Identifying variants impacting splicing of 5’ and 3’ UTRs and underpinning inherited retinal disease

Genomic variation that impacts splicing is well established as a cause of genomic disorders, but is almost exclusively limited to protein-coding exons and introns intersecting protein-coding exons. Untranslated regions (UTRs) are sequences upstream (5’UTR) and downstream (3’UTR) of the protein-coding regions of genes that are important for the stability, translocation and translation of mature RNA transcripts (mRNA). UTRs are included in mRNAs but do not directly encode protein, and genomic variation disrupting their function can underpin genomic disorders. UTRs are susceptible to variants that impact splicing, in a similar manner to protein-coding regions, and many genes that are known to underpin genomic disorders have full UTR non-coding exons which are required to be spliced from pre-mRNA transcripts. Moreover, tissue-specific transcripts have been shown to display non-canonical UTR compositions, causing complexity in the prediction of variants which will significantly impact splicing in appropriate disease tissues. Overall, there is little understanding of the role that UTR mis-splicing plays in the onset of genomic disorders.

In this PhD project we will focus on a exemplar set of genomic disorders, inherited retinal disorders (IRDs), which are leading cause of blindness and visual disability, and often associated with syndromic features, such as hearing loss, renal failure and global developmental delay. The Manchester Centre for Genomic Medicine is a European Reference Network for ophthalmic disorders and a specialist centre of excellence for Ophthalmic genomics, with readily accessible ophthalmic tissue and disease models. This PhD project we will develop understanding of: (i) genetic variation impacting UTR composition of RNA transcripts expressed in neural retina and retinal pigment epithelium, (ii) rare variants that underpin IRD through disruption to UTR splicing, (iii) general properties of UTR splice sites that can assist in the identification of disease- causing variation, and (iv) functional impact of variants disrupting UTR splicing and regulation. The findings from this project will increase our understanding of the genetic basis of inherited retinal disease, will develop new knowledge for implementation into diagnostic approaches, and will identify suitable avenues for the development of therapeutics. Moreover, the findings are expected to be generalisable across genomic disorders and close collaboration with other clinical specialities will be developed as the project progresses.

The PhD student will address the following 4 core aims:

1. Fully characterise the composition and tissue-specificity of untranslated regions(UTRs) in genes expressed in neural retina and retinal pigment epithelium

2. Identify common genomic variants driving differences in UTR splicing in neural retina and retinal pigment epithelium, and understand impact to disease penetrance

3. Use computational approaches to systematically characterise the deleteriousness of variants that impact UTR splicing, and to pinpoint rare variants causing inherited retinal disease

4. Functionally validate the effect of candidates to reveal insights into regulatory mechanisms underlying inherited retinal disease, and potential treatment avenues

The PhD student will be based in the Division of Evolution, Infection and Genomic Sciences at the University of Manchester, and physically based at the North West Genomic Laboratory Hub at Manchester Universities NHS Foundation Trust, which is one of seven GLHs across the country innovating and delivering the NHS Genomic Medicine Service. The North West GLH specialises in Ophthalmic genomics, and is a national provider of this service with several clinical academic groups embedded within the GLH, including Dr Panagiotis Sergouniotis and Prof Graeme Black. Ellingford’s bioinformatics laboratory team is closely aligned to these groups, and has worked closely with NHS teams facilitating Ophthalmic genomic diagnostic services. This powerful academic-NHS relationship has enabled our research teams’ discoveries to create the evidence base to allow a transformation of the landscape of genetic testing for individuals with inherited blindness.

The student will work with datasets generated in the Ellingford group (Macular Society), will continue to generate datasets with technology brought to the core facility through a grant led by Ellingford (MRC) and will work alongside staff funded by the NIHR Biomedical Research Centre Next-Generation Phenotyping and Diagnostics Theme.

Entry Requirements

Applicants are expected to hold (or about to obtain) a minimum upper second class undergraduate honours degree (or equivalent) in a relevant Life Sciences or Medical Sciences subject, including Biology / Bioinformatics / Genetics / Genomics / Ophthalmic Science / Neuroscience, or similar. Experience in statistical genetics, programming and/or transcriptomics is desirable.

How to Apply

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor at [email protected].

On the online application form select the PhD Genomics and Dr Jamie Ellingford as the primary supervisor.

Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application please contact our admissions team [email protected]

Equality, Diversity & Inclusion

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the websitehttps://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/