Genetic compensation triggered by mutant mRNA degradation

By Mohamed A. El-Brolosy, Zacharias Kontarakis, Andrea Rossi, C. Kuenne, S. Günther, Nana Fukuda, Khrievono Kikhi, Giulia L. M. Boezio, Carter M. Takacs, S. Lai and 4 more. 2019

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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. Transcriptional adaptation, a genetic compensation process by which organisms respond to mutations by upregulating related genes, is triggered by mRNA decay and involves a sequence-dependent mechanism.

Subfields: Genetics, Molecular Biology

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Citations in the corpus

Automated assembly scaffolding using RagTag elevates a new tomato system for high-throughput genome editing (2022, positive): “We next explored the ability to delete entire gene loci, which is important to mitigate potential confounding genetic compensation responses to mutant allele transcripts [26].”
Automated assembly scaffolding elevates a new tomato system for high-throughput genome editing (2021, positive): “We next explored the ability to delete entire gene loci, which is important to mitigate potential confounding genetic compensation responses to mutant allele transcripts [21].”