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Detailed assessment of somatic genomic copy number variants (CNVs) in multiple system atrophy (MSA)


   Institute of Neurology

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  Prof Christos Proukakis, Dr Zane Jaunmuktane  No more applications being accepted  Funded PhD Project (UK Students Only)

About the Project

MSA is a devastating sporadic neurodegenerative disorder with strong similarities to Parkinson’s disease (PD). Both are synucleinopathies, characterised by inclusions of α-synuclein, which in MSA occur mostly in oligodendrocytes. α-Synuclein is encoded by the SNCA gene, and inherited mutations in this, including copy number variants (CNVs, specifically gains), are rare. Somatic mutations, including CNVs, also occur in the brain, and the investigation of brain mosaicism is a rapidly expanding area of possible critical importance to understanding a wide range of brain disorders (1). The PI hypothesised that somatic mutations may have a role in sporadic synucleinopathies, and the wide variability of synucleinopathies could depend on the distribution of somatic mutations.

My group demonstrated somatic SNCA CNVs (gains) in PD and MSA brain using Fluorescent in situ Hybridisation (FISH), with cells with CNVs appearing more likely to have α-synuclein inclusions (2,3). To detect large somatic CNVs genome-wide, we amplified and sequenced the genomes of single cells from two MSA brains, and found CNVs in ~30% (3). We next examined whether regional mosaicism patterns for SNCA CNVs vary between MSA subtypes, comparing oligodendrocyte-rich affected brain regions (manuscript under revision).

We now aim to investigate the causality of somatic CNVs in MSA by determining the molecular signatures of oligodendrocyte populations with CNVs, in relation to the phenotype and regional atrophy patterns, and formally investigating CNVs across the genome.

The proposed PhD 

This project will allow a talented and enthusiastic young scientist to significantly advance the understanding of the role of somatic mutations in MSA using cutting-edge techniques. The student will work on post mortem human tissue samples and receive training in a wide range of techniques, mostly “wet lab”, but also computational. These will include preparation of brain tissue sections and nuclear suspensions, DNA FISH, immunofluorescence, spatial transcriptomics or other RNA analysis, single nuclear selection followed by whole genome amplification and sequencing, and analysis of microscopy and DNA sequencing data.

This project will be carried out in the Department of Clinical and Movement Neurosciences at the UCL Queen Square Institute of Neurology, which includes the Queen Square Brain Bank, one of the largest UK brain banks with >200 MSA cases. The student will work in a highly active research environment, with equipment for DNA amplification, analysis and sequencing library automated preparation available in the host lab at the Royal free site, and access to Institute of Neurology facilities including confocal microscopy, laser capture microdissection, and histology. Coding will be taught through UCL courses, and additional online courses if required. This project will be closely co-ordinated with the single cell analysis for CNVs in PD, as part of the multi-national “Aligning Science Across Parkinson’s” (ASAP) consortium, where the primary and secondary supervisor are co-PI’s in one grant each https://www.michaeljfox.org/grant/understanding-inherited-and-acquired-g... . The student will be supported by ASAP-funded post-doctoral and technical staff, and participate in regular online ASAP meetings, and departmental meetings. Both applicants have significant supervisory experience, and already collaborate closely. Further support will be provided by a “thesis committee”, which will meet 2-3x yearly, and likely include Prof Henry Houlden (UCL), a neurogeneticist studying MSA, Dr Diego Perez-Rodriguez (UCL), a senior post-doc who previously worked on this project, and Dr Fritz Sedlazeck (Baylor, Texas, USA), a leading bioinformatician in SV analysis. The mix of skills acquired will provide the student with a solid foundation for a lab-based research career, or for transition of a “wet-lab” scientist to computational research.

Person specification

Essential criteria

  • Bachelor's degree (2:1 or higher) in a relevant discipline
  • Computer literate in Windows and / or Mac environment
  • Able to understand data management and analysis
  • Strong interest in understanding molecular / genetic aspects of neurodegeneration
  • Able to work in collaboration with different teams / departments
  • Demonstrable commitment to research
  • Excellent written communication skills with the ability to train in writing scientific papers and a PhD thesis
  • Excellent oral communications skills with the ability to deliver research presentations

Desirable criteria 

  • Masters degree (obtained, or due to complete in September)
  • Research outputs eg conference presentations, co-authorship in manuscripts
  • Experience in relevant lab techniques eg immunofluorescence, DNA sequencing
  • Relevant advanced computing skills eg Linux / command line, R, automated image analysis, bioinformatic nuclei acid analysis

Application process

Deadline: 23:59 BST, 10 July 2022

Please submit applications to [Email Address Removed]  in the following format:

  1. A CV or biographical sketch (2 pages maximum)
  2. Personal statement (600 words maximum) outlining (i) why you are applying for this, (ii) what makes you the ideal candidate, (iii) what training experience you have had.
  3. Name and contact details for 2-3 persons who could be approached as a referee.

Shortlisted candidates will be notified by 15 July. 

Interviews likely to be held 25-27 July virtually, and a short presentation may be requested.

For further information contact Prof Christos Proukakis directly. Informal discussion before application / interview is highly encouraged, and lab visits can be arranged.

Please note that anyone not eligible for the UK rate fees would have to demonstrate proof that the full fees can be paid before an offer.


Funding Notes

The project is fully funded by the MSA Trust for 3 years, including UK-rate tuition fees and the standard UCL stipend.

References

1) https://doi.org/10.1016/j.nbd.2020.105021
2) https://doi.org/10.1093/brain/awy157
3) https://doi.org/10.1186/s40478-019-0873-5
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