Crossing host boundaries: the evolutionary drivers and correlates of viral host jumps

Link: bioRxiv preprint

Most emerging and re-emerging infectious diseases stem from viruses that naturally circulate in non-human vertebrates. When these viruses cross over into humans, they can cause disease outbreaks and epidemics. While zoonotic host jumps have been extensively studied from an ecological perspective, little attention has gone into characterising the evolutionary drivers and correlates underlying these events. To address this gap, we harnessed the entirety of publicly available viral genomic data, employing a comprehensive suite of network and phylogenetic analyses. We address a series of questions concerning the evolutionary mechanisms underpinning viral host jumps. Notably, we challenge conventional assumptions about the directionality of host jumps, demonstrating that humans are as much a source as a sink for viral spillover events, insofar we infer more viruses to have jumped from humans to other animals, than from animals to humans. Moreover, we demonstrate heightened evolution in viral lineages that involve putative host jumps. We further observe that the mutational threshold associated with a host jump is lower for viruses with broad host ranges. Finally, we show that the genomic targets of natural selection upon a successful host jump vary across different viral families with either structural or auxiliary genes being the prime targets of selection. Collectively, our results illuminate some of the evolutionary drivers underlying viral host jumps that may contribute to mitigating viral threats across species boundaries.

The inter-continental population dynamics of Neisseria gonorrhoeae

Link: bioRxiv preprint

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.

We found coronaviruses in UK bats – so far the danger’s minimal but we need to know more about viruses that can spread to humans

Link: Conversation article

Genomic screening of 16 UK native bat species through conservationist networks uncovers coronaviruses with zoonotic potential

Link: Nature Communications manuscript

There has been limited characterisation of bat-borne coronaviruses in Europe. Here, we screened for coronaviruses in 48 faecal samples from 16 of the 17 bat species breeding in the UK, collected through a bat rehabilitation and conservationist network. We recovered nine complete genomes, including two novel coronavirus species, across six bat species: four alphacoronaviruses, a MERS-related betacoronavirus, and four closely related sarbecoviruses. We demonstrate that at least one of these sarbecoviruses can bind and use the human ACE2 receptor for infecting human cells, albeit suboptimally. Additionally, the spike proteins of these sarbecoviruses possess an R-A-K-Q motif, which lies only one nucleotide mutation away from a furin cleavage site (FCS) that enhances infectivity in other coronaviruses, including SARS-CoV-2. However, mutating this motif to an FCS does not enable spike cleavage. Overall, while UK sarbecoviruses would require further molecular adaptations to infect humans, their zoonotic risk warrants closer surveillance.

Genomic screening of 16 UK native bat species through conservationist networks uncovers coronaviruses with zoonotic potential

END-VoC Consotrium

Members of the group attended the third General Assembly of the END-VOC Consortium, held on 7 and 8 June and hosted by the Barcelona Institute for Global Health (ISGlobal.

Coordinated surveillance is essential to monitor and mitigate the evolutionary impacts of SARS-CoV-2 spillover and circulation in animal hosts

Link: Nature Ecology & Evolution manuscript

In this comment piece we discuss how SARS-CoV-2 lineages circulating in animal reservoirs may broaden the evolutionary potential of the virus and increase the risk of novel variants emerging. We argue that there is an urgent need for more-comprehensive surveillance of SARS-CoV-2 circulating in nonhuman hosts.

Identification of Evolutionary Trajectories Shared across Human Betacoronaviruses

Link: GBE manuscript

Comparing the evolution of distantly related viruses can provide insights into common adaptive processes related to shared ecological niches. Phylogenetic approaches, coupled with other molecular evolution tools, can help identify mutations informative on adaptation, although the structural contextualization of these to functional sites of proteins may help gain insight into their biological properties. Two zoonotic betacoronaviruses capable of sustained human-to-human transmission have caused pandemics in recent times (SARS-CoV-1 and SARS-CoV-2), although a third virus (MERS-CoV) is responsible for sporadic outbreaks linked to animal infections. Moreover, two other betacoronaviruses have circulated endemically in humans for decades (HKU1 and OC43). To search for evidence of adaptive convergence between established and emerging betacoronaviruses capable of sustained human-to-human transmission (HKU1, OC43, SARS-CoV-1, and SARS-CoV-2), we developed a methodological pipeline to classify shared nonsynonymous mutations as putatively denoting homoplasy (repeated mutations that do not share direct common ancestry) or stepwise evolution (sequential mutations leading towards a novel genotype). In parallel, we look for evidence of positive selection and draw upon protein structure data to identify potential biological implications. We find 30 candidate mutations, from which 4 (codon sites 18121 [nsp14/residue 28], 21623 [spike/21], 21635 [spike/25], and 23948 [spike/796]; SARS-CoV-2 genome numbering) further display evolution under positive selection and proximity to functional protein regions. Our findings shed light on potential mechanisms underlying betacoronavirus adaptation to the human host and pinpoint common mutational pathways that may occur during establishment of human endemicity.

