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

  1. Henrike Indrischek
  2. Juliane Hammer
  3. Anja Machate
  4. Nikolai Hecker
  5. Bogdan Kirilenko
  6. Juliana Roscito
  7. Stefan Hans
  8. Caren Norden
  9. Michael Brand  Is a corresponding author
  10. Michael Hiller  Is a corresponding author
  1. Max Planck Institute of Molecular Cell Biology and Genetics, Germany
  2. TU Dresden, Germany
  3. 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

  1. Henrike Indrischek

    Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Juliane Hammer

    Center for Regenerative Therapies Dresden, TU Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2511-9537
  3. Anja Machate

    Center for Regenerative Therapies Dresden, TU Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Nikolai Hecker

    Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1693-4257
  5. Bogdan Kirilenko

    Senckenberg Research Institute, Frankfurt, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Juliana Roscito

    Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Stefan Hans

    Center for Regenerative Therapies Dresden, TU Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Caren Norden

    Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8835-1451
  9. Michael Brand

    Center for Regenerative Therapies Dresden, TU Dresden, Dresden, Germany
    For correspondence
    michael.brand@tu-dresden.de
    Competing interests
    The authors declare that no competing interests exist.
  10. Michael Hiller

    Senckenberg Research Institute, Frankfurt, Germany
    For correspondence
    Michael.Hiller@senckenberg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3024-1449

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).

Reviewing Editor

  1. George H Perry, Pennsylvania State University, United States

Publication history

  1. Received: February 18, 2022
  2. Preprint posted: February 27, 2022 (view preprint)
  3. Accepted: June 20, 2022
  4. Accepted Manuscript published: June 21, 2022 (version 1)
  5. Version of Record published: August 5, 2022 (version 2)

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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  1. Henrike Indrischek
  2. Juliane Hammer
  3. Anja Machate
  4. Nikolai Hecker
  5. Bogdan Kirilenko
  6. Juliana Roscito
  7. Stefan Hans
  8. Caren Norden
  9. Michael Brand
  10. Michael Hiller
(2022)
Vision-related convergent gene losses reveal SERPINE3's unknown role in the eye
eLife 11:e77999.
https://doi.org/10.7554/eLife.77999
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