Sleeping sickness, caused by the African trypanosome, threatens millions of people in many countries in sub-Saharan Africa. Many of the affected populations live in remote rural areas with limited access to adequate health service. Although there are curative drugs they have many undesirable side-effects. The aim of this project is to increase our understanding the genomic structure and function of trypanosomal mitochondrial DNA (the kinetoplast) in the hope of aiding drug discovery. The kinetoplast is quite remarkable and unlike human mitochondrial DNA. It is made up of thousands of interlocked DNA rings like chainmail armour. These rings, called minicircles, encode guide-RNAs that post-transcriptionally edit mRNA. In some genes almost half the genetic information is edited into the mRNA. Our groups (one theoretical and another experimental) are interested in determining the complexity of the kinetoplast and how it evolves over time. We use a combination of mathematical modelling, bioinformatics, next-generation sequencing and experimentation to reveal and understand the wonderful complexity of the kinetoplast and it’s transcriptional and proteomic products – many, we suspect, have not yet been found.
The main goal of this project is to understand how such massive redundancy is maintained and to discover the function of the non-canonical gRNAs by combining sequence and transcriptomics data. The size and complexity of kDNA and its transcription products means that standard bioinformatics methods are incapable of elucidating its structure and function. This project will develop innovative Bayesian statistical and computational modelling methods to help achieve this.
The candidate will obtain training in cutting edge molecular biology, next generation sequencing. They will learn about modern bioinformatic tools available and how to construct bioinformatic pipelines to analyse genomic and transcriptomic sequences.
The student will also learn how to develop mathematical models describing the evolution of minicircle structure and function. They will learn how to write scientific computer code to simulate their mathematical models. http://homepages.ed.ac.uk/nsavill/ http://schnauferlab.bio.ed.ac.uk/
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If you would like us to consider you for one of our scholarships you must apply by 5 January 2020 at the latest.
Liu B, Liu Y, Motyka SA, Agbo EEC and Englund PT (2005). Fellowship of the rings: the replication of kinetoplast DNA. Trends in Parasitology, 21:363-369. doi:10.1016/j.pt.2005.06.008
Savill NJ and Higgs PG (1999). A theoretical study of random segregation of minicircles in trypanosomatids. Proceedings of the Royal Society B – Biological Sciences, 266:611–620.
Schnaufer, A (2010). Evolution of dyskinetoplastic trypanosomes: how, and how often? Trends in Parasitology 26:557-558. doi:10.1016/j.pt.2010.08.001