New preprint: Identification of evolutionary trajectories shared across human betacoronaviruses

Preprint available here

Comparing the evolution of distantly related viruses can provide insights into common adaptive processes related to shared ecological niches. Phylogenetic approaches, coupled with other molecular evolution tools, can help identify mutations informative on adaptation, whilst the structural contextualization of these to functional sites of proteins may help gain insight into their biological properties. Two zoonotic betacoronaviruses capable of sustained human-to-human transmission have caused pandemics in recent times (SARS-CoV-1 and SARS-CoV-2), whilst a third virus (MERS-CoV) is responsible for sporadic outbreaks linked to animal infections. Moreover, two other betacoronaviruses have circulated endemically in humans for decades (HKU1 and OC43). To search for evidence of adaptive convergence between established and emerging betacoronaviruses capable of sustained human-to-human transmission (HKU1, OC43, SARS-CoV-1 and SARS-CoV-2), we developed a methodological pipeline to classify shared non-synonymous mutations as putatively denoting homoplasy (repeated mutations that do not share direct common ancestry) or stepwise evolution (sequential mutations leading towards a novel genotype). In parallel, we look for evidence of positive selection, and draw upon protein structure data to identify potential biological implications. We find 30 mutations, with four of these [codon sites 18121 (nsp14/residue 28), 21623 (spike/21), 21635 (spike/25) and 23948 (spike/796); SARS-CoV-2 genome numbering] displaying evolution under positive selection and proximity to functional protein regions. Our findings shed light on potential mechanisms underlying betacoronavirus adaptation to the human host and pinpoint common mutational pathways that may occur during establishment of human endemicity.

New preprint: Surveillance of 16 UK native bat species through conservationist networks uncovers coronaviruses with zoonotic potential

Preprint available here

While the COVID-19 pandemic, caused by SARS-CoV-2, has renewed genomic surveillance efforts in wildlife, there has been limited characterisation of bat-borne coronaviruses in Europe. We collected 48 faecal samples from all but one of the 17 bat species breeding in the UK, through an extensive network of bat rehabilitators and conservationists, and screened them for coronaviruses using deep RNA sequencing. We assembled nine novel, high-quality coronaviral genomes, comprising four alphacoronaviruses from Myotis daubentonii and Pipistrellus pipistrellus, a Middle East respiratory syndrome (MERS)-related coronavirus from Plecotus auritus, and four closely-related sarbecoviruses isolated from both horseshoe bat species Rhinolophus hipposideros and R. ferrumequinum. We further used in vitro assays to demonstrate that at least one of these sarbecoviruses can bind ACE2, the receptor used by SARS-CoV-2 to infect human cells, which was also supported using in silico structural and sequence analyses. Although this sarbecovirus can enter human cells in vitro when ACE2 is over-expressed, our analyses indicate that it is unlikely to infect humans and would require adaptations to do so. Our findings highlight the importance of working collaboratively with conservation networks to enable larger, coordinated viral surveillance efforts and prevent the emergence of zoonoses from wildlife.

New blog post: COVID-19: Where Could the Next Variant of Concern Come From?

As part of the END-VoC Consortium program we wrote a blog piece exploring what the future may hold in terms of SARS-CoV-2 variants of concern.

You can read the full blog post here

Population structure and hybridisation in a population of Hawaiian feral chickens

Link: Heredity manuscript

Chickens are believed to have inhabited the Hawaiian island of Kauai since the first human migrations around 1200AD, but numbers have peaked since the tropical storms Iniki and Iwa in the 1980s and 1990s that destroyed almost all the chicken coops on the island and released large numbers of domestic chickens into the wild. Previous studies have shown these now feral chickens are an admixed population between Red Junglefowl (RJF) and domestic chickens. Here, using genetic haplotypic data, we estimate the time of the admixture event between the feral population on the island and the RJF to 1981 (1976–1995), coinciding with the timings of storm Iwa and Iniki. Analysis of genetic structure reveals a greater similarity between individuals inhabiting the northern and western part of the island to RJF than individuals from the eastern part of the island. These results point to the possibility of introgression events between feral chickens and the wild chickens in areas surrounding the Koke’e State Park and the Alaka’i plateau, posited as two of the major RJF reservoirs in the island. Furthermore, we have inferred haplotype blocks from pooled data to determine the most plausible source of the feral population. We identify a clear contribution from RJF and layer chickens of the White Leghorn (WL) breed. This work provides independent confirmation of the traditional hypothesis surrounding the origin of the feral populations and draws attention to the possibility of introgression of domestic alleles into the wild reservoir.

Lucy van Dorp awarded the Genetics Society Balfour Lecture 2023

Balfour Lecture

The Balfour Lecture, named after the Genetics Society’s first President, is an award to mark the contributions to genetics of an outstanding young investigator.

