TY - JOUR TI - Vision-related convergent gene losses reveal SERPINE3’s unknown role in the eye AU - Indrischek, Henrike AU - Hammer, Juliane AU - Machate, Anja AU - Hecker, Nikolai AU - Kirilenko, Bogdan AU - Roscito, Juliana AU - Hans, Stefan AU - Norden, Caren AU - Brand, Michael AU - Hiller, Michael A2 - Perry, George H A2 - Treaster, Stephen VL - 11 PY - 2022 DA - 2022/06/21 SP - e77999 C1 - eLife 2022;11:e77999 DO - 10.7554/eLife.77999 UR - https://doi.org/10.7554/eLife.77999 AB - 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 SERPINE3, a putative serine proteinase inhibitor. A detailed investigation of 381 additional mammals revealed that SERPINE3 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 SERPINE3 has the highest expression in eyes of zebrafish and mouse. In the zebrafish retina, serpine3 is expressed in Müller glia cells, a cell type essential for survival and maintenance of the retina. A CRISPR-mediated knockout of serpine3 in zebrafish resulted in alterations in eye shape and defects in retinal layering. Furthermore, two human polymorphisms that are in linkage with SERPINE3 are associated with eye-related traits. Together, these results suggest that SERPINE3 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. KW - convergent gene loss KW - visual acuity KW - vertebrate evolution KW - serine proteinase inhibitor JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -