Variable paralog expression underlies phenotype variation
- University of Colorado Anschutz Medical Campus, United States
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).
Article and author information
Author details
Raisa Bailon-Zambrano
Abigail Mumme-Monheit
Jennyfer M Mitchell
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.
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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Variable paralog expression underlies phenotype variation
eLife 11:e79247.
https://doi.org/10.7554/eLife.79247
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