Format

Send to

Choose Destination
Nature. 2019 Apr;568(7751):193-197. doi: 10.1038/s41586-019-1064-z. Epub 2019 Apr 3.

Genetic compensation triggered by mutant mRNA degradation.

Author information

1
Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
2
Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany.
3
ECCPS Bioinformatics and Deep Sequencing Platform, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
4
Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
5
University of New Haven, New Haven, CT, USA.
6
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
7
The Francis Crick Institute, London, UK.
8
Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. didier.stainier@mpi-bn.mpg.de.

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.

PMID:
30944477
DOI:
10.1038/s41586-019-1064-z

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center