Evolution of mosaic operons by horizontal gene transfer and gene displacement in situ
© Omelchenko et al.; licensee BioMed Central Ltd. 2003
Received: 22 April 2003
Accepted: 17 July 2003
Published: 29 August 2003
Shuffling and disruption of operons and horizontal gene transfer are major contributions to the new, dynamic view of prokaryotic evolution. Under the 'selfish operon' hypothesis, operons are viewed as mobile genetic entities that are constantly disseminated via horizontal gene transfer, although their retention could be favored by the advantage of coregulation of functionally linked genes. Here we apply comparative genomics and phylogenetic analysis to examine horizontal transfer of entire operons versus displacement of individual genes within operons by horizontally acquired orthologs and independent assembly of the same or similar operons from genes with different phylogenetic affinities.
Since a substantial number of operons have been identified experimentally in only a few model bacteria, evolutionarily conserved gene strings were analyzed as surrogates of operons. The phylogenetic affinities within these predicted operons were assessed first by sequence similarity analysis and then by phylogenetic analysis, including statistical tests of tree topology. Numerous cases of apparent horizontal transfer of entire operons were detected. However, it was shown that apparent horizontal transfer of individual genes or arrays of genes within operons is not uncommon either and results in xenologous gene displacement in situ, that is, displacement of an ancestral gene by a horizontally transferred ortholog from a taxonomically distant organism without change of the local gene organization. On rarer occasions, operons might have evolved via independent assembly, in part from horizontally acquired genes.
The discovery of in situ gene displacement shows that combination of rampant horizontal gene transfer with selection for preservation of operon structure provides for events in prokaryotic evolution that, a priori, seem improbable. These findings also emphasize that not all aspects of operon evolution are selfish, with operon integrity maintained by purifying selection at the organism level.
Operons, clusters of co-transcribed genes that often encode functionally linked proteins, are the principal form of gene organization and regulation in prokaryotes [1, 2]. Comparative analysis of bacterial and archaeal genomes has shown that only a few operons are conserved across large evolutionary distances. In general, gene order in prokaryotes is poorly conserved and prone to numerous rearrangements [3–6]. A detailed analysis of gene order conservation has shown that only 5-25% of the genes in bacterial and archaeal genomes belongs to gene strings (probable operons) shared by at least two distantly related species . The presence of identical or similarly organized operons and suboperons in phylogenetically distant bacterial or archaeal lineages may result from three distinct evolutionary processes. Firstly, inheritance from the respective common ancestor - the core of the ribosomal protein superoperon is a case in point, but such conservation of operon organization is relatively rare; secondly, independent origin of identical operons or suboperons in different lineages; and thirdly, emergence of operons in a single lineage with subsequent dissemination by horizontal transfer. The potential central role of horizontal transfer in the evolution of operon organization of prokaryotic genomes is embodied in the 'selfish operon model' (SOM) [8–10]. This model posits that "the physical proximity of genes in an operon provides no selective benefit to the individual organism but does enhance the fitness of the gene cluster itself, as clusters can be efficiently inherited horizontally as well as vertically" . Under SOM, operons are conceptually analogous to integrating viruses (phages), transposons and other mobile genetic elements, although coregulation of the genes in an operon could be an important selective factor that favors retention of operons during evolution.
Horizontal gene transfer (HGT) events have been classified into distinct categories of acquisition of new genes, acquisition of paralogs of existing genes and xenologous gene displacement whereby a gene is displaced by a horizontally transferred ortholog from another lineage (xenolog ). Each of these types of horizontal transfer is common among prokaryotes, but their relative contributions differ in different lineages . Comparative-genomic analyses by many groups have suggested that, on the whole, horizontal gene transfer had substantial effects, albeit uneven in different lineages, on the gene content of bacterial and archaeal genomes [13–19]. However, in spite of the considerable popularity of the selfish operon theory, we are unaware of systematic studies of horizontal gene transfer events at the level of operons. In part, this is likely to have been caused by the scarcity of experimental data on operon organization in any prokaryote other than Escherichia coli.
Recent phylogenetic analyses of ribosomal proteins revealed several instances of apparent xenologous gene displacement within a conserved operon, in which other genes have not been horizontally transferred; in other words, these operons appear to represent an evolutionary mosaic [20–22]. Another study demonstrated a complicated mosaic organization of the leukotoxin operon in bacteria of the genus Mannheimia (Pasteurella); the observed evolutionary pattern had to be explained through multiple gene transfer events, which led to the hypothesis that, in this case, frequent gene displacement conferred selective advantage onto the bacterium by maintaining antigenic variation . In earlier studies, evolution of operons from gene blocks with distinct evolutionary fates has been considered for rfb operons coding for lipopolysaccharide biosynthesis in enterobacteria .
