Research Opportunities in the Aberdeen Worm Lab
Two 4 Year PhD Studentships
Application deadline - 6th January 2021
These projects are part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership and are open to UK and International students.
Candidates should have (or expect to achieve) a minimum of a 2:1 UK Honours degree, or the equivalent qualifications gained outside the UK, in a relevant subject.
Please feel free to get in touch if you would like to discuss these projects further.
Berndt Müller - b.mueller@abdn.ac.uk
Jonathan Pettitt - j.pettitt@abdn.ac.uk
Application deadline - 6th January 2021
These projects are part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership and are open to UK and International students.
Candidates should have (or expect to achieve) a minimum of a 2:1 UK Honours degree, or the equivalent qualifications gained outside the UK, in a relevant subject.
Please feel free to get in touch if you would like to discuss these projects further.
Berndt Müller - b.mueller@abdn.ac.uk
Jonathan Pettitt - j.pettitt@abdn.ac.uk
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Parallel genomic evolution of parasitism Using long-read sequencing to uncover the hidden diversity and evolutionary history of RNA processing mechanisms across eukaryotic parasites
Parasitism is a notable example of parallel evolution in many different groups of organisms. An emerging challenge in evolutionary biology is to understand how such ‘phenotypic parallelism’ is underpinned by genomic evolution. Are multiple molecular paths available for achieving the same phenotype, or is genomic evolution constrained to preserve ancestral molecular function, leading to ‘genomic parallelism’? Resolving this question is be key to understanding and, ultimately, predicting the evolution of biodiversity. The evolution of a parasitic lifestyle requires far-reaching modifications to fundamental molecular processes. One such adaptation is polycistronic RNA processing, a mechanism that is present in numerous eukaryotic taxa, many of which are medically and agriculturally important parasites and pathogens. Polycistronic RNA is transcribed from eukaryotic operons, where multiple adjacent genes are controlled by a single promoter. This unusual RNA metabolism is thought to increase molecular resource efficiency during developmental arrest (hypobiosis), a hallmark of the life cycle of many parasites. Polycistronic RNAs must be resolved into individual monocistronic transcripts using a process termed ‘spliced leader trans-splicing’. This mechanism is derived from the cis-splicing RNA processing machinery and should thus be constrained by the ancestral function of the spliceosome and other components. Yet, trans-splicing has independently evolved many times throughout Eukarya, with highly variable spliced leader repertoires across species. This raises the question of whether this parallel phenotypic evolution may be underpinned by varying genomic architectures derived via different mutational paths. This project will systematically examine the molecular commonalities and differences of spliced leader trans-splicing mechanisms among eukaryotic parasites in an evolutionary framework. In parallel, the project will investigate the rules underlying the evolution of polycistronic RNA processing using a yeast-based synthetic biology system. The student will: - Analyse published genome assemblies and RNA-Seq datasets with existing Linux/R-based bioinformatics pipelines to systematically explore the evolution of polycistronic RNA processing throughout Eukarya. - Generate full-length transcript sequence data using the Oxford NanoPore MinION sequencing platform, focussing on parasites with sparse or absent transcriptomic resources. - Expand and improve upon existing bioinformatics pipelines to extract trans-splicing information contained in full-length transcript sequence data. - Study molecular evolution in situ using an established yeast-based model system. Forced evolution will be used to select for increases in the efficiency of polycistronic RNA processing, allowing us to study the molecular changes that occur during its emergence. Depending on the student’s interests, other RNA processing phenomena could be explored, for example alternative splicing, genic trans-splicing or RNA editing. This project presents an exciting opportunity to delve into comparative computational biology of genomes and transcriptomes from a broad range of parasitic eukaryotes. The student will be part of bleeding-edge computational and functional genomics research, supervised by experts in genetics, RNA processing, synthetic biology and bioinformatics. This project would suit a student who is interested in gaining well-rounded skills in wet-lab molecular genetics as well as bioinformatics approaches for processing and mining large genomics and transcriptomics datasets. |
Exploiting functional fragility in parasitic nematode gene expression
Using genome editing and transcriptome analysis to investigate the genome-wide impacts of spliced leader trans-splicing Nematode parasites impose a significant global human health burden and also jeopardise food security and economic sustainability through their impacts upon both plant and animal agriculture. Controlling parasitic nematodes remains a major issue. There are only few classes of drugs to treat animal and human parasitic nematodes and resistance to existing therapeutics is a growing challenge. Similarly, control of plant parasitic nematodes is frequently reliant upon harsh soil treatments, which are environmentally damaging. There is thus a pressing need to develop new, broad-specificity drug treatments. Nematode gene expression is highly unusual because many genes are arranged in operons (polycistrons) that are controlled by a single promotor. Pre-mRNA transcribed from these operons must be processed by ‘spliced leader trans-splicing’, which resolves the polycistronic RNA into individual transcripts for translation. Research in the Aberdeen Worm Lab is directed towards understanding the molecular machinery the directs these RNA processing events, using C. elegans as a model nematode. We have identified a series of nematode-specific drug targets, the inhibition of which is predicted to lead to impaired development and reproduction by perturbation of RNA processing. This multidisciplinary project aims to understand the molecular effects of inhibiting spliced leader trans-splicing using genome editing and high-throughput transcriptome surveys. The student will work with wild-type and CRISPR genome-engineered mutant C. elegans strains using the auxin-degron system to deplete components of the nematode-specific RNA processing machinery. Transcriptome-wide changes in gene expression and splicing patterns will be identified using full-length isoform sequencing on the Oxford NanoPore MinION sequencing platform. Global analysis of changes in spliced leader trans-splicing events will be examined using in-house computational analysis pipelines, with scope for developing novel bioinformatics methods. Thus, by characterising the global post-transcriptional effects of individual molecular components, the project will allow us to refine our focus on drug development strategies that are likely to have most impact on nematode gene expression. This is a unique and exciting opportunity to gain multidisciplinary training in state-of-the-art model organism-based gene function analysis and gene editing, combined with computational biology (including recently developed high-throughput sequencing technologies) of transcriptomes. The supervisory team comprises experts in C. elegans genetics and RNA biology, molecular biology and bioinformatics; the successful applicant will join a vibrant, international research team focussed on understanding a basic biology process with likely impacts on the global treatment of parasitic disease. |