Genetic compensation triggered by mutant mRNA degradation

Mohamed A. El-Brolosy, Zacharias Kontarakis, Andrea Rossi, Carsten Kuenne, Stefan Günther, Nana Fukuda, Khrievono Kikhi, Giulia L. M. Boezio, Carter M. Takacs, Shih-Lei Lai, Ryuichi Fukuda, Claudia Gerri, Antonio J. Giraldez and Didier Y. R. Stainier ()
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Mohamed A. El-Brolosy: Max Planck Institute for Heart and Lung Research
Zacharias Kontarakis: Max Planck Institute for Heart and Lung Research
Andrea Rossi: Max Planck Institute for Heart and Lung Research
Carsten Kuenne: Max Planck Institute for Heart and Lung Research
Stefan Günther: Max Planck Institute for Heart and Lung Research
Nana Fukuda: Max Planck Institute for Heart and Lung Research
Khrievono Kikhi: Max Planck Institute for Heart and Lung Research
Giulia L. M. Boezio: Max Planck Institute for Heart and Lung Research
Carter M. Takacs: Yale University School of Medicine
Shih-Lei Lai: Max Planck Institute for Heart and Lung Research
Ryuichi Fukuda: Max Planck Institute for Heart and Lung Research
Claudia Gerri: Max Planck Institute for Heart and Lung Research
Antonio J. Giraldez: Yale University School of Medicine
Didier Y. R. Stainier: Max Planck Institute for Heart and Lung Research

Nature, 2019, vol. 568, issue 7751, 193-197

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1064-z

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