PUBLICATION
Variable paralog expression underlies phenotype variation
- Authors
- Bailon-Zambrano, R., Sucharov, J., Mumme-Monheit, A., Murry, M., Stenzel, A., Pulvino, A.T., Mitchell, J.M., Colborn, K.L., Nichols, J.
- ID
- ZDB-PUB-220923-8
- Date
- 2022
- Source
- eLIFE 11: (Journal)
- Registered Authors
- Nichols, James Tucker
- Keywords
- developmental biology, genetics, genomics, zebrafish
- Datasets
- GEO:GSE163826
- MeSH Terms
-
- Animals
- Biological Variation, Population
- Humans
- MEF2 Transcription Factors*/genetics
- MEF2 Transcription Factors*/metabolism
- Phenotype
- Transcription Factors/metabolism
- Zebrafish*/metabolism
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- PubMed
- 36134886 Full text @ Elife
Citation
Bailon-Zambrano, R., Sucharov, J., Mumme-Monheit, A., Murry, M., Stenzel, A., Pulvino, A.T., Mitchell, J.M., Colborn, K.L., Nichols, J. (2022) Variable paralog expression underlies phenotype variation. eLIFE. 11:.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping