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Author Notes:

Email Address: Paul W. Doetsch : mpedwd@emory.edu

Conceived and designed the experiments: JM ND BW PWD. Performed the experiments: JM.

Analyzed the data: JM ND BW PWD. Contributed reagents/materials/analysis tools: BW YL.

Wrote the paper: JM BW. Carried out preliminary experiments: AK.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The authors have declared that no competing interests exist.


Research Funding:

National Institutes of Health (http://www.nih.gov) grant CA120288 was awarded to PWD.

Evidence for Retromutagenesis as a Mechanism for Adaptive Mutation in Escherichia coli.

Journal Title:

PLoS Genetics


Volume 11, Number 8


, Pages e1005477-e1005477

Type of Work:

Article | Final Publisher PDF


Adaptive mutation refers to the continuous outgrowth of new mutants from a non-dividing cell population during selection, in apparent violation of the neo-Darwinian principle that mutation precedes selection. One explanation is that of retromutagenesis, in which a DNA lesion causes a transcriptional mutation that yields a mutant protein, allowing escape from selection. This enables a round of DNA replication that establishes heritability. Because the model requires that gene expression precedes DNA replication, it predicts that during selection, new mutants will arise from damage only to the transcribed DNA strand. As a test, we used a lacZ amber mutant of Escherichia coli that can revert by nitrous acid-induced deamination of adenine residues on either strand of the TAG stop codon, each causing different DNA mutations. When stationary-phase, mutagenized cells were grown in rich broth before being plated on lactose-selective media, only non-transcribed strand mutations appeared in the revertants. This result was consistent with the known high sensitivity to deamination of the single-stranded DNA in a transcription bubble, and it provided an important control because it demonstrated that the genetic system we would use to detect transcribed-strand mutations could also detect a bias toward the non-transcribed strand. When residual lacZ transcription was blocked beforehand by catabolite repression, both strands were mutated about equally, but if revertants were selected immediately after nitrous acid exposure, transcribed-strand mutations predominated among the revertants, implicating retromutagenesis as the mechanism. This result was not affected by gene orientation. Retromutagenesis is apt to be a universal method of evolutionary adaptation, which enables the emergence of new mutants from mutations acquired during counterselection rather than beforehand, and it may have roles in processes as diverse as the development of antibiotic resistance and neoplasia.

Copyright information:

© 2015 Morreall et al.

This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits distribution, public display, and publicly performance, making multiple copies, distribution of derivative works, provided the original work is properly cited. This license requires credit be given to copyright holder and/or author, copyright and license notices be kept intact.

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