The role of post-translational modifications in resistance to viral diseases in farmed fish

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Aquaculture is the fastest growing food industry worldwide, playing a critical role in feeding the world without exhausting oceans natural resources (FAO 2020, http://www.fao.org/documents/card/en/c/ca9229en). However, aquaculture faces major animal health and welfare challenges, and infectious diseases pose a constant risk. Viral pathogens are current a major threat to aquaculture sustainability, often with limited vaccine or treatment options. In this context, genetic improvement of disease resistance, including selective breeding and genome editing, constitute a highly promising approach to tackle viral diseases of aquaculture stocks (Houston et al. 2020 Nat Rev Genet 21:389-409).Our previous research in Atlantic salmon and common carp (e.g. Palaiokostas et al. 2018 G3 8:3507-3513) suggests that genes involved in post-translational modifications (the attachment of ubiquitin and ubiquitin-like molecules to proteins) such as TRIM25 may play an important role in resistance to viral diseases. TRIM25 is responsible for the activation of the interferon pathway in mammals, and is directly targeted by Influenza to avoid the host immune response. However, this gene has undergone multiple duplications in fish, with 63 copies in salmon and 83 in carp, pointing towards a huge functional diversification. While we know several of these copies are involved in immunity (Langevin et al. 2019 Fish Shellfish Immunol 86:724-733), their specific function is unknown.The main aim of this project in to understand the role of genes related to posttranslational modifications in resistance to viral diseases in Atlantic salmon and carp. To do so, the PhD student will work with immortalised cell cultures of both species to study host-virus interactions. CRISPR/Cas9 will be used to knockout or up-regulate the different copies of TRIM25 and other genes of interest, evaluating their impact on disease resistance to various viral diseases in both species. The molecular function of these genes will be further evaluated using a combination of molecular biology, virology, transcriptomic and proteomic techniques, in order to find their direct targets, the impact on their ubiquitination / ubiquitin-like status and how this affects downstream molecular pathways. The interaction of the virus with this molecular cascade will also be evaluated (i.e. if the virus targets or is targeted by these genes). The identified genes and molecules from these experiments will form targets for genome editing in vivo, with potential for developing disease resistant fish. In sum, this project will help us understand the role of posttranslational modifications in response to viral diseases in fish and contribute to the development of strategies to tackle viral diseases in aquaculture.This 4-year studentship will provide an excellent inter-disciplinary training opportunity, covering aspects of genomics and genetics, molecular biology, virology and bioinformatics, and applying a wide variety of techniques. The student will be part of a large multidisciplinary and diverse team working in aquaculture genetics at the University of Edinburgh (https://www.ed.ac.uk/roslin/aquaculture), in close collaboration with world experts in the Scottish Fish Immunology Research Centre, at the University of Aberdeen (https://www.abdn.ac.uk/sfirc/).