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Compensatory gene amplification restores fitness after inter-species gene replacements
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.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Molecular Evolution.
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2010 (English)In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 75, no 5, 1078-1089 p.Article in journal (Refereed) Published
Abstract [en]

Genes introduced by gene replacements and other types of horizontal gene transfer (HGT) represent a significant presence in many archaeal and eubacterial genomes. Most alien genes are likely to be neutral or deleterious upon arrival and their long-term persistence may require a mechanism that improves their selective contribution. To examine the fate of inter-species gene replacements, we exchanged three native S. typhimurium genes encoding ribosomal proteins with orthologues from various other microbes. The results show that replacement of each of these three genes reduces fitness to such an extent that it would provide an effective barrier against inter-species gene replacements in eubacterial populations. However, these fitness defects could be partially ameliorated by gene amplification that augmented the dosage of the heterologous proteins. This suggests that suboptimal expression is a common fitness constraint for inter-species gene replacements, with fitness costs conferred by either a lower expression level of the alien protein compared with the native protein or a requirement for an increased amount of the alien protein to maintain proper function. Our findings can explain the observation that duplicated genes are over-represented among horizontally transferred genes, and suggest a potential coupling between compensatory gene amplification after HGT and the evolution of new genes.

Place, publisher, year, edition, pages
2010. Vol. 75, no 5, 1078-1089 p.
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-131545DOI: 10.1111/j.1365-2958.2009.07030.xISI: 000274808800004PubMedID: 20088865OAI: oai:DiVA.org:uu-131545DiVA: diva2:354851
Available from: 2010-10-05 Created: 2010-10-05 Last updated: 2017-12-12Bibliographically 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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 611
Keyword
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
Microbiology
Identifiers
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)
Opponent
Supervisors
Available from: 2010-11-11 Created: 2010-10-18 Last updated: 2011-01-13Bibliographically approved
2. Removal and Replacement of Ribosomal Proteins: Effects on Bacterial Fitness and Ribosome Function
Open this publication in new window or tab >>Removal and Replacement of Ribosomal Proteins: Effects on Bacterial Fitness and Ribosome Function
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Protein synthesis is a complex process performed by sophisticated cellular particles known as ribosomes. Although RNA constitutes the major structural and functional component, ribosomes from all kingdoms contain an extensive array of proteins with largely undefined functional roles. The work presented in this thesis addresses ribosomal complexity using mutants of Salmonella typhimurium to examine the physiological effects of ribosomal protein (r-protein) removal and orthologous replacement on bacterial fitness and ribosome function.

The results of paper I demonstrate that removal of small subunit protein S20 conferred two independent translation initiation defects: (i) a significant reduction in the rate and extent of mRNA binding and (ii) a drastic decrease in the yield of 70S complexes caused by an impairment in subunit association. The topographical location of S20 in mature 30S subunits suggests that these perturbations are the result of improper orientation of helix 44 of the 16S rRNA when S20 is absent. In paper II we show that the major functional impairment associated with loss of large subunit protein L1 manifested as an increase in free ribosomal subunits at the expense of translationally active 70S particles. Furthermore, the formation of free ribosomal subunits was imbalanced suggesting that L1 is required to suppress degradation or promote formation of 30S subunits. Compensatory evolution revealed that mutations in other large subunit proteins mitigate the cost of L1 removal, in one case seemingly via an increase in 70S complex formation. As shown in paper III, the large fitness costs associated with complete removal of r-proteins is in contrast to the generally mild costs of orthologous protein replacement, even in the absence of a high degree of homology to the native protein. This clearly demonstrates the robustness and plasticity of the ribosome and protein synthesis in general and it also implies that functional constraints are highly conserved between these proteins. The findings of paper III also allowed us to examine the barriers that constrain horizontal gene transfer and we find that increased gene dosage of the sub-optimal heterologous protein may be an initial response to stabilize deleterious transfer events. Overall the results highlight the requirement of r-proteins for the maintenance of ribosomal structural integrity.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 93 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 667
Keyword
ribosome, protein synthesis, ribosomal proteins, translation initiation, ribosome biogenesis, fitness costs, compensatory evolution, horizontal gene transfer
National Category
Microbiology in the medical area Biochemistry and Molecular Biology
Research subject
Microbiology
Identifiers
urn:nbn:se:uu:diva-150401 (URN)978-91-554-8061-5 (ISBN)
Public defence
2011-05-20, C8:301, BMC, Husargatan 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2011-04-28 Created: 2011-03-29 Last updated: 2011-05-05

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