splice site usage. This means that it is currently very challenging to predict the majority of variants which alter splicing. We will use scalable mutagenesis approaches – such as prime editing and saturation genome editing to understand the relationship between genomic context, cis-regulatory elements, splice site strength and splicing. This has immediate translational utility for both diagnostic and therapeutic applications and generates calibration-scale datasets for machine-learning approaches.
Project Aims
We will perform cellular screens to systematically insert poison exons into the endogenous genomic context to understand:
- What are the distal cis-regulatory elements that determine splice site usage?
- What are the proximal cis-regulatory elements that affect splice site usage?
- Can we use this information combined with machine learning tools to predict splice-modulating deep intronic variants?
- Can we improve the diagnosis of children with rare neurodevelopmental conditions by applying these tools to clinical whole-genome sequencing datasets?
- Can we use this information to better design therapeutic poison exons (for the downregulation of gene dosage).
- Can we use this information to improve the design of therapeutic Antisense Oligonucleotides (ASOs)?
Funding Notes
For academic year October 27/28;
Gates US applications (round 1) close 14th October 26, further information available via Gates Website;
Cambridge Trust, Gates Cambridge (round 2) deadline 8th December 26 to be eligible for funding. If you apply after the funding deadlines you will not be eligible for the Cambridge Funding competition, please indicate in your application all the funding you are eligible for. You can also check funding search Search - Postgraduate Funding Search
Funding is not available for Lent or Easter 27 places as the funding deadline for these has already passed, you will need to have other funding in place to support your studies
References
References: 1. Radford, E.J. et al. Saturation genome editing of DDX3X clarifies pathogenicity of germline and somatic variation. Nature Communications 14, 7702 (2023) 2. Quarantani, G., Clarke, J., Thompson, M., Sang, F., Valcárcel, J. & Lehner, B. OpenSplice: the impact of half a million mutations on the alternative splicing of 600 human exons. bioRxiv (2026). 3. Wong, M.S., Kinney, J.B. & Krainer, A.R. Quantitative activity profile and context dependence of all human 5′ splice sites. Mol Cell 71, 1012–1026 (2018). 4. Rosenberg, A.B., Patwardhan, R.P., Shendure, J. & Seelig, G. Learning the sequence determinants of alternative splicing from millions of random sequences. Cell 163, 698–711 (2015).
Open Days
17 September 2026 - Multiple dates - University of Cambridge Postgraduate College Visit Days - Cambridge (United Kingdom) - View event
