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Accumulation of mutants in "aging" bacterial colonies is due to growth under selection, not stress-induced mutagenesis
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
2008 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, no 33, 11863-11868 p.Article in journal (Refereed) Published
Abstract [en]

Several bacterial systems show behavior interpreted as evidence for stress-induced mutagenesis (adaptive mutation), a postulated process by which nongrowing cells temporarily increase their general mutation rate. Theoretical considerations suggest that periodic stress-induced general mutagenesis would not be advantageous in the long term, due to the high cost of deleterious mutations. Alternative explanations have been tested for very few of the systems used as evidence for stress-induced mutation. In one prominent system, mutants resistant to rifampicin (RifR; rpoB; RNA polymerase) accumulate in cell populations that “age” on solid medium with little net growth. Mutant accumulation was initially attributed to stress-induced general mutagenesis in nongrowing cells. Evidence is presented that these RifR mutants accumulate because they grow faster than parent cells during the aging period. Direct tests revealed no increase in the frequency of other mutant types during the aging period.

Place, publisher, year, edition, pages
2008. Vol. 105, no 33, 11863-11868 p.
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-109091DOI: 10.1073/pnas.0804739105ISI: 000258723800051OAI: oai:DiVA.org:uu-109091DiVA: diva2:248832
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-08-01Bibliographically approved
In thesis
1. Growth in Aging Colonies: The Importance of Being Different
Open this publication in new window or tab >>Growth in Aging Colonies: The Importance of Being Different
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The accumulation of rifampicin resistant (RifR) mutants in aging bacterial colonies has previously been attributed to stress-induced mutagenesis. Mutations giving rise to RifR are located in the rpoB gene, coding for the β subunit of RNA polymerase, RpoB. We showed that these mutants accumulate because they grow faster than the wild-type in the aging colonies. We found no evidence of increased mutagenesis in the RifR cells and their distribution, as localized clones in the aging colonies, indicated that they accumulated by selection and growth rather than by an increased rate of mutagenesis. Colony competition experiments with reconstructed strains showed that the RifR mutations were responsible for the growth advantage. We also found that deletion of rpoS, coding for the stationary phase sigma factor (RpoS), also gives a growth advantage on bacterial cells in aging colonies.

We suggest that mutants lacking RpoS, having a different transcription pattern than the wild-type, may override the signals to enter stationary phase together with the rest of the population and instead keep growing for as long as possible. We found that the rpoB mutants mimicked the transcription pattern of the rpoS deletion mutant, thereby displaying a similar phenotype in the aging colonies. The pathways used in acetate metabolism (consisting of the enzymes Acs, AckA-Pta, PoxB and AceBAK) were shown to be important for the growth advantage mutants suggesting that acetate is one of the main carbon sources used to support their prolonged growth in the aging colonies.

Rifampicin is a first-line drug used to treat M. tuberculosis infections. We used S. enterica as a model system for experimental evolution to ask whether compensatory mutations might be important in RifR mutants. In every lineage evolved compensatory mutations arose without any significant reduction in resistance. These mutations altered genes for the α, β, and β’ subunits of RNA polymerase.  

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 925
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-172393 (URN)978-91-554-8342-5 (ISBN)
Public defence
2012-05-25, B42, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2012-05-04 Created: 2012-04-10 Last updated: 2012-08-01Bibliographically approved

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Wrande, MarieHughes, Diarmaid

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