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EASTBIO Parallel genomic evolution of parasitism: using long-read sequencing to uncover the hidden diversity ad evolutionary history of RNA processing mechanisms across eukaryotic parasites.


School of Medicine, Medical Sciences & Nutrition

Dr J Pettitt , Dr B Mueller , Dr M Wenzel , Prof I Stansfield Wednesday, January 06, 2021 Competition Funded PhD Project (Students Worldwide)

About the Project

Supervisors:

Dr Jonathan Pettitt (University of Aberdeen)
https://www.aberdeenwormlab.org/

Dr Berndt Mueller (University of Aberdeen)
https://www.aberdeenwormlab.org/

Dr Marius Wenzel (University of Aberdeen)
https://www.abdn.ac.uk/people/marius.wenzel

Professor Ian Stansfield (University of Aberdeen)
https://www.abdn.ac.uk/people/i.stansfield

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.

Application Procedure:

http://www.eastscotbiodtp.ac.uk/how-apply-0

Please send your completed EASTBIO application form, along with academic transcripts to Alison McLeod at . Two references should be provided by the deadline using the EASTBIO reference form. Please advise your referees to return the reference form to .

Funding Notes

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership View Website. This opportunity is open to UK and International students and provides funding to cover stipend and UK level tuition (limited funding is available to provide international tuition fees). Please refer to UKRI website and Annex B of the UKRI Training Grant Terms and Conditions for full eligibility criteria.

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.

References

Lasda, E. L., & Blumenthal, T. (2011). Trans‐splicing. Wiley Interdisciplinary Reviews: RNA, 2(3), 417-434.

Maeso, I., Roy, S. W., & Irimia, M. (2012). Widespread recurrent evolution of genomic features. GBE, 4(4), 486-500.

Wenzel, M., Johnston, C., Müller, B., Pettitt, J., & Connolly, B. (2020). Resolution of polycistronic RNA by SL2 trans-splicing is a widely conserved nematode trait. RNA, rna-076414.
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