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Adaptation to mutational inactivation of an essential gene converges to an accessible suboptimal fitness peak

The mechanisms of adaptation to inactivation of essential genes remain unknown. Here we inactivate E. coli dihydrofolate reductase (DHFR) by introducing D27G,N,F chromosomal mutations in a key catalytic residue with subsequent adaptation by an automated serial transfer protocol. The partial reversal...

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Autores principales: Rodrigues, João V, Shakhnovich, Eugene I
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828540/
https://www.ncbi.nlm.nih.gov/pubmed/31573512
http://dx.doi.org/10.7554/eLife.50509
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author Rodrigues, João V
Shakhnovich, Eugene I
author_facet Rodrigues, João V
Shakhnovich, Eugene I
author_sort Rodrigues, João V
collection PubMed
description The mechanisms of adaptation to inactivation of essential genes remain unknown. Here we inactivate E. coli dihydrofolate reductase (DHFR) by introducing D27G,N,F chromosomal mutations in a key catalytic residue with subsequent adaptation by an automated serial transfer protocol. The partial reversal G27- > C occurred in three evolutionary trajectories. Conversely, in one trajectory for D27G and in all trajectories for D27F,N strains adapted to grow at very low metabolic supplement (folAmix) concentrations but did not escape entirely from supplement auxotrophy. Major global shifts in metabolome and proteome occurred upon DHFR inactivation, which were partially reversed in adapted strains. Loss-of-function mutations in two genes, thyA and deoB, ensured adaptation to low folAmix by rerouting the 2-Deoxy-D-ribose-phosphate metabolism from glycolysis towards synthesis of dTMP. Multiple evolutionary pathways of adaptation converged to a suboptimal solution due to the high accessibility to loss-of-function mutations that block the path to the highest, yet least accessible, fitness peak.
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spelling pubmed-68285402019-11-06 Adaptation to mutational inactivation of an essential gene converges to an accessible suboptimal fitness peak Rodrigues, João V Shakhnovich, Eugene I eLife Computational and Systems Biology The mechanisms of adaptation to inactivation of essential genes remain unknown. Here we inactivate E. coli dihydrofolate reductase (DHFR) by introducing D27G,N,F chromosomal mutations in a key catalytic residue with subsequent adaptation by an automated serial transfer protocol. The partial reversal G27- > C occurred in three evolutionary trajectories. Conversely, in one trajectory for D27G and in all trajectories for D27F,N strains adapted to grow at very low metabolic supplement (folAmix) concentrations but did not escape entirely from supplement auxotrophy. Major global shifts in metabolome and proteome occurred upon DHFR inactivation, which were partially reversed in adapted strains. Loss-of-function mutations in two genes, thyA and deoB, ensured adaptation to low folAmix by rerouting the 2-Deoxy-D-ribose-phosphate metabolism from glycolysis towards synthesis of dTMP. Multiple evolutionary pathways of adaptation converged to a suboptimal solution due to the high accessibility to loss-of-function mutations that block the path to the highest, yet least accessible, fitness peak. eLife Sciences Publications, Ltd 2019-10-01 /pmc/articles/PMC6828540/ /pubmed/31573512 http://dx.doi.org/10.7554/eLife.50509 Text en © 2019, Rodrigues and Shakhnovich http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Computational and Systems Biology
Rodrigues, João V
Shakhnovich, Eugene I
Adaptation to mutational inactivation of an essential gene converges to an accessible suboptimal fitness peak
title Adaptation to mutational inactivation of an essential gene converges to an accessible suboptimal fitness peak
title_full Adaptation to mutational inactivation of an essential gene converges to an accessible suboptimal fitness peak
title_fullStr Adaptation to mutational inactivation of an essential gene converges to an accessible suboptimal fitness peak
title_full_unstemmed Adaptation to mutational inactivation of an essential gene converges to an accessible suboptimal fitness peak
title_short Adaptation to mutational inactivation of an essential gene converges to an accessible suboptimal fitness peak
title_sort adaptation to mutational inactivation of an essential gene converges to an accessible suboptimal fitness peak
topic Computational and Systems Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828540/
https://www.ncbi.nlm.nih.gov/pubmed/31573512
http://dx.doi.org/10.7554/eLife.50509
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