New article: The population genomic legacy of the second plague pandemic

Gopalakrishnan et al 2022

Human populations have been shaped by catastrophes that may have left long-lasting signatures in their genomes. One notable example is the second plague pandemic that entered Europe in ca. 1347 CE and repeatedly returned for over 300 years, with typical village and town mortality estimated at 10–40 percent. It is assumed that this high mortality affected the gene pools of these populations. First, local population crashes reduced genetic diversity. Second, a change in frequency is expected for sequence variants that may have affected survival or susceptibility to the etiologic agent (Yersinia pestis). Third, mass mortality might alter the local gene pools through its impact on subsequent migration patterns. We explored these factors using the Norwegian city of Trondheim as a model, by sequencing 54 genomes spanning three time periods: (1) prior to the plague striking Trondheim in 1,349 CE, (2) the 17th–19th century, and (3) the present. We find that the pandemic period shaped the gene pool by reducing long distance immigration, in particular from the British Isles, and inducing a bottleneck that reduced genetic diversity. Although we also observe an excess of large FST values at multiple loci in the genome, these are shaped by reference biases introduced by mapping our relatively low genome coverage degraded DNA to the reference genome. This implies that attempts to detect selection using ancient DNA (aDNA) datasets that vary by read length and depth of sequencing coverage may be particularly challenging until methods have been developed to account for the impact of differential reference bias on test statistics.

Interview with the Institute of Evolutionary Biology as part of their Women in Science Series

Link

New article: Ancient herpes simplex 1 genomes reveal recent viral structure in Eurasia

Guellil & van Dorp et al 2022

Human herpes simplex virus 1 (HSV-1), a life-long infection spread by oral contact, infects a majority of adults globally. Phylogeographic clustering of sampled diversity into European, pan-Eurasian, and African groups has suggested the virus codiverged with human migrations out of Africa, although a much younger origin has also been proposed. We present three full ancient European HSV-1 genomes and one partial genome, dating from the 3rd to 17th century CE, sequenced to up to 9.5× with paired human genomes up to 10.16×. Considering a dataset of modern and ancient genomes, we apply phylogenetic methods to estimate the age of sampled modern Eurasian HSV-1 diversity to 4.68 (3.87 to 5.65) ka. Extrapolation of estimated rates to a global dataset points to the age of extant sampled HSV-1 as 5.29 (4.60 to 6.12) ka, suggesting HSV-1 lineage replacement coinciding with the late Neolithic period and following Bronze Age migrations.

For more hear coverage of our paper on BBC Inside Science on Radio 4.

New review article out in Oxford Open Immunology: The past, current and future epidemiological dynamic of SARS-CoV-2

SARS-CoV-2, the agent of the COVID-19 pandemic, emerged in late 2019 in China, and rapidly spread throughout the world to reach all continents. As the virus expanded in its novel human host, viral lineages diversified through the accumulation of around two mutations a month on average. Different viral lineages have replaced each other since the start of the pandemic, with the most successful Alpha, Delta and Omicron variants of concern (VoCs) sequentially sweeping through the world to reach high global prevalence. Neither Alpha nor Delta was characterized by strong immune escape, with their success coming mainly from their higher transmissibility. Omicron is far more prone to immune evasion and spread primarily due to its increased ability to (re-)infect hosts with prior immunity. As host immunity reaches high levels globally through vaccination and prior infection, the epidemic is expected to transition from a pandemic regime to an endemic one where seasonality and waning host immunization are anticipated to become the primary forces shaping future SARS-CoV-2 lineage dynamics. In this review, we consider a body of evidence on the origins, host tropism, epidemiology, genomic and immunogenetic evolution of SARS-CoV-2 including an assessment of other coronaviruses infecting humans. Considering what is known so far, we conclude by delineating scenarios for the future dynamic of SARS-CoV-2, ranging from the good—circulation of a fifth endemic ‘common cold’ coronavirus of potentially low virulence, the bad—a situation roughly comparable with seasonal flu, and the ugly—extensive diversification into serotypes with long-term high-level endemicity.

Link: Balloux et al 2022

New article published in Nature Communications: Transmission of SARS-CoV-2 from humans to animals and potential host adaptation.

SARS-CoV-2, the causative agent of the COVID-19 pandemic, can infect a wide range of mammals. Since its spread in humans, secondary host jumps of SARS-CoV-2 from humans to multiple domestic and wild populations of mammals have been documented. Understanding the extent of adaptation to these animal hosts is critical for assessing the threat that the spillback of animal-adapted SARS-CoV-2 into humans poses. We compare the genomic landscapes of SARS-CoV-2 isolated from animal species to that in humans, profiling the mutational biases indicative of potentially different selective pressures in animals. We focus on viral genomes isolated from mink (Neovison vison) and white-tailed deer (Odocoileus virginianus) for which multiple independent outbreaks driven by onward animal-to-animal transmission have been reported. We identify five candidate mutations for animal-specific adaptation in mink (NSP9_G37E, Spike_F486L, Spike_N501T, Spike_Y453F, ORF3a_L219V), and one in deer (NSP3a_L1035F), though they appear to confer a minimal advantage for human-to-human transmission. No considerable changes to the mutation rate or evolutionary trajectory of SARS-CoV-2 has resulted from circulation in mink and deer thus far. Our findings suggest that minimal adaptation was required for onward transmission in mink and deer following human-to-animal spillover, highlighting the ‘generalist’ nature of SARS-CoV-2 as a mammalian pathogen.

Article Tan et al 2022

New article published in Nature Communications: Role of mobile genetic elements in the global dissemination of the carbapenem resistance gene blaNDM.

