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SWBio DTP PhD project: Exploring genotype-phenotype correlations in Sox10 mutations


   Department of Life Sciences

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  Prof Robert Kelsh  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

This project is one of a number that are in competition for funding from the South West Biosciences Doctoral Training Partnership (SWBio DTP).

The SWBio DTP is funded by BBSRC and involves a partnership of world-renown universities, research institutes and industry across the South West and Wales. This partnership represents a distinctive group of bioscientists with established international, national and regional networks and widely recognised research excellence. We aim to provide students with outstanding interdisciplinary research training.

Studentships are available for entry in October 2023.

All SWBio DTP projects will follow a structured 4-year PhD programme, combining traditional project-focussed studies with a taught first year which includes directed rotation projects.

Supervisory Team:

Lead supervisor: Prof Robert Kelsh, University of Bath, Department of Life Sciences (email: [Email Address Removed])

Co-supervisors: Dr Beck Richardson (University of Bristol) and Dr Keith Vance (University of Bath)

The Project:

What genetic variants cause what phenotypic changes? The SOX proteins form a family of transcription factors with key functions in embryonic development and cellular homeostasis, with these functions highly conserved across the vertebrates. Due to their complex roles in multiple celltypes, SOX mutant phenotypes are often diverse, even for a single gene. Whilst much is known of their protein structure and DNA binding characteristics, we are still ignorant of the relationship between their structure and their cellular functions, with the genotype-phenotype correlation remaining obscure even in well-studied examples, such as SOX10 (Pingault et al., 2022, J. Med. Genet. 59, 105-114).

SOX10 is expressed widely in the neural crest, an embryonic population of highly multipotent progenitors, and SOX10 mutations may result in pigment, hearing, olfactory and neural phenotypes, individually or in various combinations. The variation in phenotypes may reflect subtle impacts of the mutations (e.g. gain of function), or other factors (e.g. presence of modifier loci). We have shown the conserved role for Sox10 in zebrafish and mammals (e.g. Kelsh, 2006, Bioessays 28, 788-798). Furthermore, in the course of a current DTP studentship supervised by same team, we have established a method for generating CRISPR/Cas9-induced precise genomic modifications, using chemical modulation to enhance Homology-Directed Repair (Zhang et al., 2018, J. Biol. Chem. 293, 6611-6622; Aksoy et al., 2019, Communications Biology, 2, 198). This, combined with the ready accessibility and phenotypic characterisation of zebrafish embryos (e.g. Alhashem et al., 2022, eLife 11:e73550; Camargo-Sosa et al., 2019, PLoS Genetics 15, e1007941), makes the zebrafish an ideal system to explore the precise impacts of specific mutational changes in a relatively constrained genetic background.

To assess the genotype-phenotype discrepancy, the successful applicant will create an extensive series of zebrafish sox10 alleles, selected from amongst the human variants linked to disease phenotypes; mutations will be maintained as heterozygotes, since most are likely to be homozygous lethal. Dominant and recessive phenotypes will then be characterised quantitatively for all the pigment and neural cell-types. This will enable us to disentangle the currently obscure, but fundamental, structure-function relationships for this vital developmental regulatory factor.

This interdisciplinary project will give an opportunity to develop numerous specific skillsets, including in zebrafish genetics and husbandry, phenotypic analysis including by in situ hybridisation and immunofluorescence, confocal and light sheet microscopy, molecular biology, and bioinformatics. In addition, the student will benefit from collaborative interaction with mouse and human geneticists at the Institut Imagine (Paris).

Project keywords: genetics, developmental biology, Sox10, zebrafish, nervous system.

Requirements:

Applicants should have obtained, or be about to obtain, a First or Upper Second Class UK Honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science or technology. Applicants with a Lower Second Class degree will be considered if they also have Masters degree or have significant relevant non-academic experience.

In addition, due to the strong mathematical component of the taught course in the first year and the quantitative emphasis in our projects, a minimum of a grade B in A-level Maths or an equivalent qualification/experience* is required.

* Physics A-level (grade B and above) or units in your degree with a significant mathematical component, e.g. maths, statistics, bioinformatics.

Applicants must ensure they highlight their Maths background within their application and to upload any supporting evidence.

If English is not your first language, you will need to have achieved Academic IELTS 6.5 overall (with no less than 6.5 in any of the four skills). Find details of other acceptable tests and further information on our website.

Enquiries and Applications:

Informal enquiries are welcomed and should be directed to the lead supervisor.

Formal applications should be submitted on the University of Bath’s online application form for a PhD in Biosciences.

When completing the form, please identify your application as being for the SWBio DTP studentship competition in Section 3 Finance (question 2) and quote the project title and lead supervisor’s name in the ‘Your research interests’ section.  You may apply for more than one project within the same application but you should upload a separate (clearly labelled) personal statement for each one, outlining your interest and suitability for that particular project.

See our website for more information about applying for a PhD at Bath.

Equality, Diversity and Inclusion:

We want to support diverse and inclusive work environments. We therefore welcome applications from individuals regardless of their race, ethnicity, sexual orientation, religion, age, gender or disability status.

If you have circumstances that you feel we should be aware of that have affected your educational attainment, then please feel free to tell us about it in your application form. The best way to do this is a short paragraph at the end of your personal statement.


Funding Notes

Candidates may be considered for SWBio DTP studentship tenable for 4 years. Funding covers tuition fees, a stipend (£17,668 p/a in 2022/23) plus an allowance for research/training costs, fieldwork, conference attendance and a 3-month placement. Studentships are open to both Home and International students; however, International applicants should note that funding does NOT cover the cost of a student visa, healthcare surcharge and other costs of moving to the UK. In line with guidance from UK Research and Innovation (UKRI), the number of awards available to International candidates will be limited to 30% of the total.

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