Variable paralog expression underlies phenotype variation

Abstract

Human faces are variable; we look different from one another. Craniofacial disorders further increase facial variation. To understand craniofacial variation, and how it can be buffered, we analyzed the zebrafish mef2ca mutant. When this transcription factor encoding gene is mutated, zebrafish develop dramatically variable craniofacial phenotypes. Years of selective breeding for low and high penetrance of mutant phenotypes produced strains that are either resilient, or sensitive, to the mef2ca mutation. Here we compared gene expression between these strains, which revealed that selective breeding enriched for high and low mef2ca paralog expression in the low- and high-penetrance strains, respectively. We found that mef2ca paralog expression is variable in unselected wild-type zebrafish, motivating the hypothesis that heritable variation in paralog expression underlies mutant phenotype severity and variation. In support, mutagenizing the mef2ca paralogs, mef2aa, mef2b, mef2cb, and mef2d, demonstrated modular buffering by paralogs. Specifically, some paralogs buffer severity while others buffer variability. We present a novel, mechanistic model for phenotypic variation where variable, vestigial paralog expression buffers development. These studies are a major step forward in understanding the mechanisms of facial variation, including how some genetically resilient individuals can overcome a deleterious mutation.

Data availability

All raw data are provided in supplementary data table.Sequencing dataset have been deposited in GEO. The raw, feature-barcode matrix can be accessed from the GEO database (accession number GSE163826).

The following previously published data sets were used

Article and author information

Author details

  1. Raisa Bailon-Zambrano

    Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5848-3952
  2. Juliana Sucharov

    Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Abigail Mumme-Monheit

    Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0090-1418
  4. Matthew Murry

    Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Amanda Stenzel

    Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Anthony T Pulvino

    Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jennyfer M Mitchell

    Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4222-5235
  8. Kathryn L Colborn

    Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. James Nichols

    Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, United States
    For correspondence
    JAMES.NICHOLS@UCDENVER.EDU
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7263-1704

Funding

National Institute of Dental and Craniofacial Research (R01 DE029193)

  • James Nichols

National Science Foundation (Graduate RGRFP 201569)

  • Raisa Bailon-Zambrano

National Institute of Dental and Craniofacial Research (F32 DE029995)

  • Jennyfer M Mitchell

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 of our work with zebrafish has been approved by the University of Colorado Institutional Animal Care and Use Committee (IACUC), Protocol # 00188. Animals were euthanized by hypothermic shock followed by 1.5% sodium hypochlorite.

Reviewing Editor

  1. Tatjana Piotrowski, Stowers Institute for Medical Research, United States

Publication history

  1. Received: April 5, 2022
  2. Accepted: September 21, 2022
  3. Accepted Manuscript published: September 22, 2022 (version 1)

Copyright

© 2022, Bailon-Zambrano 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. Raisa Bailon-Zambrano
  2. Juliana Sucharov
  3. Abigail Mumme-Monheit
  4. Matthew Murry
  5. Amanda Stenzel
  6. Anthony T Pulvino
  7. Jennyfer M Mitchell
  8. Kathryn L Colborn
  9. James Nichols
(2022)
Variable paralog expression underlies phenotype variation
eLife 11:e79247.
https://doi.org/10.7554/eLife.79247

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