Understanding the rules of life

Bioscience for an integrated understanding of health

Category: Standard Studentships

Exploiting rare genetic disease genomes to identify novel, key developmental control genes.

Project No.2224

Primary Supervisor

Proff Matt Guille – University of Portsmouth


Prof Sarah Ennis – University of Southampton



A huge number of rare gene variants associated with phenotypes has been identified by next generation sequencing in ongoing genome projects.

The number of phenotypes analysed far exceeds that in a traditional forward genetics screen. The limitation of these data are that its analysis is in the most relevant organism, humans, which hugely limits the type of information that can be gathered about the function of the genes for ethical reasons and due to the small numbers involved. In collaboration, SE’s group has used bioinformatics to prioritise genes from these massive data sets for those that are likely to be critical for development.

We will combine bioinformatic analysis of these “mutants” and high throughput gene function determination using CRISPR/Cas in Xenopus to discover genes that have currently-unkown, important, evolutionarily conserved roles in development. The first phase of the project will involve the detection of gene variants that are deemed highly likely to underpin pathogenic human phenotypes, but where the specific gene involved is of unknown developmental function. The student will be trained to access, analyse and prioritise VUSs from clinical and genomic data generated as part of ongoing research projects at the University of Southampton and through the Genomics England Clinical Interpretation Partnerships (GECIPS). Variants to undergo modelling in Xenopus will be prioritised on the basis of variously: sequencing quality, in silico metrics of pathogenicity and frequency, inheritance patterns and biological background data gleaned from the published literature. Gene editing will then be used to make a knockout of the bioinformatically-identified genes in X. tropicalis, the western clawed frog. Since this is routinely done in >100 embryos it will test whether the role suggested by the very small number of humans with this variant gene was genuine and evolutionarily conserved. These experiments are performed in around a week allowing high throughput to be achieved. To make detailed analysis of the phenotype easier, knockouts will be performed in lines of transgenic frogs with the appropriate cell type fluorescent, we have >200 of these lines (Ref 1). The impact of this study will be to discover novel developmental genes and, by distributing them to other developmental biologists (prioritising those in SoCoBio), to integrate them into the gene regulatory networks of systems biology that underpin our understanding of health and disease.