The mobile resistance gene blaNDM encodes the NDM enzyme which hydrolyses carbapenems, a class of antibiotics used to treat some of the most severe bacterial infections. The blaNDM gene is globally distributed across a variety of Gram-negative bacteria on multiple plasmids, typically located within highly recombining and transposon-rich genomic regions, which leads to the dynamics underlying the global dissemination of blaNDM to remain poorly resolved. Here, we compile a dataset of over 6000 bacterial genomes harbouring the blaNDM gene, including 104 newly generated PacBio hybrid assemblies from clinical and livestock-associated isolates across China. We develop a computational approach to track structural variants surrounding blaNDM, which allows us to identify prevalent genomic contexts, mobile genetic elements, and likely events in the gene’s global spread. We estimate that blaNDM emerged on a Tn125 transposon before 1985, but only reached global prevalence around a decade after its first recorded observation in 2005. The Tn125 transposon seems to have played an important role in early plasmid-mediated jumps of blaNDM, but was overtaken in recent years by other elements including IS26-flanked pseudo-composite transposons and Tn3000. We found a strong association between blaNDM-carrying plasmid backbones and the sampling location of isolates. This observation suggests that the global dissemination of the blaNDM gene was primarily driven by successive between-plasmid transposon jumps, with far more restricted subsequent plasmid exchange, possibly due to adaptation of plasmids to their specific bacterial hosts.

Article link

New article published in Biology: Genomic Analysis of 18th-Century Kazakh Individuals and their Oral Microbiome.

Paleogenomic research has enhanced our understanding of past human populations and migrations. Moreover, ancient DNA can also provide information on the interactions between humans and their associated pathogens. Periodontitis, currently suffered by millions of people worldwide, is a gum infection that is caused by pathogenic oral bacteria, widely referred to as the “red complex”, which can lead to tooth loss and has been linked to an increased risk of oesophageal cancer. In this study we combine human population genetics with genomic analysis of the oral microbiome of 18th-century people from the Kazakh Khanate in Kazakhstan to gain insight into their health status and explore bacterial coadaptation to recent dietary changes.

Article link

New preprint: A series of terribly unfortunate events: How environment and infection synergized to cause the Kihansi spray toad extinction

Preprint Link

Outbreaks of emerging infectious diseases are trained by local biotic and abiotic factors, with host declines occurring when conditions favour the pathogen. Extinction of the Tanzanian Kihansi spray toad (Nectophrynoides asperginis) in 2004 was contemporaneous with the construction of a dam, implicating habitat modification in the loss of this species. However, high burdens of a globally emerging infection, Batrachochytrium dendrobatidis (Bd) were synchronously observed implicating infectious disease in this toads extinction. Here, by shotgun sequencing skin DNA from archived toad mortalities and assembling chytrid mitogenomes, we prove this outbreak was caused by the BdCAPE lineage and not the panzootic lineage BdGPL that is widely associated with global amphibian extinctions. Molecular dating showed an invasion of BdCAPE across Southern Africa overlapping with the timing of the extinction event. However, post-outbreak surveillance of conspecific species inhabiting this mountainous region showed widespread infection by BdCAPE yet no signs of amphibian ill-health or species decline. Our findings show that despite efforts to mitigate the environmental impact caused by dams construction, invasion of the pathogen ultimately led to the loss of the Kihansi spray toad; a synergism between emerging infectious disease and environmental change that likely heralds wider negative impacts on biodiversity in the Anthropocene.

Drivers of methicillin-resistant Staphylococcus aureus (MRSA) lineage replacement in China link

Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial pathogen subdivided into lineages termed sequence types (STs). Since the 1950s, successive waves of STs have appeared and replaced previously dominant lineages. One such event has been occurring in China since 2013, with community-associated (CA-MRSA) strains including ST59 largely replacing the previously dominant healthcare-associated (HA-MRSA) ST239. We previously showed that ST59 isolates tend to have a competitive advantage in growth experiments against ST239. However, the underlying genomic and phenotypic drivers of this replacement event are unclear.

Here, we investigated the replacement of ST239 using whole-genome sequencing data from 204 ST239 and ST59 isolates collected in Chinese hospitals between 1994 and 2016. We reconstructed the evolutionary history of each ST and considered two non-mutually exclusive hypotheses for ST59 replacing ST239: antimicrobial resistance (AMR) profile and/or ability to colonise and persist in the environment through biofilm formation. We also investigated the differences in cytolytic activity, linked to higher virulence, between STs. We performed an association study using the presence and absence of accessory virulence genes.

ST59 isolates carried fewer AMR genes than ST239 and showed no evidence of evolving towards higher AMR. Biofilm production was marginally higher in ST59 overall, though this effect was not consistent across sub-lineages so is unlikely to be a sole driver of replacement. Consistent with previous observations of higher virulence in CA-MRSA STs, we observed that ST59 isolates exhibit significantly higher cytolytic activity than ST239 isolates, despite carrying on average fewer putative virulence genes. Our association study identified the chemotaxis inhibitory protein (chp) as a strong candidate for involvement in the increased virulence potential of ST59. We experimentally validated the role of chp in increasing the virulence potential of ST59 by creating Δchp knockout mutants, confirming that ST59 can carry chp without a measurable impact on fitness.

Our results suggest that the ongoing replacement of ST239 by ST59 in China is not associated to higher AMR carriage or biofilm production. However, the increase in ST59 prevalence is concerning since it is linked to a higher potential for virulence, aided by the carriage of the chp gene.

Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2 link

Individuals with potential exposure to SARS-CoV-2 do not necessarily develop PCR or antibody positivity, suggesting some may clear sub-clinical infection before seroconversion. T-cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections. We hypothesised that pre-existing memory T-cell responses, with cross-protective potential against SARS-CoV-2, would expand in vivo to support rapid viral control, aborting infection. We measured SARS-CoV-2-reactive T-cells, including those against the early transcribed replication transcription complex (RTC), in intensively monitored healthcare workers (HCW) remaining repeatedly negative by PCR, antibody binding, and neutralisation (seronegative HCW, SN-HCW). SN-HCW had stronger, more multispecific memory T-cells than an unexposed pre-pandemic cohort, and more frequently directed against the RTC than the structural protein-dominated responses seen post-detectable infection (matched concurrent cohort). SN-HCW with the strongest RTC-specific T-cells had an increase in IFI27, a robust early innate signature of SARS-CoV-214, suggesting abortive infection. RNA-polymerase within RTC was the largest region of high sequence conservation across human seasonal coronaviruses (HCoV) and SARS-CoV-2 clades. RNA-polymerase was preferentially targeted (amongst regions tested) by T-cells from pre-pandemic cohorts and SN-HCW. RTC epitope-specific T-cells cross-recognising HCoV variants were identified in SN-HCW. Enriched pre-existing RNA-polymerase-specific T-cells expanded in vivo to preferentially accumulate in the memory response after putative abortive compared to overt SARS-CoV-2 infection. Our data highlight RTC-specific T-cells as targets for vaccines against endemic and emerging Coronaviridae.

Pre-existing T cell-mediated cross-reactivity to SARS-CoV-2 cannot solely be explained by prior exposure to endemic human coronaviruses link

T-cell-mediated immunity to SARS-CoV-2-derived peptides in individuals unexposed to SARS-CoV-2 has been previously reported. This pre-existing immunity was suggested to largely derive from prior exposure to 'common cold' endemic human coronaviruses (HCoVs). To test this, we characterised the sequence homology of SARS-CoV-2-derived T-cell epitopes reported in the literature across the full proteome of the Coronaviridae family. 54.8% of these epitopes had no homology to any of the HCoVs. Further, the proportion of SARS-CoV-2-derived epitopes with any level of sequence homology to the proteins encoded by any of the coronaviruses tested is well-predicted by their alignment-free phylogenetic distance to SARS-CoV-2 (Pearson's r = -0.958). No coronavirus in our dataset showed a significant excess of T-cell epitope homology relative to the proportion of expected random matches, given their genetic similarity to SARS-CoV-2. Our findings suggest that prior exposure to human or animal-associated coronaviruses cannot completely explain the T-cell repertoire in unexposed individuals that recognise SARS-CoV-2 cross-reactive epitopes.

Salmonella enterica from a soldier from the 1652 siege of Barcelona (Spain) supports historical transatlantic epidemic contacts: Link

Ancient pathogen genomics is an emerging field allowing reconstruction of past epidemics. The demise of post-contact American populations may, at least in part, have been caused by paratyphoid fever brought by Europeans. We retrieved genome-wide data from two Spanish soldiers who were besieging the city of Barcelona in 1652, during the Reapers' War. Their ancestry derived from the Basque region and Sardinia, respectively, (at that time, this island belonged to the Spanish kingdom). Despite the proposed plague epidemic, we could not find solid evidence for the presence of the causative plague agent in these individuals. However, we retrieved from one individual a substantial fraction of the Salmonella enterica serovar Paratyphi C lineage linked to paratyphoid fever in colonial period Mexico. Our results support a growing body of evidence that Paratyphi C enteric fever was more prevalent in Europe and the Americas in the past than it is today.

Metagenomic evidence for a polymicrobial signature of sepsis link

In this study, published in Microbial Genomics and led by Cedric Tan, we provide evidence for a polymicrobial signature of sepsis.

Our understanding of the host component of sepsis has made significant progress. However, detailed study of the microorganisms causing sepsis, either as single pathogens or microbial assemblages, has received far less attention. Metagenomic data offer opportunities to characterize the microbial communities found in septic and healthy individuals. In this study we apply gradient-boosted tree classifiers and a novel computational decontamination technique built upon SHapley Additive exPlanations (SHAP) to identify microbial hallmarks which discriminate blood metagenomic samples of septic patients from that of healthy individuals. Classifiers had high performance when using the read assignments to microbial genera [area under the receiver operating characteristic (AUROC=0.995)], including after removal of species ‘culture-confirmed’ as the cause of sepsis through clinical testing (AUROC=0.915). Models trained on single genera were inferior to those employing a polymicrobial model and we identified multiple co-occurring bacterial genera absent from healthy controls. While prevailing diagnostic paradigms seek to identify single pathogens, our results point to the involvement of a polymicrobial community in sepsis. We demonstrate the importance of the microbial component in characterising sepsis, which may offer new biological insights into the aetiology of sepsis, and ultimately support the development of clinical diagnostic or even prognostic tools.

