Genetic compensation triggered by mutant mRNA degradation

Mohamed A. EI-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; Didier Y. R. Stainier

doi:10.1038/s41586-019-1064-z

Genetic compensation triggered by mutant mRNA degradation

Mohamed A. EI-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, Didier Y. R. Stainier

SCMMS Denmark Hill

Research output: Contribution to journal › Article › peer-review

626 Citations (Scopus)

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.

Original language	English
Journal	NATURE
DOIs	https://doi.org/10.1038/s41586-019-1064-z https://doi.org/10.1038/s41586-019-1064-z
Publication status	Published - Apr 2019

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@article{6229284b0fb44df6b2e826bf7d1e1af0,

title = "Genetic compensation triggered by mutant mRNA degradation",

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.",

author = "EI-Brolosy, {Mohamed A.} and Zacharias Kontarakis and Andrea Rossi and Carsten Kuenne and Stefan G{\"u}nther and Nana Fukuda and Khrievono Kikhi and {M. Boezio}, {Giulia L.} and Takacs, {Carter M.} and Shih-Lei Lai and Ryuichi Fukuda and Claudia Gerri and {J. Giraldez}, Antonio and Stainier, {Didier Y. R.}",

year = "2019",

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doi = "10.1038/s41586-019-1064-z",

language = "English",

journal = "NATURE",

issn = "0028-0836",

publisher = "Nature Publishing Group",

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TY - JOUR

T1 - Genetic compensation triggered by mutant mRNA degradation

AU - EI-Brolosy, Mohamed A.

AU - Kontarakis, Zacharias

AU - Rossi, Andrea

AU - Kuenne, Carsten

AU - Günther, Stefan

AU - Fukuda, Nana

AU - Kikhi, Khrievono

AU - M. Boezio, Giulia L.

AU - Takacs, Carter M.

AU - Lai, Shih-Lei

AU - Fukuda, Ryuichi

AU - Gerri, Claudia

AU - J. Giraldez, Antonio

AU - Stainier, Didier Y. R.

PY - 2019/4

Y1 - 2019/4

N2 - 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.

AB - 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.

U2 - 10.1038/s41586-019-1064-z

DO - 10.1038/s41586-019-1064-z

M3 - Article

SN - 0028-0836

JO - NATURE

JF - NATURE

ER -

Genetic compensation triggered by mutant mRNA degradation

Abstract

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