Evolution: Poor eyesight reveals a new vision gene

Comparing the genomes of mammals which evolved to have poor vision identifies an important gene for eyesight.
  1. Tathagata Biswas
  2. Jaya Krishnan
  3. Nicolas Rohner  Is a corresponding author
  1. Stowers Institute for Medical Research, United States
  2. Department of Molecular and Integrative Physiology, University of Kansas Medical Center, United States

With hundreds of cell types smoothly working together to form clear images of the world, the vertebrate eye can put the most sophisticated digital cameras to shame. Yet many of the genes which establish and maintain this delicate machine remain unknown.

Most mammals have good vision, yet some species have naturally evolved poor eyesight: mice and rats, for instance, have very poor eyesight, while species like the naked mole rat have lost their vision entirely. One way to identify the genetic sequences important for vision is to compare the genomes of species with contrasting visual capacities. Now, in eLife, Michael Hiller (Senckenberg Research Institute), Michael Brand (TU Dresden) and colleagues – including Henrike Indrischek (Max Planck Institute for Molecular Cell Biology and Genetics) as first author – report that a largely uncharacterized gene called Serpine3 is inactivated in many animals with poor or compromised vision, suggesting it may play an important role in the eye (Indrischek et al., 2022).

First, the team screened the genomes of 49 mammalian species for mutations associated with a severe loss in eye function. This sample included ten species which had poor visual capacity, such as rodents, moles and echolocating bats. A gene was classified as playing a role in eyesight if mutations stopped it from working in more than three species with poor vision. This led to the identification of 29 genes, 15 of which had not been linked to eye development or function before. However, poor vision is mostly restricted to mammals living in low-light habitats which are often limited in nutrients and biodiversity (Olsen et al., 2021). As such, the loss-of-function mutations detected by Indrischek et al. may be unrelated to vision and instead be the result of animals adapting to these challenging environments.

Indrischek et al. then focused on one gene, Serpine3, which was predicted to be inactive in seven out of the ten low-vision species (Figure 1). Conversely, animals with excellent vision, such as elephants and chimpanzees, have intact Serpine3 coding regions (Figure 1). To strengthen their hypothesis, Indrischek et al. added 381 other species with varying visual capabilities to their analysis. Out of the 430 species studied, 70 with poor eyesight had inactivated Serpine3.

Mutations in Serpine3 are associated with vision loss.

To identify genes that shape the eyes of vertebrates, Indrischek et al. screened the genome of mammals with poor (left, red) and good (right, green) vision. Most animals with poor eyesight – such as cape-golden moles, bats and naked mole rats – had mutations in the gene Serpine3 which led to its inactivation. However, in mammals with better vision – such as elephants, humans and chimpanzees – the coding region for Serpine3 was intact and the gene was active. Further experiments confirmed that the product of the Serpine3 gene is important for good vision.

The product of the Serpine3 gene belongs to a family of proteins secreted into the extracellular space and implicated in blood clotting, neuroprotection and some human diseases (Law et al., 2006; Barnstable and Tombran-Tink, 2004). To better understand the role Serpine3 plays in vision, the team carried out functional experiments in zebrafish, as their retinas are organized into layers which are similar to those found in humans (Fadool, 2003). This showed that Serpine3 is highly expressed in the zebrafish eye, particularly in the inner nuclear layer of the retina. Next, Indrischek et al. deleted Serpine3 during zebrafish development, causing adult animals to have deformed eyes and disrupting the organization of the cell layers in the retina. This suggests that vertebrate eyes need the product of Serpine3 in order to function properly.

Finally, Indrischek et al. analyzed a human dataset of genomic sequences from patients with eye-related diseases. They found mutations near to the transcription start site for Serpine3 are associated with refractive errors in the eye and macular degeneration, suggesting that this gene may also play a role in human eye diseases.

Taken together, these findings suggest that Serpine3 is important for good vision. In the future, it would be interesting to explore whether the gene is primarily important during development, or to maintain retinal cells and layers during adulthood. This knowledge could help identify new therapies for debilitating eye diseases associated with Serpine3 or other related genes.

More importantly, Indrischek et al. elegantly demonstrate how studying natural variation in traits such as eyesight can identify the function of uncharacterized genes and the role they may play in disease. Nature is full of characteristics which converged between species over the course of evolution (Farhat et al., 2013; Bergmann and Morinaga, 2019). Applying a comparative genomic approach similar to the one used in this study could transform our understanding of a multitude of other biological processes (Liu et al., 2021; Valenzano et al., 2015; Rohner, 2018). We just have to look.


