 Mycobacterium tuberculosis lineage 4 (L4) genomes, we find that dispersal of L4 has been completely dominated by historical migrations out of Europe. We demonstrate an intimate temporal relationship between European colonial expansion into Africa and the Americas and the spread of L4 tuberculosis (TB). Markedly, in the age of antibiotics, mutations conferring antimicrobial resistance overwhelmingly emerged locally (at the level of nations), with minimal cross-border transmission of resistance. The latter finding was found to reflect the relatively recent emergence of these mutations, as a similar degree of local restriction was observed for susceptible variants emerging on comparable time scales. The restricted international transmission of drug-resistant TB suggests that containment efforts at the level of individual countries could be successful.

Lineage (genetic)

Human migration

10.1126/sciadv.aat5869

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Citations (141)

Genetic Characterization and Population Structure of Drug Resistant <em>Mycobacterium tuberculosis </em>Isolated from Brazilian Patients Using Whole-Genome Sequencing

Leonardo Souza Esteves Lia Lima Gomes Daniela Brites Fátima Cristina Onofre Fandinho Marcela Bhering

The present study aimed to determine the genetic diversity of isolates of Mycobacterium tuberculosis (Mtb) from presumed drug resistant tuberculosis patients from several states of Brazil. The isolates had been submitted to conventional drug susceptibility testing for first- and second-line drugs. Multidrug-resistant (MDR-TB) (54.8%) was the most frequent phenotypic resistance profile, in addition to an important high frequency of pre-extensively resistant (p-XDR-TB) (9.2%). Using whole-genome sequencing (WGS), we characterized 298 Mtb isolates from Brazil. Besides analysis of genotype distribution and possible correlations between molecular and clinical data, we determined the performance of an in-house WGS pipeline with other online pipelines for Mtb lineages and drug resistance profile definition. Sub-lineage 4.3 (52%) was the most frequent genotype and the genomic approach revealed a p-XDR-TB level of 22.5%. We detected 20 novel mutations in three resistance genes, and six of these were observed in eight phenotypically resistant isolates. Cluster analysis of 170 isolates showed that 43.5% of the TB patients belonged to 24 genomic clusters, suggesting considerable ongoing transmission of DR-TB, including two interstate transmissions. The in-house WGS pipeline showed the best overall performance in drug-resistance prediction, presenting the best accuracy values to five of nine drugs tested. Significant associations were observed between suffering from fatal disease and genotypic p-XDR-TB (p = 0.03) and either phenotypic (p = 0.006) and genotypic (p = 0.0007) ethambutol resistance. The use of WGS analysis improved our understanding of the population structure of MTBC in Brazil, genetic and clinical data correlations and demonstrating its utility for surveillance efforts for spread of DR-TB, hopefully helping to avoid the emergence of even more resistant strains and to reduce TB incidence and mortality rates.

Genetic Analysis

10.20944/preprints202404.1209.v1

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Citations (1)

Microevolution of a MDR outbreak strain of Mycobacterium tuberculosis (Mtb) in the light of Whole Genome Sequencing (WGS)

F1000Research (2015)

Vegard Eldholm Johana Monteserin Adrien Rieux Benjamin Sobkowiak Beatriz López

Microevolution

Open peer review

Strain (injury)

10.7490/f1000research.1097739.1

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Sudden emergence of a Neisseria gonorrhoeae clade with reduced susceptibility to extended-spectrum cephalosporins, Norway

Microbial Genomics (2020)

Magnus N Osnes Xavier Didelot Jolinda de Korne-Elenbaas Kristian Alfsnes Ola Brynildsrud

Neisseria gonorrhoeae multilocus sequence type (ST)-7827 emerged in a dramatic fashion in Norway in the period 2016-2018. Here, we aim to shed light on the provenance and expansion of this ST. ST-7827 was found to be polyphyletic, but the majority of members belonged to a monophyletic clade we termed PopPUNK cluster 7827 (PC-7827). In Norway, both PC-7827 and ST-7827 isolates were almost exclusively isolated from men. Phylogeographical analyses demonstrated an Asian origin of the genogroup, with multiple inferred exports to Europe and the USA. The genogroup was uniformly resistant to fluoroquinolones, and associated with reduced susceptibility to both azithromycin and the extended-spectrum cephalosporins (ESCs) cefixime and ceftriaxone. From a genetic background including the penA allele 13.001, associated with reduced ESC susceptibility, we identified repeated events of acquisition of porB alleles associated with further reduction in ceftriaxone susceptibility. Transmission of the strain was significantly reduced in Norway in 2019, but our results indicate the existence of a recently established global reservoir. The worrisome drug-resistance profile and rapid emergence of PC-7827 calls for close monitoring of the situation.

Neisseria gonorrhoeae

Multilocus sequence typing

Cefixime

Monophyly

10.1099/mgen.0.000480

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Citations (21)

The inter-continental population dynamics ofNeisseria gonorrhoeae

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Magnus N Osnes Ola Brynildsrud Kristian Alfsnes Lucy van Dorp Samantha A McKeand

Abstract Neisseria gonorrhoeae is a globally distributed sexually transmitted bacterial pathogen. Recent studies have revealed that its evolution has been shaped by antibiotic use, while molecular surveillance efforts have demonstrated large changes in lineage composition over relatively short time-spans. However, the global population dynamics of N. gonorrhoeae remain unsatisfyingly characterized. To reconstruct recent large-scale population dynamics, we generated a dated phylogeny from 9,732 N. gonorrhoeae genomes and found the effective population size of the species to have expanded gradually over the past two centuries. While the effective population size of clades with reduced susceptibility to extended-spectrum cephalosporins started declining around 2010, a major clade containing a mosaic mtr operon associated with cephalosporin susceptibility and decreased azithromycin did not display any reduction in population size. Using ancestral trait reconstruction analyses, we delineated transmission lineages, defined as groups of sequences in which all the samples can be traced back to the same import event to a given location. Import, export and local transmission dynamics across two densely sampled locations (Norway and Victoria, Australia) were investigated in detail. Norway exhibited substantially higher rates of strain import and export compared to Victoria, where incidence was to a larger extent fuelled by locally transmitted lineages. Taken together, our work highlights the power of large-scale phylogenomic analyses to uncover the complex dynamics of lineage transmission in N. gonorrhoeae .

Neisseria gonorrhoeae

Lineage (genetic)

Evolutionary Dynamics

Effective population size

10.1101/2023.08.02.551601

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