Drosophila melanogaster is a fruit fly species that has been used in research for many years and are a successful model due to their superlative genetics, vast array of tools, a simple genome that is easy to alter, and the fact that 75% of human disease genes have a recognisable orthologue within flies.
With increasing use of whole genome sequencing as a first line of investigation into developmental delay (DD) and intellectual disability (ID), we are finding ASXL1-3 are one of the top-hitting genes. Although it is thought that the disorder is caused by haplo-insufficiency, disease mechanisms remain unclear and research to find new treatments are hampered by lack of understanding of pathophysiology.
Asx is the sole ASXL family member in Drosophila but has not been exploited to study ASXL-related disorders including Bohring-Opitz (ASLX1); Shashi-Pena (ASXL2) and Bainbridge-Ropers (ASXL3) syndromes which share common phenotypes. Asx encodes a chromatin-binding protein required for segment identity during development. Asx encodes a Polycomb protein, necessary for stable repression of homeotic and other loci. Understanding disease mechanisms using Drosophila will decipher mechanisms of ASXL-related disorders.
The Additional sex combs gene (Asx) in flies encodes a chromatin-binding protein involved in antennal development, the embryonic cell cycle and functions in the repression of homeotic gene transcription. Homeotic genes control the development of body segments of the fly. Understanding disease mechanisms using Drosophila will decipher mechanisms of ASXL-related disorders.
Next generation sequencing has expanded our patient cohort and range of mutations driving DD. As a clinician within an international network coordinating study of these patients, the primary supervisor’s group is well placed to capitalise on this new data. Coupling this with Drosophila expertise (from the secondary supervisor’s group) with access to this patient data will enable the student to utilise the powerful genetics/high-throughput capacity of the fly to understand pathophysiology underscoring ASXL-related disorders.
Objectives:
1. Characterise a Drosophila model to decipher ASXL3-related disorder mechanisms
2. Use patient variants in combination with loss/gain-of-function approaches to dissect pathophysiology of this disorder
3. Identify modifiers of disease and avenues for development of therapeutic interventions
Entry Requirements:
Candidates must have a first or upper second class honours degree or significant research experience.
How to apply:
Please complete a University Postgraduate Research Application form available here: https://www.sheffield.ac.uk/postgraduate/phd/apply/applying
Please clearly state the prospective main supervisor in the respective box and select School of Medicine & Population Health (Oncology & Metabolism) as the department.
Enquiries:
Interested candidates should in the first instance contact Dr Meena Balasubramanian ([Email Address Removed]).
Proposed start date - October 2023
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