A 4-year funded PhD studentship is available to join the Marsh (https://www.ed.ac.uk/mrc-human-genetics-unit/research/marsh-group) and Kudla (https://www.ed.ac.uk/mrc-human-genetics-unit/research/kudla-group) labs at the MRC Human Genetics Unit. The project will involve using deep mutational scanning experiments, also known as multiplexed assays of variant effect, to measure the phenotypic effects of all possible single amino acid substitutions in one or more human Mendelian disease genes. Specifically, the student will employ a yeast-based synthetic biology strategy we have been developing for the high-throughput measurement of variant effects and elucidation of molecular mechanisms underlying mutations, allowing distinction between loss-of-function, gain-of-function and dominant-negative effects. This project will also involve computational analyses, using structural bioinformatics methods to understand the effects of mutations and a protein structural level, and comparing the utility of the deep mutational scanning measurements to variant effect predictors based upon machine learning for their ability to distinguish between clinically identified pathogenic and putatively benign human variants. Ultimately, the goal of this work is to improve our ability to identify and understand novel pathogenic variants, and thus diagnose human genetic disorders.
Applicants should hold at least an upper second-class degree in a relevant subject and comply with English language requirements (https://www.ed.ac.uk/studying/postgraduate/applying/your-application/entry-requirements/english-requirements).
Please contact Dr Joe Marsh ([Email Address Removed]) and Dr Grzegorz Kudla ([Email Address Removed]) if you have any questions about the project, or would like to discuss it more detail, including potential gene targets.
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