Vision-related convergent gene losses reveal SERPINE3's unknown role in the eye

Research output: Preprint/documentation/reportPreprint

Contributors

  • Henrike Indrischek - , Max Planck Institute of Molecular Cell Biology and Genetics (Author)
  • Juliane Hammer - , Chair of Molecular Developmental Genetics (Author)
  • Anja Machate - , Centre for Regenerative Therapies Dresden (Author)
  • Nikolai Hecker - , Max Planck Institute of Molecular Cell Biology and Genetics (Author)
  • Bogdan Kirilenko - , Senckenberg Gesellschaft für Naturforschung (Author)
  • Juliana Roscito - , Center for Regenerative Therapies Dresden (Author)
  • Stefan Hans - , Center for Regenerative Therapies Dresden (Author)
  • Caren Norden - , Max Planck Institute of Molecular Cell Biology and Genetics (Author)
  • Michael Brand - , Centre for Regenerative Therapies Dresden (Author)
  • Michael Hiller - , Goethe University Frankfurt (Author)

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 Mueller 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.

Details

Original languageEnglish
Number of pages51
Publication statusPublished - 27 Feb 2022
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External IDs

unpaywall 10.1101/2022.02.25.481972

Keywords

Keywords

  • evolutionary-biology