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Parallel and divergent genotypic evolution in experimental populations of Ralstonia sp.

Genetic rearrangements within a population of bacteria were analyzed to understand the degree of divergence occurring after experimental evolution. We used 18 replicate populations founded from Ralstonia sp. strain TFD41 that had been propagated for 1,000 generations with 2,4-dichlorophenoxyacetic acid (2,4-D) as the carbon source. Genetic divergence was examined by restriction fragment length polymorphism analysis of the incumbent plasmid that carries the 2,4-D catabolic genes and by amplification of random regions of the genome via PCR. In 18 evolved clones examined, we observed duplication within the plasmid, including the tfdA gene, which encodes a 2,4-D dioxygenase that catalyzes the first step in the 2,4-D catabolic pathway. In 71 of 72 evolved clones, a common 2.4-kb PCR product was lost when genomic fingerprints produced by PCR amplification using degenerate primers based on repetitive extragenic palindromic (REP) sequences (REP-PCR) were compared. The nucleotide sequence of the 2.4-kb PCR product has homology to the TRAP (tripartite ATP-independent periplasmic) solute transporter gene family. Hybridization of the 2. 4-kb REP-PCR product from the ancestor to genomic DNA from the evolved populations showed that the loss of the PCR product resulted from deletions in the genome. Deletions in the plasmid and presence and/or absence of other REP-PCR products were also found in these clones but at much lower frequencies. The common and uncommon genetic changes observed show that both parallel and divergent genotypic evolution occurred in replicate populations of this bacterium.

Chlorophenols↗

Characterization of the cea gene of the ColE7 plasmid.

The complete nucleotide sequence (1731 nucleotides) of the gene encoding colicin E7 (cea) of plasmid ColE7-K317 was determined. This sequence encoded a deduced polypeptide of 576 amino acids of molecular weight 61349 Da. Comparison of the nucleotide and amino acid sequences of cea E7 with those of other E-group colicins revealed that colicin E7 was closely related to colicin E2, both in gene sequence and in predicted secondary structure of the deduced protein. Judging from the results of cross-immunity tests, we postulated that ColE7 is probably a proximate ancestor of ColE2 and ColE8. Based on results from colicin production tests on cells harboring a 5' end deleted form of the cea E7 gene, we propose that a previously unknown, non-inducible promoter may be involved in regulation of the constitutive expression of the cea E7 gene.

Amino Acid Sequence↗

Mutations affecting primer RNA interaction with the replication repressor RNA I in plasmid CoIE1: potential RNA folding pathway mutants.

The control of plasmid ColE1 copy number is mediated by the kinetics of interaction of two complementary plasmid-encoded RNAs. One RNA is the primer precursor and the other is a small counter-transcript called RNA I. The interaction of these highly structured RNAs results in inhibition of formation of mature primer RNA necessary for replication initiation. We have studied several plasmid copy number mutants which have single base changes in the primer which render the primer resistant to inhibition by RNA I despite the fact that the mutations are located outside the overlap between primer and RNA I. We propose a model to account for the resistance of the mutant primers which is based on the differential folding of the nascent primer transcripts during transcription. We propose that the mutant primers diverge in structure from their wild-type counterparts during a discrete period during transcription. During this brief divergence, they are proposed to interact kinetically more slowly with RNA I than wild-type primer because a particular domain (the anti-tail) required for efficient interaction with RNA I is buried in a stem-loop structure while this same domain is predicted to be single-stranded in the wild-type. Despite substantial sequence divergence from ColE1, the primer precursors of the related plasmids CloDF13, RSF1030 and p15A also have retained the potential to expose their anti-tail in a similar manner to ColE1, suggesting that the folding pathway has been conserved in evolution.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗

Chromosomal genotypes (evolutionary lines) of Salmonella berta.

The copy number and location of the insertion sequence IS200, a mobile DNA element, was established across a collection of Salmonella berta. All strains contained one common site, assumed to be present in the evolutionary ancestor of this serovar. With one exception, all strains, including recent outbreak isolates from the UK and sporadic isolates of world-wide distribution, were representatives of a single genotypic clone which carried three common IS200 insertion sites. This clone has acquired diverse combinations of plasmids, reflecting its actual or recent distribution and host. A single isolate, belonging to a second, minor genotypic clone was characterised by two IS200 insertion sites.

Animals↗

Mutual adaptation of bacteriophage fd, pfd plasmids and their host strains.

The synthetic plasmid pfdC1 with the replication origin of phage fd and fd gene 2 grows autonomously in E. coli cells. DNA sequencing revealed several mutations compared to the fd genome causing reduced expression of viral gene 2 protein, which can be toxic for the host cell. Another adaptation was noticed for E. coli strains with a copy of fd gene 2 on the F-episome and a pfdA-plasmid with a minimal fd replication origin, when maintained at 42 degrees C. The carrier cells adjusted their cellular metabolism to these stress conditions, whereas replication functions of the plasmid or expression of fd gene 2 on the F-episome were not changed. The filamentous bacteriophages tend to reduce their genome size into miniphages, which was also observed for phages with an antibiotic resistance gene. Bacteriophages with a transposon insertion in the viral gene 2 had a tendency to restore the mutated gene by exchange with the functional gene 2 carried in recA-host cells. Mobilization of pfd-plasmids with RP4 transfer functions was reduced due to interference of replication and transfer in the rolling circle mode. The vectors used in these studies can also be applied as cloning vectors, which are compatible with many other plasmid vectors.

Adaptation, Physiological↗

Redesigning metabolic routes: manipulation of TOL plasmid pathway for catabolism of alkylbenzoates.

Increasing quantities of man-made organic chemicals are released each year into the biosphere. Some of these compounds are both toxic and relatively resistant to physical, chemical, or biological degradation, and they thus constitute an environmental burden of considerable magnitude. Genetic manipulation of microbial catabolic pathways offers a powerful means by which to accelerate evolution of biodegradative routes through which such compounds might be eliminated from the environment. In the experiments described here, a catabolic pathway for alkylbenzoates specified by the TOL plasmid of Pseudomonas was restructured to produce a pathway capable of processing a new substrate, 4-ethylbenzoate. Analysis of critical steps in the TOL pathway that prevent metabolism of 4-ethylbenzoate revealed that this compound fails to induce synthesis of the catabolic enzymes and that one of its metabolic intermediates inactivates catechol 2,3-dioxygenase (C23O), the enzyme that cleaves the aromatic ring. Consequently, the pathway was sequentially modified by recruitment of genes from mutant bacteria selected for their production of either an altered pathway operon regulator that is activated by 4-ethylbenzoate or an altered C23O that is less sensitive to metabolite inactivation. The redesigned pathway was stably expressed and enabled host bacteria to degrade 4-ethylbenzoate in addition to the normal substrates of the TOL pathway.

Benzoates↗

An orthogonal T7 replisome for continuous hypermutation and accelerated evolution in E. coli.

Systems that perform continuous hypermutation of designated genes without compromising the integrity of the host genome can substantially accelerate the evolution of new or enhanced protein functions. We describe an orthogonal DNA replication system in Escherichia coli based on the controlled expression of the replisome of bacteriophage T7 (T7-ORACLE). The system replicates circular plasmids that enable high transformation efficiencies and seamless integration into standard molecular biology workflows. Engineering of T7 DNA polymerase yielded variant proteins with mutation rates of 1.7 × 10-5 substitutions per base in vivo-100,000-fold above the genomic mutation rate. We demonstrated continuous evolution using the T7 replisome by expanding the substrate scope of TEM-1 β-lactamase and increasing activity 5000-fold against clinically relevant monobactam and cephalosporin antibiotics in less than 1 week.

Bacteriophage T7↗

Black holes, antivirulence genes, and gene inactivation in the evolution of bacterial pathogens.

The evolution of bacterial pathogens from nonpathogenic ancestors is marked principally by the acquisition of virulence gene clusters on plasmids and pathogenicity islands via horizontal gene transfer. The flip side of this evolutionary force is the equally important adaptation of the newly minted pathogen to its new host niche. Pathoadaptive mutations take the form of modification of gene expression such that the pathogen is better fit to survive within the new niche. This mini-review describes the concept of pathoadaptation by loss of gene function. In this process, genes that are no longer compatible with the novel lifestyle of the pathogen are selectively inactivated either by point mutation, insertion, or deletion. These genes are called 'antivirulence genes'. Selective pressure sometimes leads to the deletion of large regions of the genome that contain antivirulence genes generating 'black holes' in the pathogen genome. Inactivation of antivirulence genes leads to a pathogen that is highly adapted to its host niche. Identification of antivirulence genes for a particular pathogen can lead to a better understanding of how it became a pathogen and the types of genetic traits that need to be silenced in order for the pathogen to colonize its new host niche successfully.

Adaptation, Biological↗

Trimethoprim and brodimoprim resistance of gram-positive and gram-negative bacteria.

