Biology subjects

Earl, A.

Publications and source records attributed to Earl, A..

6 recordsLinked to original sources

bioRxiv2025

Complex exchanges among plasmids and clonal expansion of lineages shape the population structure and virulence of Borrelia burgdorferi

The many plasmids (commonly >20 per strain) of Borrelia burgdorferi (Bb) pose challenges for studies of Lyme disease. The genetic content of most plasmids cannot be resolved using short-read sequencing. We generated long-read assemblies (LRA) of 183 isolates of human-derived Bb and analyzed patterns of genome variation in the Lyme spirochete. LRAs confirm that populations consist of strongly-structured genotypes with nearly-clonal structure and tight-knit blocks of accessory genome elements. Notably, these patterns of linkage were statistical but not physical, with linkage blocks distributed across multiple plasmids. A consequence of this structure is that plasmid name and/or plasmid subtype does not capture strain-specific genetic content. We used network methods to characterize patterns of genetic linkage. We demonstrate that co-occurring gene networks, here termed genetic modules, are the fundamental unit of genome variation in Bb and designate genetic modules consisting of co-occurring genes. We linked genetic modules to Bb phenotype by identifying modules that influence dissemination in humans. This modular decomposition clarifies previously observed associations between strain and virulence. For example, virulent RST1/OspC type A strains are distinguished by the presence of virulence-associated modules containing gene content from lp28-1, lp56, and the chromosome along with the absence of gene content on lp28-1 and lp28-4 associated with localized disease. LRAs also demonstrate that the well-established statistical linkage between physical unlinked genetic markers (e.g. RST and OspC) is a general pattern among accessory genome elements. In summary, genetic modules containing genes linked across multiple replicons, rather than strain-defining plasmids, organize the Bb accessory genome and the strain-specific variation responsible for differences in human virulence.

microbiology↗

bioRxiv2024

Assessment of the levels of resistance of Tropilaelaps mercedesae to a variety of synthetic miticide.

The introduction of the western honey bee Apis mellifera to Asia has seen the parasitic mites Varroa destructor and Tropilaelaps spp. transfer from their native Asian honey bee hosts (Apis cerana and Apis dorsata respectively) to infest the brood of A. mellifera causing significant damage to colonies and colony losses. T. mercedesae was recently detected in Europe for the first time in A. mellifera colonies and is considered a more damaging parasite of A. mellifera than Varroa. Beekeepers rely heavily on the use of synthetic miticides and organic chemicals to control Varroa and Tropilaelaps which has resulted in Varroa developing resistance to many synthetic miticides and these treatments becoming less effective. Less is known about chemical resistance in Tropilaelaps as no study has been undertaken that specifically looks at this issue, but there is evidence to suggest that Tropilaelaps do have resistance to chemicals such as Amitraz, Coumaphos, Flumethrin and Fluvalinate. The use of synthetic miticides is widely recommended for surveillance and detection of Tropilaelaps and this recommendation forms a part of the contingency response of several government agencies. The study developed a novel chemical resistance test for Tropilaelaps and sought to test the efficacy of commercially available synthetic miticides and found that mites were resistant to all the synthetic chemical treatments tested apart from Amitraz which was shown to be 64% effective. Understanding and managing miticide resistance in this species is critical to prevent its further spread and colony losses.

zoology↗

bioRxiv2024

An in vitro investigation into the survival of Tropilaelaps mercedesae on a range of matrices.

Tropilaelaps spp. are a parasitic mite that feed and reproduce within honey bee brood (Apis spp.) and cause significant damage and mortality to Apis mellifera colonies. T. mercedesae is found outside the range of its natural host A. dorsata and was recently detected in Europe for the first time in 2024. It is widely believed that Tropilaelaps spp. are unable to survive without brood. However, studies have demonstrated that T. mercedesae can survive during broodless periods while parasitising A. dorsata and without brood in overwintering colonies of A. mellifera in temperate climates. This study sought to examine the survival of T. mercedesae on a range of matrices and found that mites could survive for more than 96 hours on live adult A. mellifera and more than 144 hours and 168 hours on decomposing A. mellifera pupae and adults respectively. These findings could indicate one possible mechanism which allows T. mercedesae to survive without brood. These findings also have implications towards better understanding possible transmission routes for Tropilaelaps. Previously bee sales in the form of queens and packages and used beekeeping equipment were considered a relatively low risk for transmitting Tropilaelaps spp. due to the absence of live brood. This study demonstrates Tropilaelaps ability to survive in these scenarios and the increased potential for it to spread globally.

