PUBLICATION

Selective breeding modifies mef2ca mutant incomplete penetrance by tuning the opposing Notch pathway

Authors
Sucharov, J., Ray, K., Brooks, E.P., Nichols, J.T.
ID
ZDB-PUB-191204-12
Date
2019
Source
PLoS Genetics   15: e1008507 (Journal)
Registered Authors
Brooks, Elliott, Nichols, James Tucker
Keywords
none
MeSH Terms
  • Animals
  • Epistasis, Genetic
  • Female
  • Gene Expression Regulation, Developmental
  • Homeodomain Proteins/genetics
  • Loss of Function Mutation
  • MEF2 Transcription Factors/genetics*
  • MEF2 Transcription Factors/metabolism*
  • Male
  • Ossification, Heterotopic/genetics
  • Penetrance
  • Phenotype
  • Receptors, Notch/metabolism*
  • Selective Breeding
  • Signal Transduction
  • Transcription Factors/genetics
  • Zebrafish/genetics*
  • Zebrafish/growth & development
  • Zebrafish/metabolism*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed
31790396 Full text @ PLoS Genet.
Abstract
Deleterious genetic mutations allow developmental biologists to understand how genes control development. However, not all loss of function genetic mutants develop phenotypic changes. Many deleterious mutations only produce a phenotype in a subset of mutant individuals, a phenomenon known as incomplete penetrance. Incomplete penetrance can confound analyses of gene function and our understanding of this widespread phenomenon remains inadequate. To better understand what controls penetrance, we capitalized on the zebrafish mef2ca mutant which produces craniofacial phenotypes with variable penetrance. Starting with a characterized mef2ca loss of function mutant allele, we used classical selective breeding methods to generate zebrafish strains in which mutant-associated phenotypes consistently appear with low or high penetrance. Strikingly, our selective breeding for low penetrance converted the mef2ca mutant allele behavior from homozygous lethal to homozygous viable. Meanwhile, selective breeding for high penetrance converted the mef2ca mutant allele from fully recessive to partially dominant. Comparing the selectively-bred low- and high-penetrance strains revealed that the strains initially respond similarly to the mutation, but then gene expression differences between strains emerge during development. Thus, altered temporal genetic circuitry can manifest through selective pressure to modify mutant penetrance. Specifically, we demonstrate differences in Notch signaling between strains, and further show that experimental manipulation of the Notch pathway phenocopies penetrance changes occurring through selective breeding. This study provides evidence that penetrance is inherited as a liability-threshold trait. Our finding that vertebrate animals can overcome a deleterious mutation by tuning genetic circuitry complements other reported mechanisms of overcoming deleterious mutations such as transcriptional adaptation of compensatory genes, alternative mRNA splicing, and maternal deposition of wild-type transcripts, which are not observed in our system. The selective breeding approach and the resultant genetic circuitry change we uncovered advances and expands our current understanding of genetic and developmental resilience.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes