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Whole-genome mutational biases in bacteria
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
2008 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, Vol. 105, no 46, 17878-83 p.Article in journal (Refereed) Published
Abstract [en]

A fundamental biological question is what forces shape the guanine plus cytosine (GC) content of genomes. We studied the specificity and rate of different mutational biases in real time in the bacterium Salmonella typhimurium under conditions of strongly reduced selection and in the absence of the major DNA repair systems involved in repairing common spontaneous mutations caused by oxidized and deaminated DNA bases. The mutational spectrum was determined by whole-genome sequencing of two S. typhimurium mutants that were serially passaged for 5,000 generations. Analysis of 943 identified base pair substitutions showed that 91% were GC-to-TA transversions and 7% were GC-to-AT transitions, commonly associated with 8-oxoG- and deamination-induced damages, respectively. Other types of base pair substitutions constituted the remaining 2% of the mutations. With regard to mutational biases, there was a significant increase in C-to-T transitions on the nontranscribed strand, and for highly expressed genes, C/G-to-T mutations were more common than expected; however, no significant mutational bias with regard to leading and lagging strands of replication or chromosome position were found. These results suggest that, based on the experimentally determined mutational rates and specificities, a bacterial genome lacking the relevant DNA repair systems could, as a consequence of these underlying mutational biases, very rapidly reduce its GC content.

Place, publisher, year, edition, pages
2008. Vol. 105, no 46, 17878-83 p.
Keyword [en]
dna repair, experimental evolution, gc bias, mutation spectra, Salmonella typhimurium
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-98295DOI: 10.1073/pnas.0804445105ISI: 000261225600057PubMedID: 19001264OAI: oai:DiVA.org:uu-98295DiVA: diva2:174048
Available from: 2009-02-18 Created: 2009-02-18 Last updated: 2011-06-29Bibliographically approved
In thesis
1. Evolutionary Dynamics of Mutation and Gene Transfer in Bacteria
Open this publication in new window or tab >>Evolutionary Dynamics of Mutation and Gene Transfer in Bacteria
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The study of bacterial evolution is fundamental for addressing current problems of antibiotic resistance and emerging infectious diseases and lays a solid foundation for successful and rational design in biotechnology and synthetic biology. The main aim of this thesis is to test evolutionary hypotheses, largely based on theoretical considerations and sequence analysis, by designing scenarios in a laboratory setting to obtain experimental data. Paper I examines how genomic GC-content can be reduced following a change in mutation rate and spectrum. Transcription-related biases in mutation location were found, but no replicative bias was detected. Paper II explores the distribution of fitness effects of random substitutions in two ribosomal protein genes using a highly sensitive fitness assay. The substitutions had a weakly deleterious effect, with low frequencies of both neutral and inactivating mutations. The surprising finding that synonymous and non-synonymous substitutions have very similar distribution of fitness effects suggests that, at least for these genes, fitness constraints are present mainly on the level of mRNA instead of protein. Paper III examines selective barriers to inter-species gene transfer by constructing mutants with a native gene replaced by an orthologue from another species. Results suggest that the fitness costs of these gene replacements are large enough to provide a barrier to this kind of horizontal gene transfer in nature. The paper also examines possible compensatory mechanisms that can reduce the cost of the poorly functioning alien genes and found that gene amplification acts as a first step to improve the selective contribution after transfer. Paper IV investigates the fitness constraints on horizontal gene transfer by inserting DNA from other species into the Salmonella chromosome. Results suggest that insertion of foreign DNA often is neutral and the manuscript provides new experimental data for theoretical analysis of interspecies genome variation and horizontal gene transfer between species.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 80 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 611
fitness cost, bacterial evolution, gene amplification, mutational biases, GC content, synonymous substitutions, horizontal gene transfer, experimental evolution
National Category
Microbiology in the medical area Microbiology Genetics Biological Sciences
Research subject
urn:nbn:se:uu:diva-132262 (URN)978-91-554-7923-7 (ISBN)
Public defence
2010-12-03, C4:301, BMC, Husargatan 3, Uppsala, 13:00 (English)
Available from: 2010-11-11 Created: 2010-10-18 Last updated: 2011-01-13Bibliographically approved

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