Trimethoprim and brodimoprim act by selectively inhibiting bacterial dihydrofolate reductase. There are a number of mechanisms by which bacteria can develop resistance to these agents. These include thymineless mutation, impermeability, alteration in chromosomal dihydrofolate reductase and the plasmid-encoded production of an additional dihydrofolate reductase which is insensitive to inhibition by antifolate agents. Clinically the most important of these is the plasmid-encoded production of additional dihydrofolate reductases and such resistance is found in both gram-positive and gram-negative species. These plasmid-encoded enzymes were initially divided into a number of classes based principally on their biochemical profiles. More recently sequence analysis has been used to study these proteins and thus the classification of dihydrofolate reductases now also takes into account sequence information. The number of plasmid-mediated dihydrofolate reductases has increased markedly in recent years. Whilst this probably results from the continuing evolution of resistance it can also be partly attributed to more discriminatory methods for studying these enzymes.

Folic Acid Antagonists↗

Capture of a catabolic plasmid that encodes only 2,4-dichlorophenoxyacetic acid:alpha-ketoglutaric acid dioxygenase (TfdA) by genetic complementation.

The modular pathway for the metabolism of 2,4-dichlorophenoxyacetic acid (2,4-D) encoded on plasmid pJP4 of Alcaligenes eutrophus JMP134 appears to be an example in which two genes, tfdA and tfdB, have been recruited during the evolution of a catabolic pathway. The products of these genes act to convert 2,4-D to a chloro-substituted catechol that can be further metabolized by enzymes of a modified ortho-cleavage pathway encoded by tfdCDEF. Given that modified ortho-cleavage pathways are comparatively common and widely distributed among bacteria, we sought to determine if microbial populations in soil carry tfdA on plasmid vectors that lack tfdCDEF or tfdB. To capture such plasmids from soil populations, we used a recipient strain of A. eutrophus that was rifampin resistant and carried a derivative of plasmid pJP4 (called pBH501aE) in which the tfdA had been deleted. Upon mating with mixed bacterial populations from soil treated with 2,4-D, transconjugants that were resistant to rifampin yet able to grow on 2,4-D were obtained. Among the transconjugants obtained were clones that contained a ca. 75-kb plasmid, pEMT8. Bacterial hosts that carried this plasmid in addition to pBH501aE metabolized 2,4-D, whereas strains with only pEMT8 did not. Southern hybridization showed that pEMT8 encoded a gene with a low level of similarity to the tfdA gene from plasmid pJP4. Using oligonucleotide primers based on known tfdA sequences, we amplified a 330-bp fragment of the gene and determined that it was 77% similar to the tfdA gene of plasmid pJP4 and 94% similar to tfdA from Burkholderia sp. strain RASC. Plasmid pEMT8 lacked genes that exhibited significant levels of homology to tfdB and tfdCDEF. Moreover, cell extracts from A. eutrophus(pEMT8) cultures did not exhibit TfdB, TfdC, TfdD, and TfdE activities, whereas cell extracts from A. eutrophus(pEMT8)(pBH501aE) cultures did. These data suggest that pEMT8 encodes only tfdA and that this gene can effectively complement the tfdA deletion mutation of pBH501aE.

2,4-Dichlorophenoxyacetic Acid↗

The newly characterized colicin Y provides evidence of positive selection in pore-former colicin diversification.

Two evolutionary mechanisms have been proposed in the process of protein diversification of the large family of antimicrobial toxins of Escherichia coli, known as the colicins. Data from previous studies suggest that the relatively rare nuclease colicins appear to diversify primarily through the action of positive selection, whilst the more abundant pore-former colicins appear to diversify through the action of recombination. The complete DNA sequence of the newly characterized colicin plasmid, pCol-Let, isolated from a Yanomama Indian of South America, is presented here. This plasmid encodes a newly identified pore-former colicin, colicin Y. DNA and protein sequence comparisons of the colicin Y gene cluster and the encoded proteins with those of published pore-former colicins provide the first evidence that positive selection may also act to increase pore-former colicin diversity.

Colicins↗

Trade-off between segregational stability and metabolic burden: a mathematical model of plasmid ColE1 replication control.

