About the Project
MicroRNAs are a class of highly conserved ~22 nucleotide non-coding RNAs that impact gene expression through binding to target sequences in messenger RNAs (mRNA). The correct timing and spatial expression of microRNAs is essential during development and throughout an organisms’ lifetime. In order for microRNAs to function appropriately they must be able to recognise and bind to their mRNA target sites. There are around 2000 annotated microRNA gene sequences in the human genome.
Individual microRNAs are predicted to have thousands of target mRNA sites, and individual mRNAs can be regulated by multiple microRNA sequences. This complexity makes studying microRNAs an interesting and relatively unexplored area of human genomics. MicroRNAs are expressed in highly tissue- and time-specific patterns, and therefore knowledge of microRNA and mRNA expression in specific tissues at different developmental stages is pivotal for understanding the regulatory interactions between microRNAs and their mRNA targets. While some of this work has been done in mouse models, our understanding of microRNA expression and function in the retina, a tissue at the back of the eye responsible for vision, is limited.
Through this studentship we aim to expand the characterised human miRNome to include two specific tissues in the retina (retinal pigment epithelium and neurosensory retina), and to develop understanding of how genomic variation in microRNA genes and their mRNA target sites disrupts normal function of the retina. We will explore the extent to which these types of variation can cause and impact human genomic disorders through disruption to normal gene expression. This project will require the development of truly interdisciplinary skills, including quantitative computational biology, bioinformatics, genomics, transcriptomics, cell culture, genetic engineering and the analysis of human phenotypes in the context of rare disease. The candidate should be motivated to translate basic biological discoveries through to patient impact, through improvement to diagnostic tests, and the potential for discoveries from this project to lead to new avenues for treatments. The project will be based at the University of Manchester but the student will have the opportunity to develop their skills at the Ocular Genome Institute, Harvard Medical School, Boston, USA.
https://www.mangen.co.uk/mcgm/rare-disease/
http://www.mirbase.org/
http://sgjlab.org/
https://oculargenomics.meei.harvard.edu/
Entry Requirements:
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.
UK applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).
If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.
Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.
To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the MRC Doctoral Training Partnership (DTP) website www.manchester.ac.uk/mrcdtpstudentships
References
1. Ellingford, J., Barton, S., Bhaskar, S., Williams, S., Sergouniotis, P., O'Sullivan, J., Lamb, J., Perveen, R., Hall, G., Newman, W., Bishop, P., Roberts, S., Leach, R., Tearle, R., Bayliss, S., Ramsden, S., Nemeth, A. H. & Black, G. (2016). Whole genome sequencing increases molecular diagnostic yield compared with current diagnostic testing for inherited retinal disease. Ophthalmology 123:1143–1150.
2. Bronstein R, Capowski EE, Mehrotra S, Jansen AD, Navarro-Gomez D, Maher M, Place E, Sangermano R, Bujakowska KM, Gamm DM, Pierce EA. (2020). A combined RNA-seq and whole genome sequencing approach for identification of non-coding pathogenic variants in single families. Hum Mol Genet. doi: 10.1093/hmg/ddaa016. PMID: 32011687
3. Green DJ, Sallah SR, Ellingford JM, Lovell SC, Sergouniotis PI. (2020). Variability in Gene Expression is Associated with Incomplete Penetrance in Inherited Eye Disorders. Genes. doi: 10.3390/genes11020179.
4. Conte, I., Hadfield, K. D., Barbato, S., Carrella, S., Pizzo, M., Bhat, R. S., Carissimo, A., Karali, M., Porter, L. F., Urquhart, J., Hateley, S., O'Sullivan, J., Manson, F. D., Neuhauss, S. C., Banfi, S., & Black, G. C. (2015). MiR-204 is responsible for inherited retinal dystrophy associated with ocular coloboma. PNAS. 112(25), E3236–E3245. https://doi.org/10.1073/pnas.1401464112
5. Kozomara A, Birgaoanu M, Griffiths-Jones S (2019). miRBase: from microRNA sequences to function. Nucleic Acids Res. 47:D155-D162
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