zoology↗

bioRxiv2023

Cell of origin epigenetic priming determines susceptibility to Tet2 mutation

Hematopoietic stem cell mutations can result in clonal hematopoiesis (CH) but the clinical outcomes are heterogeneous. The nature of the founder mutation and secondary mutations likely drive emergent neoplastic disease. We investigated how the state of the cell of origin where the Tet2 mutation occurs affects susceptibility to that commonly occurring CH mutation. Here, we provide evidence that risk is written in the epigenome of the cell of origin. By characterizing cell states that underlie myeloid differentiation and linking this information to an inducible system to assess myeloid progenitor clones, we provide evidence that epigenetic markers of the cell where Tet2 mutation occurs stratifies clonal behaviors. Specifically, Sox4 fosters a global cell state of high sensitization towards Tet2 KO. Using GMP and primary HSC models, we show that Sox4 promotes cell dedifferentiation, alters cell metabolism and increases the in vivo clonal output of mutant cells. Our results validate the hypothesis that epigenetic features can predispose specific clones for dominance and explain why an identical mutation can result in different outcomes.

cancer biology↗

bioRxiv2021

Functional Inference of Gene Regulation using Single-Cell Multi-Omics

Cells require coordinated control over gene expression when responding to environmental stimuli. Here, we apply scATAC-seq and scRNA-seq in resting and stimulated human blood cells. Collectively, we generate [~]91,000 single-cell profiles, allowing us to probe the cis-regulatory landscape of immunological response across cell types, stimuli and time. Advancing tools to integrate multi-omic data, we develop FigR - a framework to computationally pair scATAC-seq with scRNA-seq cells, connect distal cis-regulatory elements to genes, and infer gene regulatory networks (GRNs) to identify candidate TF regulators. Utilizing these paired multi-omic data, we define Domains of Regulatory Chromatin (DORCs) of immune stimulation and find that cells alter chromatin accessibility prior to production of gene expression at time scales of minutes. Further, the construction of the stimulation GRN elucidates TF activity at disease-associated DORCs. Overall, FigR enables the elucidation of regulatory interactions across single-cell data, providing new opportunities to understand the function of cells within tissues.

genomics↗

bioRxiv2021

Genetic determinants facilitating the evolution of resistance to carbapenem antibiotics

In this era of rising antibiotic resistance, in contrast to our increasing understanding of mechanisms that cause resistance, our understanding of mechanisms that influence the propensity to evolve resistance remains limited. Here, we identified genetic factors that facilitate the evolution of resistance to carbapenems, the antibiotic of "last resort," in Klebsiella pneumoniae, the major carbapenem resistant species. In clinical isolates, we found that high-level transposon insertional mutagenesis plays an important role in contributing to high-level resistance frequencies in several major and emerging carbapenem-resistant lineages. A broader spectrum of resistance-conferring mutations for select carbapenems such as ertapenem also enables higher resistance frequencies and importantly, creates stepping-stones to achieve high-level resistance to all carbapenems. These mutational mechanisms can contribute to the evolution of resistance, in conjunction with the loss of systems that restrict horizontal resistance gene uptake, such as the CRISPR-Cas system. Given the need for greater antibiotic stewardship, these findings argue that in addition to considering the current efficacy of an antibiotic for a clinical isolate in antibiotic selection, considerations of future efficacy are also important. The genetic background of a clinical isolate and the exact antibiotic identity can and should also be considered as it is a determinant of a strains propensity to become resistant. Together, these findings thus provide a molecular framework for understanding acquisition of carbapenem resistance in K. pneumoniae with important implications for diagnosing and treating this important class of pathogens.

evolutionary biology↗