A model of ColE1 copy number control has been developed where molecular details of replication are connected both to segregational stability and metabolic burden. Efficient replication control reduces copy number variation and increases segregational stability for a given average copy number. Copy number variation is predicted to depend on the type of inhibition mechanism as well as RNA I and RNA II turnover rate constants. It is shown that when both RNA I and RNA II transcription frequencies and the rate constant for degradation of free RNA I are very large, a hyperbolic inhibition mechanism must compensate with a 1.4 times greater average copy number to obtain the same segregational stability as an exponential inhibition mechanism. How sensitively the replication frequency responds to changes in RNA I concentration depends on the type of inhibition mechanism and the number of attempts to form an RNA II replication primer per plasmid and cell cycle. If RNA I is too stable, it will not follow changes in plasmid concentration closely, and when the transcription frequency for RNA I is only slightly higher than for RNA II, RNA I concentration becomes randomized. In both these cases, the proportionality between the single cell RNA I and plasmid concentrations is lost and this impairs copy number control. Thresholds in the rate for degradation of free RNA I as well as in RNA I and RNA II transcription frequencies have been computed, where an increase in these rate constants has a negligible effect on segregational stability but a corresponding decrease leads to segregational disaster. This indicates that there exists a well defined optimal set of rate constants where the regulation system works well without excessive metabolic load. A number of new experiments are suggested to address features of particular importance for the evolution of ColE1 copy number control.

DNA Replication↗

Whole genome sequencing of Yersinia pestis isolates from Central Asian natural plague foci revealed the role of adaptation to different hosts and environmental conditions in shaping specific genotypes.

The genetic diversity and biovar classification of Yersinia isolates from Central Asia were investigated using whole-genome sequencing. In total, 98 isolates from natural plague foci were sequenced using the MiSeq platform. Computational pipelines were developed for accurate assembly of Y. pestis replicons, including small cryptic plasmids, and for identifying genetic polymorphisms. A panel of 99 diagnostic polymorphisms was established, enabling the distinction of dominant Medievalis isolates derived from desert and upland regions. Evidence of convergent evolution was observed in polymorphic allele distributions across genetically distinct Y. pestis biovars, Y. pseudotuberculosis, and other Y. pestis strains, likely driven by adaptation to similar environmental conditions. Genetic polymorphisms in the napA, araC, ssuA, and rhaS genes, along with transposon and CRISPR-Cas insertion patterns, were confirmed as suitable tools for identifying Y. pestis biovars, although their homoplasy suggests limited utility for phylogenetic inference. Notably, a novel cryptic plasmid, pCKF, previously associated with the strain of the population 2.MED0 from the Central-Caucasus high-altitude autonomous plague focus, was detected in a genetically distinct isolate of 2.MED1 population from the Ural-Embi region, indicating potential plasmid transfer across the 2.MED lineage. These findings emphasize the need for ongoing genomic surveillance to monitor the spread of virulence-associated genetic elements and to improve our understanding of Y. pestis evolution and ecology.

Yersinia pestis↗

Sequence, transcription activity, and evolutionary origin of the R-body coding plasmid pKAP298 from the intracellular parasitic bacterium Caedibacter taeniospiralis.

We isolated the intracellular parasitic bacterium Caedibacter taeniospiralis from cultures of the freshwater ciliate Paramecium tetraurelia strain 298. Plasmid pKAP298 as well as the total RNA were isolated from the bacteria. pKAP298 was totally sequenced (49.1 kb; NCBI accession number AY422720). From southern blots of pKAP-fragments and Digoxigenin-labeled cDNA of the Caedibacter-RNA, we generated transcription maps of pKAP298. The observed transcription activity indicated functions of the plasmid besides the synthesis of the R-body, a complex protein inclusion associated with toxic effects of Caedibacter cells on host paramecia. We identified 63 potential protein coding regions on pKAP298, and a novel transposon as well as known transposons were characterized. A group II intron was identified. Homologies with putative phage genes were detected on pKAP298 that direct to the evolution of pKAP298 from a bacteriophage. This original phage most probably belonged to the Caudovirales. Hints on a toxin coding region of pKAP298 are given: a protein with homology to the Soj-/ParA-family also has homologies to a membrane associated ATPase, which is involved in eukaryotic ATPase dependent ion carriers and may be associated with toxic effects on paramecia ingesting this protein.

Alphaproteobacteria↗

Revisiting the molecular evolutionary history of Shigella spp.

The theory that Shigella is derived from multiple independent origins of Escherichia coli (Pupo et al. 2000) has been challenged by recent findings that the virulence plasmids (VPs) and the chromosomes share a similar evolutionary history (Escobar-Paramo et al. 2003), which suggests that an ancestral VP entered an E. coli strain only once, which gave rise to Shigella spp. In an attempt to resolve these conflicting theories, we constructed three phylogenetic trees in this study: a robust chromosomal tree using 23 housekeeping genes from 46 strains of Shigella and enteroinvasive E. coli (EIEC), a chromosomal tree using 4 housekeeping genes from 19 EcoR strains and 46 Shigella/EIEC strains, and a VP tree using 5 genes outside of the VP cell-entry region from 38 Shigella/EIEC strains. Both chromosomal trees group Shigella into three main clusters and five outliers, and strongly suggest that Shigella has multiple origins within E. coli. Most strikingly, the VP tree shows that the VPs from two main Shigella clusters, C1 and C2, are more closely related, which contradicts the chromosomal trees that place C2 and C3 next to each other but C1 at a distance. Additionally, we have identified a complete tra operon of the F-plasmid in the genome sequence of an EIEC strain and found that two other EIEC strains are also likely to possess a complete tra operon. All lines of evidence support an alternative multiorigin theory that transferable diverse ancestral VPs entered diverse origins of E. coli multiple times during a prolonged period of time, resulting in Shigella species with diverse genomes but similar pathogenic properties.

