Vision-related convergent gene losses reveal SERPINE3's unknown role in the eye
- Max Planck Institute of Molecular Cell Biology and Genetics, Germany
- TU Dresden, Germany
- Senckenberg Research Institute, Germany
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 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.
Data availability
All data needed to evaluate the conclusions in the paper are present in the paper and the Supplementary Materials. The annotated protein alignment of intact and complete mammalian SERPINE3 genes (Supplementary File 1), the predicted structure of human SERPINE3 (Supplementary File 2) and the raw microscopy images of fish eyes (Figure 4 - source data 3) are available at https://genome.senckenberg.de/download/SERPINE3/.TOGA annotations of SERPINE3 and a visualization of gene-inactivating mutations are available at our UCSC genome browser mirror https://genome.senckenberg.de.
Article and author information
Author details
Funding
Boehringer Ingelheim
- Michael Hiller
Max Planck Society
- Michael Hiller
Hessen State Ministry of Higher Education, Research and Arts
- Michael Hiller
German research foundation (BR 1746/3 and BR 1746/6)
- Michael Brand
European Research Council (Zf-BrainReg)
- Michael Brand
Studienstiftung des Deutschen Volkes
- Juliane Hammer
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments in mouse and zebrafish were performed in accordance with the German animal welfare legislation. Protocols were approved by the Institutional Animal Welfare Officer (Tierschutzbeauftragter), and licensed by the regional Ethical Commission for Animal Experimentation (Landesdirektion Sachsen, Germany; license no. DD24-5131/354/11, DD24.1-5131/451/8, DD24-5131/346/11, DD24-5131/346/12).
Copyright
© 2022, Indrischek et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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