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Glucose limitation in Lactococcus shapes a single-peaked fitness landscape exposing membrane occupancy as a constraint

By Claire E. Price, Filipe Branco dos Santos, Anne Hesseling, Jaakko J. Uusitalo, Herwig Bachmann, Vera Benavente, Anisha Goel, Jan Berkhout, Frank J. Bruggeman, Siewert-Jan Marrink, Manolo Montalban-Lopez, Anne de Jong, Jan Kok, Douwe Molenaar, Bert Poolman, Bas Teusink, Oscar P. Kuipers

Posted 08 Jun 2017
bioRxiv DOI: 10.1101/147926

A central theme in biology is to understand the molecular basis of fitness: which strategies succeed under which conditions; how are they mechanistically implemented; and which constraints shape trade-offs between alternative strategies. We approached these questions with parallel bacterial evolution experiments in chemostats. Chemostats provide a constant environment with a defined resource limitation (glucose), in which the growth rate can be controlled. Using Lactococcus lactis, we found a single mutation in a global regulator of carbon metabolism, CcpA, to confer predictable fitness improvements across multiple growth rates. In silico protein structural analysis complemented with biochemical and phenotypic assays, show that the mutation reprograms the CcpA regulon, specifically targeting transporters. This supports that membrane occupancy, rather than biosynthetic capacity, is the dominant constraint for the observed fitness enhancement. It also demonstrates that cells can modulate a pleiotropic regulator to work around limiting constraints.

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