Vision-related convergent gene losses reveal <i>SERPINE3</i>'s unknown role in the eye.

Abstract

Despite decades of research, knowledge about the genes that are important for development and function of the mammalian eye and are involved in human eye disorders remains incomplete. During mammalian evolution, mammals that naturally exhibit poor vision or regressive eye phenotypes have independently lost many eye-related genes. This provides an opportunity to predict novel eye-related genes based on specific evolutionary gene loss signatures. Building on these observations, we performed a genome-wide screen across 49 mammals for functionally uncharacterized genes that are preferentially lost in species exhibiting lower visual acuity values. The screen uncovered several genes, including <i>SERPINE3</i>, a putative serine proteinase inhibitor. A detailed investigation of 381 additional mammals revealed that <i>SERPINE3</i> is independently lost in 18 lineages that typically do not primarily rely on vision, predicting a vision-related function for this gene. To test this, we show that <i>SERPINE3</i> has the highest expression in eyes of zebrafish and mouse. In the zebrafish retina, <i>serpine3</i> is expressed in Müller glia cells, a cell type essential for survival and maintenance of the retina. A CRISPR-mediated knockout of <i>serpine3</i> in zebrafish resulted in alterations in eye shape and defects in retinal layering. Furthermore, two human polymorphisms that are in linkage with <i>SERPINE3</i> are associated with eye-related traits. Together, these results suggest that <i>SERPINE3</i> has a role in vertebrate eyes. More generally, by integrating comparative genomics with experiments in model organisms, we show that screens for specific phenotype-associated gene signatures can predict functions of uncharacterized genes.