2,040 research outputs found

    Context-Dependent Acquisition of Antimicrobial Resistance Mechanisms

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    Natural transformation is a process whereby bacteria actively take up free DNA from the environment while in a physiological state termed competence. Uptaken DNA is then recombined into the recipient’s genome or reconverted into extra-chromosomal genetic elements. The inducing stimuli for competence vary widely between transformable species and competence induction is affected by a host of abiotic factors found in bacterial environments. Natural transformation is recognised to be responsible for the dissemination of antimicrobial resistance genes both within and between species, contributing to the global antimicrobial resistance crisis threatening modern medicine. Despite being the first mechanism of horizontal gene transfer discovered, the evolutionary benefits of natural transformation are still under debate. This thesis is comprised of four standalone research chapters which aimed 1) to determine if chemotherapeutic compounds affect the transformation frequencies of transformable bacteria. This provides important information which can have implications on the contraction of a life-threatening infection in cancer patients. 2) to determine if other environmentally relevant bacteria affect the transformation frequencies of transformable bacteria. Understanding the contexts under which bacteria transform in their natural environments can help us to predict the spread of antimicrobial resistance mechanisms via natural transformation. 3) to produce a resource of genomic information for the scientific community, allowing researchers to improve our understanding of the Acinetobacter genus. And 4) to determine if environmentally relevant bacteria affect the transformation frequencies of transformable bacteria to find evidence for the sex hypothesis for natural transformation. This was performed by using biotic interactions as a selection pressure and DNA from a range of related species as a substrate for transformation. Together, these chapters provide information about the contexts under which transformation is both regulated and selected for in realistic environmental contexts. Enhancing our understanding of how and when bacteria naturally transform, in both natural and clinical environments, can help us to monitor and establish preventative measures to limit the spread of antimicrobial resistance genes between bacteria

    On the robustness of Bayesian phylogenetic gene tree estimation

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    Methods for large-scale genome-wide association studies

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    Genome-wide association studies (GWAS) have led to the identification of thousands of associations between genetic polymorphisms and complex traits or diseases, facilitating several downstream applications such as genetic risk prediction and drug target prioritisation. Biobanks containing extensive genetic and phenotypic data continue to grow, creating new opportunities for the study of complex traits, such as the analysis of rare genomic variation across multiple populations. These opportunities are coupled with computational challenges, creating the need for the development of novel methodology. This thesis develops computational tools to facilitate large-scale association studies of rare and common variation. First, we develop methods to improve the analysis of ultra-rare variants, leveraging the sharing of identical-by-descent (IBD) genomic regions within large biobanks. We compare ∼ 400k genotyped UK Biobank (UKBB) samples with 50k exome-sequenced samples and devise a score that quantifies the extent to which a genotyped individual shares IBD segments with carriers of rare loss-of-function mutations. Our approach detects several associations and replicates 11/14 loci of a pilot exome sequencing study. Second, we develop a linear mixed model framework, FMA, that builds on previous techniques and is suitable for scalable and robust association testing. We benchmark FMA and several state-of-the-art approaches using synthetic and UKBB data, evaluating computational performance, statistical power, and robustness to known confounders, such as cryptic relatedness and population stratification. Finally, we integrate FMA with recently developed methods for genealogical analysis of complex traits, enabling it to perform scalable genealogy-based estimation of narrow-sense heritability and association

