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An evolutionary module in central metabolism

Andrew F. Schober, Christine Ingle, Junyoung O. Park, Li Chen, Joshua D. Rabinowitz, Ivan Junier, Olivier Rivoire, Kimberly A. Reynolds
doi: https://doi.org/10.1101/120006
Andrew F. Schober
1The Green Center for Systems Biology, Dallas, TX 75390, USA
2Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
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Christine Ingle
1The Green Center for Systems Biology, Dallas, TX 75390, USA
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Junyoung O. Park
3Lewis-Sigler Institute for Integrative Genomics, Princeton, NJ 08544, USA
4Department of Chemical and Biological Engineering, Princeton, NJ 08544, USA
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Li Chen
3Lewis-Sigler Institute for Integrative Genomics, Princeton, NJ 08544, USA
5Department of Chemistry, Princeton University, Princeton, NJ 08544, USA
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Joshua D. Rabinowitz
3Lewis-Sigler Institute for Integrative Genomics, Princeton, NJ 08544, USA
5Department of Chemistry, Princeton University, Princeton, NJ 08544, USA
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Ivan Junier
6Centre National de la Recherche Scientifique (CNRS), TIMC-IMAG, F-38000 Grenoble, France
7Université Grenoble Alpes, TIMC-IMAG, F-38000 Grenoble, France
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Olivier Rivoire
6Centre National de la Recherche Scientifique (CNRS), TIMC-IMAG, F-38000 Grenoble, France
8Center for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS, INSERM, PSL Research University, F-75005 Paris, France
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Kimberly A. Reynolds
1The Green Center for Systems Biology, Dallas, TX 75390, USA
2Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
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  • For correspondence: kimberly.reynolds@utsouthwestern.edu
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Abstract

The ability to predict cell behavior is complicated by an unknown pattern of functional interdependence among genes. Here, we use the conservation of gene proximity across species (synteny) to infer functional couplings between genes. For the folate metabolic pathway, we observe a sparse, modular architecture of interactions, with two small groups of genes coevolving in the midst of others that evolve independently. For one such module – dihydrofolate reductase and thymidylate synthase – we use epistasis measurements and forward evolution to demonstrate both internal functional coupling and independence from the remainder of the genome. Mechanistically, the coupling is driven by a constraint on their relative activities, which must be balanced to prevent accumulation of a metabolic intermediate. The results indicate an organization of cellular systems not apparent from inspection of biochemical pathways or physical complexes, and support the strategy of using evolutionary information to decompose cellular systems into functional units.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 23, 2017.
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An evolutionary module in central metabolism
Andrew F. Schober, Christine Ingle, Junyoung O. Park, Li Chen, Joshua D. Rabinowitz, Ivan Junier, Olivier Rivoire, Kimberly A. Reynolds
bioRxiv 120006; doi: https://doi.org/10.1101/120006
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An evolutionary module in central metabolism
Andrew F. Schober, Christine Ingle, Junyoung O. Park, Li Chen, Joshua D. Rabinowitz, Ivan Junier, Olivier Rivoire, Kimberly A. Reynolds
bioRxiv 120006; doi: https://doi.org/10.1101/120006

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