Can epigenetic changes drive evolution of antihelminth resistance in nematodes?

The project will provide training in the following areas aligning with MRC's key priorities: Molecular and cellular medicine

The project seeks to investigate whether epigenetic changes, in the absence of DNA sequence changes, can drive evolution of drug resistance, using a nematode (C. elegans) as a model system. The contribution of epigenetic mechanisms to evolution is an example of a dynamic biological system, a key area of interest for the MRC. Importantly, epigenetic changes have been proposed to be a mechanism whereby cancer cells evolve resistance to chemotherapeutic agents.

The complex genetic make up of cancers make this very hard to test directly, so studying this in a simple model will provide key fundamental insight that will subsequently be applicable to human disease. Global health and Infection and Immunity

In addition to application to human cancer, the development of antihelminth resistance is itself relevant to human disease because parasitic nematodes are a major public health burden, particularly in the developing world. Parasitic nematodes frequently acquire resistance to antihelminthic drugs and the mechanisms for this are poorly understood. Testing whether the resistance can ever be driven by epigenetic processes will potentially offer a new avenue to treating parasitic nematode infection, using drugs that interfere with epigenetic mechanisms to block evolution of resistance in parasitic nematode populations.

The project will also provide training in the following areas within MRC's remit:

Data science at the interface of human health and biology (including modelling, data analytics, artificial intelligence and machine learning);

Identification of epimutations that might contribute to evolution of resistance will require advanced statistical techniques, incorporating machine learning methods to identify regions of the genome where epigenetic marks differ significantly in resistant populations from sensitive populations. The Sarkies laboratory has a track record in developing new methods to identify and analyse epimutations and thus will provide training in this area, as well as guiding the improvement of these methods over the course of the studentship.

Interdisciplinary skills and ways of working

The project will involve close interaction between laboratory work and computational analysis, providing the student with training in both these areas. Additionally, the computational aspects described above will involve up to date computer science algorithms. The studentship will therefore provide interdisciplinary skills.