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Accelerated gene evolution through replication–transcription conflicts

Nature volume 495, pages 512–515 (2013)Cite this article

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Abstract

Several mechanisms that increase the rate of mutagenesis across the entire genome have been identified; however, how the rate of evolution might be promoted in individual genes is unclear. Most genes in bacteria are encoded on the leading strand of replication1,2,3,4. This presumably avoids the potentially detrimental head-on collisions that occur between the replication and transcription machineries when genes are encoded on the lagging strand1,2,3,4. Here we identify the ubiquitous (core) genes in Bacillus subtilis and determine that 17% of them are on the lagging strand. We find a higher rate of point mutations in the core genes on the lagging strand compared with those on the leading strand, with this difference being primarily in the amino-acid-changing (nonsynonymous) mutations. We determine that, overall, the genes under strong negative selection against amino-acid-changing mutations tend to be on the leading strand, co-oriented with replication. In contrast, on the basis of the rate of convergent mutations, genes under positive selection for amino-acid-changing mutations are more commonly found on the lagging strand, indicating faster adaptive evolution in many genes in the head-on orientation. Increased gene length and gene expression amounts are positively correlated with the rate of accumulation of nonsynonymous mutations in the head-on genes, suggesting that the conflict between replication and transcription could be a driving force behind these mutations. Indeed, using reversion assays, we show that the difference in the rate of mutagenesis of genes in the two orientations is transcription dependent. Altogether, our findings indicate that head-on replication–transcription conflicts are more mutagenic than co-directional conflicts and that these encounters can significantly increase adaptive structural variation in the coded proteins. We propose that bacteria, and potentially other organisms, promote faster evolution of specific genes through orientation-dependent encounters between DNA replication and transcription.

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Figure 1: Highly conserved ‘core’ genes show a higher rate of nonsynonymous mutations on the lagging compared with the leading strand.
Figure 2: For head-on genes, a significant positive correlation exists between increased length, mutagenesis and positive selection.
Figure 3: Increased rates of mutagenesis in the head-on orientation are transcription dependent.
Figure 4: Functional categories of leading- and lagging-strand genes.

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Acknowledgements

We acknowledge the work of others that has contributed to our understanding of the topic, which we were unable to cite here. We thank B. Brewer, J. Mougous, F. Fang, M. Parsek and S. Miller for reading the manuscript. We thank C. Merrikh for comments on the manuscript and technical help with sequencing of revertants. We thank E. Robleto for the auxotrophic YB955 strain. H.M. was supported by start-up funds from the Department of Microbiology at the University of Washington. S.M.-W. was supported by the University of Washington Biophysics Training Grant. E.S., S.P, and S.C. were supported by National Institutes of Health (NIH) grants RC4 AI092828 and R01 GM084318.

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  1. Department of Microbiology, Health Sciences Building—J-wing, University of Washington, Seattle, 98195, Washington, USA

    Sandip Paul, Samuel Million-Weaver, Sujay Chattopadhyay, Evgeni Sokurenko & Houra Merrikh

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  1. Sandip Paul
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  2. Samuel Million-Weaver
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  4. Evgeni Sokurenko
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  5. Houra Merrikh
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Contributions

H.M., E.S., S.P. and S.M.-W. designed experiments, S.P., S.C. and S.M.-W. performed the bioinformatics analysis and the experiments, H.M., E.S., S.P., S.C. and S.M.-W. analysed the data. H.M. and E.S. wrote the paper.

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Correspondence to Evgeni Sokurenko or Houra Merrikh.

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The authors declare no competing financial interests.

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Paul, S., Million-Weaver, S., Chattopadhyay, S. et al. Accelerated gene evolution through replication–transcription conflicts. Nature 495, 512–515 (2013). https://doi.org/10.1038/nature11989

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