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Functional Trade-Offs in Promiscuous Enzymes Cannot Be Explained by Intrinsic Mutational Robustness of the Native Activity.

ABSTRACT: The extent to which an emerging new function trades off with the original function is a key characteristic of the dynamics of enzyme evolution. Various cases of laboratory evolution have unveiled a characteristic trend; a large increase in a new, promiscuous activity is often accompanied by only a mild reduction of the native, original activity. A model that associates weak trade-offs with "evolvability" was put forward, which proposed that enzymes possess mutational robustness in the native activity and plasticity in promiscuous activities. This would enable the acquisition of a new function without compromising the original one, reducing the benefit of early gene duplication and therefore the selection pressure thereon. Yet, to date, no experimental study has examined this hypothesis directly. Here, we investigate the causes of weak trade-offs by systematically characterizing adaptive mutations that occurred in two cases of evolutionary transitions in enzyme function: (1) from phosphotriesterase to arylesterase, and (2) from atrazine chlorohydrolase to melamine deaminase. Mutational analyses in various genetic backgrounds revealed that, in contrast to the prevailing model, the native activity is less robust to mutations than the promiscuous activity. For example, in phosphotriesterase, the deleterious effect of individual mutations on the native phosphotriesterase activity is much larger than their positive effect on the promiscuous arylesterase activity. Our observations suggest a revision of the established model: weak trade-offs are not caused by an intrinsic robustness of the native activity and plasticity of the promiscuous activity. We propose that upon strong adaptive pressure for the new activity without selection against the original one, selected mutations will lead to the largest possible increases in the new function, but whether and to what extent they decrease the old function is irrelevant, creating a bias towards initially weak trade-offs and the emergence of generalist enzymes.

SUBMITTER: Kaltenbach M

PROVIDER: S-EPMC5065130 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Functional Trade-Offs in Promiscuous Enzymes Cannot Be Explained by Intrinsic Mutational Robustness of the Native Activity.

Kaltenbach Miriam M Emond Stephane S Hollfelder Florian F Tokuriki Nobuhiko N

PLoS genetics 20161007 10

The extent to which an emerging new function trades off with the original function is a key characteristic of the dynamics of enzyme evolution. Various cases of laboratory evolution have unveiled a characteristic trend; a large increase in a new, promiscuous activity is often accompanied by only a mild reduction of the native, original activity. A model that associates weak trade-offs with "evolvability" was put forward, which proposed that enzymes possess mutational robustness in the native act ...[more]

PMID: 27716796

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Project description:The current WHO-led initiative to eradicate the macroparasitic disease, lymphatic filariasis (LF), based on single-dose annual mass drug administration (MDA) represents one of the largest health programs devised to reduce the burden of tropical diseases. However, despite the advances made in instituting large-scale MDA programs in affected countries, a challenge to meeting the goal of global eradication is the heterogeneous transmission of LF across endemic regions, and the impact that such complexity may have on the effort required to interrupt transmission in all socioecological settings.Here, we apply a Bayesian computer simulation procedure to fit transmission models of LF to field data assembled from 18 sites across the major LF endemic regions of Africa, Asia and Papua New Guinea, reflecting different ecological and vector characteristics, to investigate the impacts and implications of transmission heterogeneity and complexity on filarial infection dynamics, system robustness and control.We find firstly that LF elimination thresholds varied significantly between the 18 study communities owing to site variations in transmission and initial ecological parameters. We highlight how this variation in thresholds lead to the need for applying variable durations of interventions across endemic communities for achieving LF elimination; however, a major new result is the finding that filarial population responses to interventions ultimately reflect outcomes of interplays between dynamics and the biological architectures and processes that generate robustness/fragility trade-offs in parasite transmission. Intervention simulations carried out in this study further show how understanding these factors is also key to the design of options that would effectively eliminate LF from all settings. In this regard, we find how including vector control into MDA programs may not only offer a countermeasure that will reliably increase system fragility globally across all settings and hence provide a control option robust to differential locality-specific transmission dynamics, but by simultaneously reducing transmission regime variability also permit more reliable macroscopic predictions of intervention effects.Our results imply that a new approach, combining adaptive modelling of parasite transmission with the use of biological robustness as a design principle, is required if we are to both enhance understanding of complex parasitic infections and delineate options to facilitate their elimination effectively.

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Functional Trade-Offs in Promiscuous Enzymes Cannot Be Explained by Intrinsic Mutational Robustness of the Native Activity.

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Functional Trade-Offs in Promiscuous Enzymes Cannot Be Explained by Intrinsic Mutational Robustness of the Native Activity.

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