PUBLICATION

Genetic compensation triggered by mutant mRNA degradation

Authors
El-Brolosy, M.A., Kontarakis, Z., Rossi, A., Kuenne, C., Günther, S., Fukuda, N., Kikhi, K., Boezio, G.L.M., Takacs, C.M., Lai, S.L., Fukuda, R., Gerri, C., Giraldez, A.J., Stainier, D.Y.R.
ID
ZDB-PUB-190405-15
Date
2019
Source
Nature   568(7751): 193-197 (Journal)
Registered Authors
Giraldez, Antonio, Kontarakis, Zacharias, Lai, Shih-Lei (Ben), Stainier, Didier, Takacs, Carter M.
Keywords
none
MeSH Terms
  • Adaptation, Physiological/genetics*
  • Alleles
  • Animals
  • Epigenesis, Genetic/genetics
  • Histones/metabolism
  • Mice
  • Mutation*
  • RNA Stability/genetics*
  • RNA, Messenger/genetics*
  • RNA, Messenger/metabolism*
  • Transcription, Genetic/genetics*
  • Up-Regulation/genetics*
  • Zebrafish/genetics
PubMed
30944477 Full text @ Nature
Abstract
Genetic robustness, or the ability of an organism to maintain fitness in the presence of harmful mutations, can be achieved via protein feedback loops. Previous work has suggested that organisms may also respond to mutations by transcriptional adaptation, a process by which related gene(s) are upregulated independently of protein feedback loops. However, the prevalence of transcriptional adaptation and its underlying molecular mechanisms are unknown. Here, by analysing several models of transcriptional adaptation in zebrafish and mouse, we uncover a requirement for mutant mRNA degradation. Alleles that fail to transcribe the mutated gene do not exhibit transcriptional adaptation, and these alleles give rise to more severe phenotypes than alleles displaying mutant mRNA decay. Transcriptome analysis in alleles displaying mutant mRNA decay reveals the upregulation of a substantial proportion of the genes that exhibit sequence similarity with the mutated gene's mRNA, suggesting a sequence-dependent mechanism. These findings have implications for our understanding of disease-causing mutations, and will help in the design of mutant alleles with minimal transcriptional adaptation-derived compensation.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Errata and Notes