Link: Listen here

It was a pleasure to discuss our work with Natasha Mitchell on ABC Australia's Science Friction podcast.

You can find the synopsis below:

More than 31,000 years ago, two children shed baby teeth in the wild, cold world of northern Siberia. Over 200 years ago, a famous French Revolutionary was assassinated while taking a bath, his blood spattered across the newspaper he was reading.

Around 80 years ago, a microscope slide was smeared with the blood of a sick Spaniard.

All have something in common.

Hidden in the threads of their genomes are the ghost stories of pandemics past. Many of which have upended civilisations before our own.

Meet the DNA detectives rapidly rewriting the deep history of infectious diseases, and helping us understand future pandemic possibilities.

Review article on the genomics of SARS-CoV-2 published in Current Opinion in Virology.

The COVID-19 pandemic has shone a spotlight on the value of large-scale, open, and near real-time genomic surveillance of pathogens. In this review we discuss some of the insights that have been gained through the study of SARS-CoV-2 genomes, commenting in particularly on the contribution of phylogenetics and immunology to identifying signatures of adaptation in the viral population.

Article link

New preprint: 31,600-year-old human virus genomes support a Pleistocene origin for common childhood infections

Link available here.

The origins of viral pathogens and the age of their association with humans remains largely elusive. To date, there is no direct evidence about the diversity of viral infections in early modern humans pre-dating the Holocene. We recovered two near-complete genomes (5.2X and 0.7X) of human adenovirus C (HAdV-C), as well as low-coverage genomes from four distinct species of human herpesvirus obtained from two 31,630-year-old milk teeth excavated at Yana, in northeastern Siberia. Phylogenetic analysis of the two HAdV-C genomes suggests an evolutionary origin around 700,000 years ago consistent with a common evolutionary history with hominin hosts. Our findings push back the earliest direct molecular evidence for human viral infections by ∼25,000 years, and demonstrate that viral species causing common childhood viral infections today have been in circulation in humans at least since the Pleistocene.

Paper out in Microbial Genomics on the genomic epidemiology of the first epidemic wave of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Palestine

Link: Qutob et al 2021

Our latest work explores the genomic epidemiology of SARS-CoV-2 in Palestine during the first epidemic wave of COVID-19. We identify the presence of cosmopolitan lineages early in the pandemic, consistent with at least nine independent introduction events. These included one locally predominant transmission lineage (B.1.1.50) largely found in #Palestine and neighbouring countries. We estimate the age of emergence of this lineage to early February 2020, predating the first reported cases of COVID19 in Bethlehem in March.

SARS-CoV-2 remains understudied in Palestine, though there is clear global benefit for more focused genomic surveillance in the region given the proximity to Israel where vaccine coverage is amongst the highest in the world.

New paper in Nature Communications: Evidence of the interplay of genetics and cuture in Ethiopia

Link available here.

The rich linguistic, ethnic and cultural diversity of Ethiopia provides an unprecedented opportunity to understand the level to which cultural factors correlate with–and shape–genetic structure in human populations. Using primarily new genetic variation data covering 1,214 Ethiopians representing 68 different ethnic groups, together with information on individuals’ birthplaces, linguistic/religious practices and 31 cultural practices, we disentangle the effects of geographic distance, elevation, and social factors on the genetic structure of Ethiopians today. We provide evidence of associations between social behaviours and genetic differences among present-day peoples. We show that genetic similarity is broadly associated with linguistic affiliation, but also identify pronounced genetic similarity among groups from disparate language classifications that may in part be attributable to recent intermixing. We also illustrate how groups reporting the same culture traits are more genetically similar on average and show evidence of recent intermixing, suggesting that shared cultural traits may promote admixture. In addition to providing insights into the genetic structure and history of Ethiopia, we identify the most important cultural and geographic predictors of genetic differentiation and provide a resource for designing sampling protocols for future genetic studies involving Ethiopians.

New preprint: A phylogeny-based metric for estimating changes in transmissibility from recurrent mutations in SARS-CoV-2

Link available here.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and spread globally to cause the COVID-19 pandemic. Despite the constant accumulation of genetic variation in the SARS-CoV-2 population, there was little evidence for the emergence of significantly more transmissible lineages in the first half of 2020. Around November 2020, several more contagious and possibly more virulent ‘Variants of Concern’ (VoCs) were detected near-simultaneously in various regions of the world. These VoCs share some mutations and deletions that haven arisen recurrently in distinct genetic backgrounds. Here, we build on our previous work modelling the association of mutations to SARS-CoV-2 transmissibility and characterise the contribution of individual recurrent mutations and deletions to estimated viral transmissibility. We estimate enhanced transmissibility associated to mutations characteristic of VoCs and identify a tendency for cytidine to thymidine (C→T) substitutions to be associated to a reduction in estimated transmissibility. We then assess how patterns of estimated transmissibility in all SARS-CoV-2 clades have varied over the course of the COVID-19 pandemic by summing transmissibility estimates for all individual mutations carried by any sequenced genome analysed. Such an approach recovers 501Y.v1 (B.1.1.7) as the most transmissible clade currently in circulation. By assessing transmissibility over the time of sampling, we observe a tendency for estimated transmissibility within clades to slightly decrease in most clades. Although subtle, this pattern is consistent with the expectation of a decay in transmissibility in mainly non-recombining lineages caused by the accumulation of weakly deleterious mutations. SARS-CoV-2 remains a highly transmissible pathogen, though such a trend could conceivably play a role in the turnover of different global viral clades observed over the pandemic so far.

Talk at Ancient Biomolecules of Plants, Animals and Microbes 2021

Keynote lecture at Ancient Biomolecules of Plants, Animals and Microbes entitled Tracking Pathogens in space and time: something old, something new.

The full talk is available to view here and below:

Role of the mobilome in the global dissemination of the carbapenem resistance gene blaNDM

Link: bioRxiv preprint

The mobile resistance gene blaNDM encodes the NDM enzyme capable of hydrolysing carbapenems, a class of antibiotics used to treat some of the most severe bacterial infections. blaNDM is globally distributed across a variety of Gram-negative bacteria and is typically located within a transposon-rich genomic region common to multiple plasmids.

We compiled a dataset of over 2000 bacterial genomes harbouring the blaNDM gene including 112 new PacBio hybrid assemblies from China and developed a novel computational approach to track structural variants in bacterial genomes. We were able to correlate specific structural variants with plasmid backbones, bacterial host species and sampling locations, and identified multiple transposition events that occurred during the global dissemination of blaNDM.

This preprint, led by Mislav Acman, highlights the importance of transposons in the global spread of antimicrobial resistance genes and suggest that genetic recombination, rather than mutation, was the dominant force driving the evolution of the blaNDM genomic region.

No detectable signal for ongoing genetic recombination in SARS-CoV-2

bioRxiv preprint

Recombination-mediated rearrangement of variants that arose independently can be of major evolutionary importance. Though, whether SARS-CoV-2 undergoes genetic recombination has been largely overlooked to date. Here, we analyse the extant genomic diversity of SARS-CoV-2 and show that, to date, there is no detectable hallmark of recombination.

Pre-existing T cell-mediated cross-reactivity to SARS-CoV-2 cannot solely be explained by prior exposure to endemic human coronaviruses

Link: bioRxiv preprint

Our latest preprint considers sources of T-cell cross-reactivity to SARS-CoV-2 identified in pre-pandemic samples. Counter to initial expectations we found prior exposure to circulating 'common cold' coronaviruses plays at best a modest role in eliciting the response. We scanned the homology of 177 published T-cell epitopes reported in unexposed donors to the protein sequences of a large, phylogenetically resolved, dataset of coronaviruses from mammals and birds, including the four species of circulating endemic ‘common cold’ coronaviruses. We found only 55% of the tested epitopes had noticeable homology to these common cold coronaviruses, with the degree of homology being near perfectly predicted by the phylogenetic distance of each of these viruses to SARS-CoV-2. In fact, none of the wide range of #coronavirus species tested could explain a higher proportion of epitopes than expected by their relationship to SARS-CoV-2, leaving a fraction of cross-reactive T-cell epitopes unexplained by any coronavirus. These ‘unexplained’ epitopes show partial homology to a wide range of diverse possible antigens. We're not sure where they come from but they aren't other sampled coronaviruses and may arise from life-long exposures to heterogenous antigens.

Recurrent mutations in SARS-CoV-2 genomes isolated from mink point to rapid host-adaptation

Link: bioRxiv preprint

In line with other coronaviruses, SARS-CoV-2 has the potential to infect a broad range of hosts. SARS-CoV-2 genomes have now been isolated from cats, dogs, lions, tigers and minks. SARS-CoV-2 seems to transmit particularly well in mink farms. Genomic data from SARS-CoV-2 isolated from infected minks provides a natural case study of a secondary host jump of the virus, in this case from humans to animals, and occasionally back again.

We screened published SARS-CoV-2 genomes isolated from minks for the presence of recurrent mutations common in mink but infrequent in SARS-CoV-2 genomes isolated from human infections. We identify 23 recurrent mutations including three nonsynonymous mutations in the Receptor Binding Domain of the SARS-CoV-2 spike protein that independently emerged at least four times but are only rarely observed in human lineages. The repeat emergence of mutations across phylogenetically distinct lineages of the virus isolated from minks points to ongoing adaptation of SARS-CoV-2 to a new host. The rapid acquisition and spread of SARS-CoV-2 mutations in minks suggests that if a similar phenomenon of host adaptation had occurred upon its jump into humans, those human-specific mutations would likely have reached fixation already before the first SARS-CoV-2 genomes were generated.

You can read more on adaptive mutations in SARS-CoV-2 to mink infections in a piece I wrote for the Conversation.

Denmark to cull mink herd over coronavirus mutation fears – here’s what the science says link

Antibiotic treatment regimes as a driver of the global population dynamics of a major gonorrhea lineage

Link: MBE Paper

The Neisseria gonorrhoeae multilocus sequence type (ST) 1901 is among the lineages most commonly associated with treatment failure. In this work, led by colleagues at the Norwegian Institute of Public Health, we analyzed a global collection of ST-1901 genomes to shed light on the emergence and spread of alleles associated with reduced susceptibility to extended-spectrum cephalosporins (ESCs).

