PT - JOURNAL ARTICLE AU - Andrew F. Schober AU - Christine Ingle AU - Junyoung O. Park AU - Li Chen AU - Joshua D. Rabinowitz AU - Ivan Junier AU - Olivier Rivoire AU - Kimberly A. Reynolds TI - An evolutionary module in central metabolism AID - 10.1101/120006 DP - 2017 Jan 01 TA - bioRxiv PG - 120006 4099 - http://biorxiv.org/content/early/2017/03/23/120006.short 4100 - http://biorxiv.org/content/early/2017/03/23/120006.full AB - 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.