Identification of novel genes involved in fovea formation

Visual acuity depends on the fovea, located at the back of the retina, in the centre of a structure called the macula. Congenital ocular diseases resulting from genetic mutations that affect macula formation during embryogenesis can disrupt the fovea and lead to a defect called foveal hypoplasia, associated to visual deficiency. In conditions such as aniridia or ocular albinism, foveal hypoplasia accompanies other structural defects of the eye. However, foveal hypoplasia also occurs in patients with normal eyes but severe visual deficiency, a condition known as isolated foveal hypoplasia. Cone dystrophies, affecting the cones, a type of photoreceptor that is highly abundant in the fovea, and macular dystrophies, affecting cell types specific of the macula, also lead to fovea defects and visual deficiencies.

Genetic mutations likely underlie the cause of congenital disease. However, most cases of congenital foveal hypoplasia lack a genetic diagnosis, limiting our ability to predict disease progression or provide patient counselling. Improving genetic diagnosis requires identifying those genes important for fovea formation, and uncovering how they work. We can do so by studying the formation of similar high acuity areas in model organisms. Zebrafish, like humans, bear in their retina an area specialised in high acuity vision. In previous work, we generated a genetically modified strain of zebrafish with a mutation in a gene involved in the formation of the high acuity area. By comparing the genes that are turned on in the retina of these mutants with those genes turned on in wild type zebrafish, we have identified a subset of genes that may be important for the formation and function of the zebrafish high acuity area.

The aim of the project is to advance our understanding of the mechanisms controlling fovea formation by characterising the function of those novel genes. Several genes important to modulate the function of a molecule called Retinoic Acid have been identified in our dataset. We will focus on dissecting their role during high acuity area formation. In addition, together with our clinical collaborators, we will search in their cohorts of patients with ocular disease for potential variants in our genes of interest. We will also work with computational geneticists to search databases such as the 100K Genome Project and GeneMatcher, to identify further individuals with potentially pathogenic variants in our genes of interest.

Skills acquisition

The student will be primarily based at SGUL, but experiments will also be performed at UCL, where one of the co-supervisors is based. The student will be trained in the latest approaches in gene editing and mis-expression to abrogate gene function in zebrafish. They will then analyse the effect of these manipulations with molecular and imaging approaches. In addition, visual function will be assessed by subjecting the larvae to visual performance tests.

The student will be trained in robust computational analysis. Together with our clinical collaborators, they will search in their cohorts of patients with ocular disease for potential variants in the genes of interest. They will also search databases such as the 100K Genome Project and GeneMatcher, to identify further individuals with potentially pathogenic variants in our genes of interest.

Entry requirements

Applicants should have obtained, or be about to obtain, a UK or overseas equivalent, master-level degree and previous experience in molecular biology and laboratory work.

Application process

Please visit the St George’s website for the application and equal opportunities forms. Please send the completed application form to [email protected] by no later than Sunday 26 May. An equal opportunities form should also be submitted as a separate document. References will be requested should you be successful in being offered the studentship.

Applications will undergo shortlisting and successful applicants will then be invited to interview on the week of the 17 – 21 June.

The successful candidate will be given a verbal offer and once it has been accepted, will be sent a formal offer letter and a registration pack with joining information. Unsuccessful candidates will be contacted with their outcomes at the earliest opportunity and will be able to request feedback if required.