The genetic diversity of ST-1901 could be reconstructed into a minor and a major clade, both of which were inferred to have originated in East Asia, spreading out of Asia in two seperate waves. The ancestor of the most recent wave acquired the penA 34.001 allele, which significantly reduces susceptibility to extended-spectrum cephalosporins (ESCs).

Our work suggest that the acquisition of this allele granted the second wave a fitness advantage at a time when ESCs became the key drug class used to treat gonorrhea.

New Student

Welcome to new MSci project student Kristina Kordova who has joined the lab to work on the genomics of carbapenem resistance in Acinetobacter baumanii.

Link: The genomic epidemiology of SARS-CoV-2 in Palestine

Our latest preprint reports the first SARS-CoV-2 genomes from Palestine. As with most regions of the world, Palestine experienced many imported cases of COVID-19 at many different times meaning that there is no unique index case or patient zero. We estimate at minimum nine independent introductions which recapitulate at least some of the circulating diversity of SARS-CoV-2, including a clade of genetically identical sequences sampled over 21 countries.

At the same time local structure is emerging. We identified a closely related set of 59 SARS-CoV-2 which have likely been circulating largely in Palestine. We estimate the age of this transmission cluster to early February predating the first confirmed cases in Bethlehem in March.

Our work demonstrates the importance of genomic analyses and open data for identifying COVID-19 transmission patterns and epidemiological links at local and global scales.

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

Tuberculosis remains the biggest infectious disease killer today, even in the midst of the ongoing COVID-19 pandemic. The high mortality caused by TB is in part due to the widespread appearance of bacteria resistant to many, if not all, of our first- and second-line drugs.

The discovery of a new TB drug, bedaquiline, in 2004 was heralded as a major breakthrough in the treatment of drug-resistant TB. However, this remarkable success may come to a halt with the emergence of bedaquiline resistant strains, leading to treatment failure and poor patient outcomes. Resistance to bedaquiline is primarily mediated by a range of mutations in the Rv0678 gene, which additionally provide cross resistance to clofazimine, a repurposed leprosy drug that is frequently included in MDR and XDR-TB treatment.

We assembled a comprehensive dataset of 3682 Mtb whole genome sequences screened for mutatinos in Rv0678. Using phylogenetic dating methods, we estimated the age of emergence for all detected variants in Rv0678. While bedaquiline resistant mutations predating the use of the drug have been previously observed, their emergence has been attributed to the use of clofazimine. We report a large number of cases where genotypic resistance emerged predating the use of bedaquiline. Though, we additionally identify three events where Rv0678 variants were acquired before the turn of the 20th century, thus establishing the circulation of Rv0678 variants prior to not only the use of clofazimine but predating the antibiotic era.

We hypothesise that currently circulating bedaquiline and clofazimine cross-resistance is largely due to selection of strains with Rv0678 mutations from a historic reservoir. Bedaquiline and clofazimine cross-resistance may therefore occur even in settings with minimal or no previous clofazimine use, and may expand rapidly as these drugs are rolled out further.

Coronavirus mutations: what we've learned so far

A short accessible piece on mutations in SARS-CoV-2.

Link: The Conversation article

Population-level emergence of bedaquiline and clofazimine resistance-associated variants among patients with drug-resistant tuberculosis in southern Africa: a phenotypic and phylogenetic analysis

Link: The Lancet Microbe manuscript

In our recent paper we report 671 Mycobacterium tuberculosis genomes from 391 patients with drug resistant tuberculosis in KwaZulu-Natal South Africa sampled over six years.

We screened for resistance to bedaquiline, a drug now central to effective Tuberculosis (TB) treatment. We found around 4% of patients harboured M. tuberculosis with variants in genes known to mediate resistance to bedaquiline and clofazimine. Phylogenetic analyses showed repeated and independent acquisitions of resistance variants, including onward transmission of resistant strains across South Africa.

Bedaquiline is a reasonably new, but now cornerstone, drug in the fight against drug-resistant TB. The lack of routine bedaquiline susceptibility testing may allow these resistant strains to continue to spread, unwatched, posing further significant challenges to TB treatment & control.

You can find a great summary of our work here.

STROBE-metagenomics: a STROBE extension statement to guide the reporting of metagenomics studies

The Lancet Infectious Diseases Manuscript Link

The term metagenomics refers to the use of sequencing methods to simultaneously identify genomic material from all organisms present in a sample, with the advantage of greater taxonomic resolution than culture or other methods. Applications include pathogen detection and discovery, species characterisation, antimicrobial resistance detection, virulence profiling, and study of the microbiome and microecological factors affecting health. However, metagenomics involves complex and multistep processes and there are important technical and methodological challenges that require careful consideration to support valid inference.

I was involved in working with a large multidisciplinary team to establish reporting guidelines that address specimen processing, nucleic acid extraction, sequencing platforms, bioinformatics considerations, quality assurance, limits of detection, power and sample size, confirmatory testing, causality criteria, cost, and ethical issues. The guidance recognises that metagenomics research requires pragmatism and caution in interpretation, and that this field is rapidly evolving.

You can hear more about our work on the genomics of SARS-CoV-2, the viral agent of Covid-19, in a talk I delivered for the University of Copenhagen Population Genetics Summer Series.