How the fovea shapes our world: genetic and functional insights into foveal morphology (360G-Wellcome-224643_Z_21_Z)

The fovea is the small depression at the neurosensory retina that underlies high-resolution central vision. It is particularly vulnerable to disease and disruption of its normal architecture causes visual disability. Notably, foveal morphology varies significantly across individuals and this is thought to be linked to variations in foveal development. The molecular causes and functional consequences of this anatomical diversity are incompletely understood. Addressing this knowledge gap is this proposal’s main objective. My central hypothesis is that variation in foveal morphology is caused by variation in the pigmentation of the retinal pigment epithelium (RPE), the monolayer supporting retinal neurons. To test this, I will analyse retinal scans available through the UK Biobank and perform a genome-wide association study of image-derived foveal phenotypes. Preliminary analyses have highlighted a number of variants including a common missense change in tyrosinase, the rate-limiting enzyme of melanogenesis. I will use high- resolution imaging to study how foveal morphology is altered in people carrying this tyrosinase variant. I will also generate iPSC from these individuals and use CRISPR-Cas9 editing to study/rescue melanin defects in iPSC-RPE. This work will elucidate the molecular factors that underlie variability in foveal morphology and will advance understanding of both fundamental and clinically-relevant neurobiology.