The role of gene isoforms in human brain development

Summary Our research sits at the intersection of genomics and neuroscience, utilising a number of genomic approaches to investigate gene expression and function in the human brain and in neuropsychiatric disorders. We are investigating how the expression and splicing of risk genes (both protein coding and noncoding) can change to create disease risk and how detecting these changes can help us understand what causes neuropsychiatric disorders and identify novel treatment targets. A second interest of our research is to develop novel sequencing methods. Recently we have focused on Nanopore sequencing, a technology that can sequence both DNA and native RNA. We are applying Nanopore sequencing to many research questions and developing novel applications for this technology.

Project Details

Human brain development is an exquisitely complex process, which is tightly controlled by networks of gene products. Almost all human genes make multiple RNA products (known as isoforms). While current technologies allow the measurement of which genes are active in the developing brain, until now we lacked the ability to resolve the repertoire of gene isoforms and understand their functional roles.

We will achieve this by combining single cell RNA sequencing (scRNA-seq), which profiles expression in single cells, with long-read Nanopore sequencing, an emerging technique we have demonstrated has great potential for characterising isoform expression. To examine gene isoforms in the developing brain we will differentiate cortical neurons and cerebral organoids from stem cells, two cutting-edge models of human brain development, which recapitulate early in-vivo human brain development.

The knowledge gained from this project will begin to illuminate the role of gene isoforms in brain development and form a foundation for understanding how gene isoforms regulate brain cell functions and fates. The opportunity exists to focus on either the lab side or the computational analysis side of this project.