    An Ecological Perspective of American Rodent-Borne Orthohantavirus Surveillance

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    Orthohantaviruses are a global group of viruses found primarily in rodents, though several viruses have also been found in shrews and moles. Many rodent-borne orthohantaviruses are capable of causing one of several diseases in humans, and the mortality associated with these diseases ranges from \u3c 0.1% - 50% depending on the specific etiological virus. In North and South America, orthohantavirus research was ignited by an outbreak of severe disease in the Four Corners region of the United States in 1993. However, despite the discovery of over 20 orthohantaviruses in the Americas, our understanding of orthohantavirus ecology and virus-host dynamics in this region is still limited, and orthohantavirus surveillance is generally restricted in scope to select regions and small portions of host distributional ranges. In Chapter I, I present a literature review on the current understanding of American rodent-borne orthohantavirus ecology. This review focused on under-studied orthohantaviruses, addressing gaps in knowledge by extrapolating information from well-studied orthohantaviruses, general rodent ecology, and occassionally from Eurasian orthohantavirus-host ecology. There were several key conclusions generated from this review that warrant further research: 1) the large number of putative orthohantaviruses and gaps in orthohantavirus evolution necessitate further surveillance and characterization, 2) orthohantavirus traits differ and are more generalizable based on host taxonomy rather than geography, and 3) orthohantavirus host species are disproportionately found in grasslands and disturbed habitats. In Chapter II, I present a prioritized list of rodent species to target for orthohantavirus surveillance based on predictive modeling using machine learning. Probable orthohantavirus hosts were predicted based on traits of known orthohantavirus hosts using two different types of evidence: RT-PCR and virus isolation. Predicted host distributions were also mapped to identify geographic hotspots to spatially guide future surveillance efforts. In Chapter III, I present a framework for understanding and predicting orthohantavirus traits based on reservoir host phylogeny, as opposed to the traditional geographic dichotomy used to group orthohantaviruses. This framework establishes three distinct orthohantavirus groups: murid-borne orthohantaviruses, arvicoline-borne orthohantaviruses, and non-arvicoline cricetid-borne orthohantaviruses, which differ in several key traits, including the human disease they cause, transmission routes, and virus-host fidelity. In Chapter IV, I compare rodent communities and orthohantavirus prevalence among grassland management regimes. Sites that were periodically burned had high rodent diversity and a high proportion of grassland species. However, rodent seroprevalence for orthohantavirus was also highest in burned sites, representing a trade-off in habitat management outcomes. The high seroprevalence in burned sites is likely due to the robust populations supported by the high quality habitat resulting from prescribed burning. In Chapters V and VI, I describe Ozark virus and Sager Creek virus, two novel orthohantaviruses discovered from specimens collected during Chapter IV. Both chapters report full genome sequences of the respective viruses and compare both nucleotide and protein phylogenies with related orthohantaviruses. Additionally in Chapter VI, I support the genetic analyses with molecular and ecological characterizations, including seasonal fluctuations in host abundance, correlates of prevalence, evidence of virus shedding, and information on host cell susceptibility to Sager Creek virus

    Speciation and sex-biased gene expression in the scarce swallowtails

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    Speciation is the process by which closely related populations of organisms differentiate following reductions in the effective rate of genetic exchange between them over time. For most speciation events, population genetic data is the only available information about how reproductive isolation has arisen. We have a poor understanding of how evolutionary forces and genomic features contribute to reproductive isolation, primarily due to the difficulty of inferring barriers to gene flow. In particular, it is unclear what role genes that are sex-biased in expression and/or sex-linked play in speciation. In my thesis, I aim to infer the locations of putative barriers to gene flow to understand to what extent different genomic features, in particular fast-evolving sex-biased genes, contribute to reproductive isolation between a sister species pair of scarce swallowtail (Iphiclides) butterflies. In my first research project, I estimate core population genetic parameters across all sister species pairs of European butterflies and fit simple models of divergence to ask how well classic phylogeographic hypotheses fit recent diversification events in this taxonomic group. In my second research project, I infer explicit models of the speciation process and model effective migration rates along the genome to locate putative barriers to gene flow. I ask whether these barriers to long-term gene flow are associated with areas of the genome that show a reduction in recent introgression across a hybrid zone. In my third and final research project, I extend the demographic modeling of speciation in the Iphiclides species pair to the Z chromosome and ask whether barrier regions are associated with sex-biased genes, as a result of their faster rate of evolution. In summary, my findings suggest that fast-evolving male-biased genes likely contribute to extensive sex-linked reproductive isolation, as well as paving the way for future research on the population genetics of European butterflies and the evolutionary genomics of speciation

    Investigating tricky nodes in the Tree of Life

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    Pancrustacean evolution illuminated by taxon-rich genomic-scale data sets with an expanded remipede sampling

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    The relationships of crustaceans and hexapods (Pancrustacea) have been much discussed and partially elucidated following the emergence of phylogenomic data sets. However, major uncertainties still remain regarding the position of iconic taxa such as Branchiopoda, Copepoda, Remipedia, and Cephalocarida, and the sister group relationship of hexapods. We assembled the most taxon-rich phylogenomic pancrustacean data set to date and analyzed it using a variety of methodological approaches. We prioritized low levels of missing data and found that some clades were consistently recovered independently of the analytical approach used. These include, for example, Oligostraca and Altocrustacea. Substantial support was also found for Allotriocarida, with Remipedia as the sister of Hexapoda (i.e., Labiocarida), and Branchiopoda as the sister of Labiocarida, a clade that we name Athalassocarida (='nonmarine shrimps'). Within Allotriocarida, Cephalocarida was found as the sister of Athalassocarida. Finally, moderate support was found for Hexanauplia (Copepoda as sister to Thecostraca) in alliance with Malacostraca. Mapping key crustacean tagmosis patterns and developmental characters across the revised phylogeny suggests that the ancestral pancrustacean was relatively short-bodied, with extreme body elongation and anamorphic development emerging later in pancrustacean evolution

    An Ecological Perspective of American Rodent-Borne Orthohantavirus Surveillance

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    Orthohantaviruses are a global group of viruses found primarily in rodents, though several viruses have also been found in shrews and moles. Many rodent-borne orthohantaviruses are capable of causing one of several diseases in humans, and the mortality associated with these diseases ranges from \u3c 0.1% - 50% depending on the specific etiological virus. In North and South America, orthohantavirus research was ignited by an outbreak of severe disease in the Four Corners region of the United States in 1993. However, despite the discovery of over 20 orthohantaviruses in the Americas, our understanding of orthohantavirus ecology and virus-host dynamics in this region is still limited, and orthohantavirus surveillance is generally restricted in scope to select regions and small portions of host distributional ranges. In Chapter I, I present a literature review on the current understanding of American rodent-borne orthohantavirus ecology. This review focused on under-studied orthohantaviruses, addressing gaps in knowledge by extrapolating information from well-studied orthohantaviruses, general rodent ecology, and occassionally from Eurasian orthohantavirus-host ecology. There were several key conclusions generated from this review that warrant further research: 1) the large number of putative orthohantaviruses and gaps in orthohantavirus evolution necessitate further surveillance and characterization, 2) orthohantavirus traits differ and are more generalizable based on host taxonomy rather than geography, and 3) orthohantavirus host species are disproportionately found in grasslands and disturbed habitats. In Chapter II, I present a prioritized list of rodent species to target for orthohantavirus surveillance based on predictive modeling using machine learning. Probable orthohantavirus hosts were predicted based on traits of known orthohantavirus hosts using two different types of evidence: RT-PCR and virus isolation. Predicted host distributions were also mapped to identify geographic hotspots to spatially guide future surveillance efforts. In Chapter III, I present a framework for understanding and predicting orthohantavirus traits based on reservoir host phylogeny, as opposed to the traditional geographic dichotomy used to group orthohantaviruses. This framework establishes three distinct orthohantavirus groups: murid-borne orthohantaviruses, arvicoline-borne orthohantaviruses, and non-arvicoline cricetid-borne orthohantaviruses, which differ in several key traits, including the human disease they cause, transmission routes, and virus-host fidelity. In Chapter IV, I compare rodent communities and orthohantavirus prevalence among grassland management regimes. Sites that were periodically burned had high rodent diversity and a high proportion of grassland species. However, rodent seroprevalence for orthohantavirus was also highest in burned sites, representing a trade-off in habitat management outcomes. The high seroprevalence in burned sites is likely due to the robust populations supported by the high quality habitat resulting from prescribed burning. In Chapters V and VI, I describe Ozark virus and Sager Creek virus, two novel orthohantaviruses discovered from specimens collected during Chapter IV. Both chapters report full genome sequences of the respective viruses and compare both nucleotide and protein phylogenies with related orthohantaviruses. Additionally in Chapter VI, I support the genetic analyses with molecular and ecological characterizations, including seasonal fluctuations in host abundance, correlates of prevalence, evidence of virus shedding, and information on host cell susceptibility to Sager Creek virus

    A survey of Bayesian Network structure learning

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