PhD Project - EASTBIO: Investigating the 16p11.2 genetic autism risk factor in brain development.

Vacancy Reference Number
Closing Date
16 Dec 2021
University of Edinburgh

Deanery of Biomedical Sciences

Autism spectrum condition or ‘autism’ is associated with numerous genetic risk factors including the polygenic 16p11.2 microdeletion. Patients heterozygous for the 16p11.2 microdeletion (16p11.2+/-) account for about 1% of autism cases making it one of the most common genetic causes of autism. A central question is what neural cells are affected and how their cell and molecular biology is perturbed to predispose the brain to developing autism.

The proper functioning of the mature cerebral cortex depends on the balance between excitatory neurons (originating from progenitors located in the ventricular zone of the cerebral cortex) and inhibitory interneurons (originating from progenitors located in the ganglionic eminences) that migrate to the cortex. This Excitatory/Inhibitory (E/I) balance is important for normal brain function and disruption to the E/I balance is hypothesised to underpin autism. The onset of autism in infancy suggests the hypothesis that genetic risk factors act during pre-natal brain development and we have used bioinformatic analysis to identify cells in developing human forebrain that are vulnerable to the 16p11.2 microdeletion (Morson et al., 2021, Yang et al BioRxiv).

This project will investigate 16p11.2 microdeletion cell and molecular phenotypes, specifically those affecting the E/I balance, during brain development. The project will employ human induced pluripotent stem cell (hIPSC) derived 16p11.2+/- neurons and/or a complementary 16p11.2+/- rat model. Techniques will include a combination of hIPSC neural differentiation, RNA sequencing, bioinformatic analysis, immunohistochemistry, and in situ hybridisation.