Our new MRC programme grant “Resolving the basis of phenotypically variable hereditary abnormalities of eye formation” has started!
Although abnormalities of eye formation are a major cause of blindness, the genetic bases of such phenotypes are poorly understood. The list of genes implicated in Microphthalmia (small eyes), Anophthalmia (lack of eyes) and Coloboma (a failure in optic fissure fusion) is growing but only accounts for a minority of cases. This proposal will identify new genes involved in eye formation and will elucidate why MAC phenotypes show variable penetrance. We have established (thanks to a previous MRC grant) novel zebrafish mutants lines that show MAC phenotypes with very low penetrance (eg. only in one eye and/or only in some of the mutants). We suggested that due to the robustness of eye formation, MAC phenotypes may only be consistently present when embryos carry more than one genetic mutation (eg. FIG 1).
Fig 1: Combining tcf7l1a and gdf6a mutations gives rise to variably penetrant microphthalmia (B,C) or anophthalmia (D). tcf7l1a mutants alone show no overt phenotype and gdf6a mutants have misshapen eyes.
For this grant, we will use Crispr/Cas9 F0 gene editing to screen for genetic interactions between hundreds of genes in different mutants sensitised to showing coloboma, anophthalmia and microphthalmia phenotypes. Once the world returns to more normal times and we can get experiments under way, we will create a database that will make all the results of the screen and some of the resources available, so stay tuned to our web pages!! We also aim to understand the molecular and tissue level functions of selected genes that are critical in the expression of MAC phenotypes. We will clarify the conserved roles for Yap and Mab21l1/2 proteins in eye morphogenesis using genome wide screens in worms to complement novel transgenic approaches in zebrafish. Among our collaborators on this project will be Rod Young, Florencia Cavodeassi, Leo Valdivia and Tatjana Sauka-Spengler.
This research will both inform and be informed by large-scale human genomics studies, will deliver a comprehensive analysis of genetic interactions that build the eyes and aims to provide a wealth of information to inform diagnosis and understanding of debilitating abnormalities of eye formation.
Gaia Gestri and Steve Wilson
31 March 2020