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Elife. 2019 Dec 9;8. pii: e53535. doi: 10.7554/eLife.53535.

Mutations that improve efficiency of a weak-link enzyme are rare compared to adaptive mutations elsewhere in the genome.

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Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, United States.
Cooperative Institute for Research in Environmental Sciences, University of Colorado Boulder, Boulder, United States.
Department of Ecology and Evolutionary Biology, University of Colorado Boulder, Boulder, United States.
Center for Evolutionary Biology and Medicine, University of Pittsburgh, Pittsburgh, United States.


New enzymes often evolve by gene amplification and divergence. Previous experimental studies have followed the evolutionary trajectory of an amplified gene, but have not considered mutations elsewhere in the genome when fitness is limited by an evolving gene. We have evolved a strain of Escherichia coli in which a secondary promiscuous activity has been recruited to serve an essential function. The gene encoding the 'weak-link' enzyme amplified in all eight populations, but mutations improving the newly needed activity occurred in only one. Most adaptive mutations occurred elsewhere in the genome. Some mutations increase expression of the enzyme upstream of the weak-link enzyme, pushing material through the dysfunctional metabolic pathway. Others enhance production of a co-substrate for a downstream enzyme, thereby pulling material through the pathway. Most of these latter mutations are detrimental in wild-type E. coli, and thus would require reversion or compensation once a sufficient new activity has evolved.


E. coli; ProA; amplification and divergence; evolution; evolutionary biology; genetics; genomics; promiscuity

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