Article and author information

Author details

  1. Tathagata Biswas

    Tathagata Biswas is in the Stowers Institute for Medical Research, Kansas City, United States

    Contributed equally with
    Jaya Krishnan
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4067-3643
  2. Jaya Krishnan

    Jaya Krishnan is in the Stowers Institute for Medical Research, Kansas City, United States

    Contributed equally with
    Tathagata Biswas
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2302-5748
  3. Nicolas Rohner

    Nicolas Rohner is in the Stowers Institute for Medical Research and Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, United States

    For correspondence
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3248-2772

Publication history

  1. Version of Record published: August 5, 2022 (version 1)


© 2022, Biswas, Krishnan et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.


  • 1,307
    Page views
  • 140
  • 1

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Tathagata Biswas
  2. Jaya Krishnan
  3. Nicolas Rohner
Evolution: Poor eyesight reveals a new vision gene
eLife 11:e81520.
  1. Further reading

Further reading

    1. Developmental Biology
    2. Evolutionary Biology
    Erliang Yuan, Huijuan Guo ... Yucheng Sun
    Research Article

    Wing dimorphism in insects is an evolutionarily adaptive trait to maximize insect fitness under various environments, by which the population could be balanced between dispersing and reproduction. Most studies concern the regulatory mechanisms underlying the stimulation of wing morph in aphids, but relatively little research addresses the molecular basis of wing loss. Here, we found that, while developing normally in winged-destined pea aphids, the wing disc in wingless-destined aphids degenerated 30-hr postbirth and that this degeneration was due to autophagy rather than apoptosis. Activation of autophagy in first instar nymphs reduced the proportion of winged aphids, and suppression of autophagy increased the proportion. REPTOR2, associated with TOR signaling pathway, was identified by RNA-seq as a differentially expressed gene between the two morphs with higher expression in the thorax of wingless-destined aphids. Further genetic analysis indicated that REPTOR2 could be a novel gene derived from a gene duplication event that occurred exclusively in pea aphids on autosome A1 but translocated to the sex chromosome. Knockdown of REPTOR2 reduced autophagy in the wing disc and increased the proportion of winged aphids. In agreement with REPTOR’s canonical negative regulatory role of TOR on autophagy, winged-destined aphids had higher TOR expression in the wing disc. Suppression of TOR activated autophagy of the wing disc and decreased the proportion of winged aphids, and vice versa. Co-suppression of TOR and REPTOR2 showed that dsREPTOR2 could mask the positive effect of dsTOR on autophagy, suggesting that REPTOR2 acted as a key regulator downstream of TOR in the signaling pathway. These results revealed that the TOR signaling pathway suppressed autophagic degradation of the wing disc in pea aphids by negatively regulating the expression of REPTOR2.

    1. Evolutionary Biology
    2. Genetics and Genomics
    Xinzhu Wei, Christopher R Robles ... Sriram Sankararaman
    Research Article

    The genetic variants introduced into the ancestors of modern humans from interbreeding with Neanderthals have been suggested to contribute an unexpected extent to complex human traits. However, testing this hypothesis has been challenging due to the idiosyncratic population genetic properties of introgressed variants. We developed rigorous methods to assess the contribution of introgressed Neanderthal variants to heritable trait variation relative to that of modern human variants. We applied these methods to analyze 235,592 introgressed Neanderthal variants and 96 distinct phenotypes measured in about 300,000 unrelated white British individuals in the UK Biobank. Introgressed Neanderthal variants have a significant contribution to trait variation consistent with the polygenic architecture of complex phenotypes (contributing 0.12% of heritable variation averaged across phenotypes). However, the contribution of introgressed variants tends to be significantly depleted relative to modern human variants matched for allele frequency and linkage disequilibrium (about 59% depletion on average), consistent with purifying selection on introgressed variants. Different from previous studies (McArthur 2021), we find no evidence for elevated heritability across the phenotypes examined. We identified 348 independent significant associations of introgressed Neanderthal variants with 64 phenotypes . Previous work (Skov 2020) has suggested that a majority of such associations are likely driven by statistical association with nearby modern human variants that are the true causal variants. We therefore developed a customized statistical fine-mapping methodology for introgressed variants that led us to identify 112 regions (at a false discovery proportion of 16%) across 47 phenotypes containing 4,303 unique genetic variants where introgressed variants are highly likely to have a phenotypic effect. Examination of these variants reveal their substantial impact on genes that are important for the immune system, development, and metabolism. Our results provide the first rigorous basis for understanding how Neanderthal introgression modulates complex trait variation in present-day humans.