Chromosomes, Bacterial↗

Comparison of the meta pathway operons on NAH plasmid pWW60-22 and TOL plasmid pWW53-4 and its evolutionary significance.

The regulated meta pathway operon for the catabolism of salicylate on the naphthalene plasmid pWW60-22 was cloned into the broad-host-range vector pKT230 on a 17.5 kbp BamHI fragment. The recombinant plasmid conferred the ability to grow on salicylate when mobilized into plasmid-free Pseudomonas putida PaW130. A detailed restriction map of the insert was derived and the locations of some of the genes were determined by subcloning and assaying for their gene products in Escherichia coli and P. putida hosts. The existence of a regulatory gene was demonstrated by the induction of enzyme activities in the presence of salicylate. DNA-DNA hybridization indicated a high degree of structural homology between the pWW60-22 operon and the analogous meta pathway operon on TOL plasmid pWW53-4. The data are consistent with the structural genes being arranged in an identical linear array and suggest an evolutionary link between the two catabolic systems.

Biological Evolution↗

Global epidemiology, genomic evolution, and clinical implications of dual- and multiple-carbapenemase-producing Klebsiella pneumoniae: A systematic qualitative review.

BACKGROUND: The global emergence of dual- and multiple-carbapenemase-producing Klebsiella pneumoniae, particularly isolates co-harbouring blaNDM and blaOXA-48/OXA-48-like determinants, represents a critical threat to global health because of limited therapeutic options and expanding genomic complexity. METHODS: This systematic qualitative review synthesized evidence from 44 English-language peer-reviewed studies published between 2017 and 2026 and indexed in Scopus, with a focus on genomic evolution and spatiotemporal distribution. RESULTS: High-risk clones ST147, ST101, and ST11 were identified as major drivers of dissemination. Genomic analysis revealed key adaptive mechanisms, including stable IncL 96-kb fusion plasmids and IS10-mediated truncation of blaNDM-1, potentially reducing fitness costs while preserving resistance. Convergence events were also documented in which dual-carbapenemase-producing isolates acquired additional colistin resistance determinants (mcr-1 or mgrB alterations) and virulence-associated markers such as iuc1. Importantly, related resistance determinants were identified beyond hospital settings, including community, environmental, and food-associated reservoirs. CONCLUSION: The shift from single to dual and multiple carbapenemase production in K. pneumoniae underscores the need for integrated genomic surveillance, improved antimicrobial stewardship, and broader reservoir monitoring to address this evolving public health threat.

Klebsiella pneumoniae↗

Plasmid pBP136 from Bordetella pertussis represents an ancestral form of IncP-1beta plasmids without accessory mobile elements.

The complete 41,268 bp nucleotide sequence of the IncP-1beta plasmid pBP136 from the human pathogen Bordetella pertussis, the primary aetiological agent of whooping cough, was determined and analysed. This plasmid carried a total of 46 ORFs: 44 ORFs corresponding to the genes in the conserved IncP-1beta backbone, and 2 ORFs similar to the XF1596 and XF1597 genes with unknown function of the plant pathogen Xylella fastidiosa. Interestingly, pBP136 had no accessory genes carrying genetic traits such as antibiotic or mercury resistance and/or xenobiotic degradation. Moreover, pBP136 had only two of the kle genes (kleAE) that have been reported to be important for the stability of IncP-1 plasmid in Pseudomonas aeruginosa. Phylogenetic analysis of the Kle proteins revealed that the KleA and KleE of pBP136 were phylogenetically distant from those of the present IncP-1 plasmids. In contrast, IncC1 and KorC, encoded upstream and downstream of the kle genes respectively, and the replication-initiation protein, TrfA, were closely related to those of the IncP-1beta 'R751 group'. These results suggest that (i) pBP136 without any apparent accessory genes diverged early from an ancestor of the present IncP-1beta plasmids, especially those of the R751 group, and (ii) the kle genes might be incorporated independently into the backbone region of the IncP-1 plasmids for their stable maintenance in various host cells.

Bacterial Proteins↗