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Non-optimal codon usage is a mechanism to achieve circadian clock conditionality

Nature volume 495, pages 116–120 (2013)Cite this article

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Abstract

Circadian rhythms are oscillations in biological processes that function as a key adaptation to the daily rhythms of most environments. In the model cyanobacterial circadian clock system, the core oscillator proteins are encoded by the gene cluster kaiABC1. Genes with high expression and functional importance, such as the kai genes, are usually encoded by optimal codons, yet the codon-usage bias of the kaiBC genes is not optimized for translational efficiency. We discovered a relationship between codon usage and a general property of circadian rhythms called conditionality; namely, that endogenous rhythmicity is robustly expressed under some environmental conditions but not others2. Despite the generality of circadian conditionality, however, its molecular basis is unknown for any system. Here we show that in the cyanobacterium Synechococcus elongate, non-optimal codon usage was selected as a post-transcriptional mechanism to switch between circadian and non-circadian regulation of gene expression as an adaptive response to environmental conditions. When the kaiBC sequence was experimentally optimized to enhance expression of the KaiB and KaiC proteins, intrinsic rhythmicity was enhanced at cool temperatures that are experienced by this organism in its natural habitat. However, fitness at those temperatures was highest in cells in which the endogenous rhythms were suppressed at cool temperatures as compared with cells exhibiting high-amplitude rhythmicity. These results indicate natural selection against circadian systems in cyanobacteria that are intrinsically robust at cool temperatures. Modulation of circadian amplitude is therefore crucial to its adaptive significance3. Moreover, these results show the direct effects of codon usage on a complex phenotype and organismal fitness. Our work also challenges the long-standing view of directional selection towards optimal codons4,5,6,7, and provides a key example of natural selection against optimal codons to achieve adaptive responses to environmental changes.

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Figure 1: Non-optimal codon usage of cyanobacterial clock genes.
Figure 2: Conditional circadian phenotypes of the kai -optimized strains.
Figure 3: Kai protein expression and circadian regulation of cells expressing wild-type or optimized versions of kaiBC.
Figure 4: Optimizing the kaiBC sequence causes slower growth rate at cool temperatures.

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Acknowledgements

We are grateful for the suggestions of M. Woelfle and the technical assistance of D. Zelli and C. Chintanaphol. This research was supported by grants from the National Institute of General Medical Science to C.H.J. (R01 GM067152 and R01 GM088595) and to Y.L. (GM068496 and GM062591), the Welch Foundation (I-1560) to Y.L., and the National Science Foundation (DEB-0844968) and the Searle Scholars Program to A.R. P.S. acknowledges support from a Burroughs Wellcome Fund Career Award and a David & Lucille Packard Foundation Fellowship awarded to Joshua B. Plotkin.

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Authors and Affiliations

  1. Department of Biological Sciences, Vanderbilt University, Nashville, 37235, Tennessee, USA

    Yao Xu, Peijun Ma, Antonis Rokas & Carl Hirschie Johnson

  2. Department of Biology, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Premal Shah

  3. Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, 75390, Texas, USA

    Yi Liu

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  1. Yao Xu
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  6. Carl Hirschie Johnson
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Contributions

Y.X. and P.M. collected data; Y.X., P.M. and Y.L. analysed the experimental data; Y.X., P.S. and A.R. analysed the bioinformatic data; Y.L. and C.H.J. designed the original conceptual basis for the study; Y.X. and C.H.J. designed the experimental bases for the study; Y.X., P.S. and C.H.J. wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Carl Hirschie Johnson.

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Xu, Y., Ma, P., Shah, P. et al. Non-optimal codon usage is a mechanism to achieve circadian clock conditionality. Nature 495, 116–120 (2013). https://doi.org/10.1038/nature11942

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