To assess the role of horizontal gene transfer in the evolution of operons systematically, we undertook phylogenetic analysis of members of highly conserved gene neighborhoods that are predicted to constitute operons . We focused primarily on mosaic operons in which one or more of the genes apparently have been transferred from distantly related species such that the phylogeny of the transferred genes is obviously incongruent with the phylogeny of the remaining genes in the respective operons.
Results and discussion
Identification of horizontal gene transfer
Experimental data on operons in organisms other than E. coli and, to a lesser extent, B. subtilis are scarce. Therefore we used conserved gene pairs and connected gene neighborhoods associated with them as an approximation of operon organization of genes in other prokaryotic genomes. Several studies have suggested strongly that all gene pairs that are conserved in multiple genomes belong to the same operon [7, 25, 26]. Here we used an extremely conservative threshold (conservation of a gene pair in 10 genomes) to ensure that only genuine operons were analyzed. BLASTP searches for potential horizontal gene transfer identified 729 candidate genes (9% of all genes comprising conserved neighborhoods in 41 analyzed genomes), that is, genes whose encoded protein sequences were more similar to homologs from phylogenetically distant taxa than to those from the reference taxon (it might be worth noting that, throughout this analysis, we treated genes as atomic units and did not consider the relatively unlikely possibility of HGT for portions of genes). Phylogenetic analysis of these genes and their neighbors revealed different types of evolutionary events, some of which involve whole operons, whereas others seem to reflect operon mosaicity.
Examples of horizontally transferred operons
Recipient organism and correspondent genes
Other probable recipients
Thermotoga maritima TM0015-TM0018
Aae, Hpy, Bha/Sau
Apparently, the related operon for 2-oxoisovalerate oxidoreductase (TM1758-TM1759) was also transferred from archaea
Bacillus halodurans BH3128-BH3130
No other such operons in Bacillus-Clostridium group members
Putative effector of murein hydrolase
Pyrococcus horikoshii PH1801-PH1802
Allophanate hydrolase subunits
Pyrococcus horikoshii PH0987-PH0988
Paralogous operon acquisition
Vibrio cholerae VC0620-VC0616
It has several another bacterial operons including VC1091-VC1095
Ribonucleotide reductase alpha and beta subunit
Halobacterium sp. VNG2384G VNG2383G
Additional to "archaeal:" Ribonucleotide reductase alpha subunit VNG1644G, beta subunit is apparently lost
Aromatic amino-acid biosynthesis
Halobacterium sp. VNG0384G VNG0386G
Paralogs of this pair are VNG1646G-VNG1647G
Xenologous operon displacement
Histidine biosynthesis suboperon
Pseudomonas aeruginosa PA3151-PA3152
Campylobacter jejuni Cj0297c-Cj0298c
DNA repair SbcDC
Vibrio cholerae VCA0520-VCA0521
DNA gyrase A and B
Halobacterium sp. VNG0887G-VNG0889G
Hbs, Tac, Tvo, Afu,
Streptococcus pyogenes SPy2000-SPy2004
Glutamate synthase complex
Thermotoga maritima TM0394-TM0398
There is another homolog for gene TM0397 of possible archaeal origin
Halobacterium sp. VNG0635G-VNG0637G
Methanothermobacter thermoautotrophicum MTH1727-MTH1734
Examples of probable mosaic operons
General operon function
Horizontally acquired genes
Probable source of horizontally acquired genes
Functions of horizontally acquired genes
Rickettsia prowazekii Rickettsia conorii
Rickettsia prowazekii Rickettsia conorii
RP804 RC1238 Gram-positive bacteria
UU128, UU132_1, UU133, UU134
Epsilon subunit, alpha subunit, delta subunit, delta subunit
A chain protein
Rickettsia prowazekii Rickettsia conorii
Ribosomal proteins, transcription antiterminator, SecE
Preprotein translocase subunit SecE
Aq1968_1_2 two domains
Tryptophan synthase beta chain
Tryptophan synthase alpha chain
Tryptophan synthase beta chain
Bacillus subtilis Bacillus halodurans
Anthranilate/para-aminobenzoate synthases component I
NADH dehydrogenase-like protein
Rickettsia prowazekii Rickettsia conorii
Undecaprenyl pyrophosphate synthase
Succinate dehydrogenase/fumarate reductase
Succinate dehydrogenase subunit C
Mycoplasma genitalium Mycoplasma pneumoniae
Ribosomal protein L34
TM0552 TM0555 TM0554
2-Isopropylmalate synthase 3-Isopropylmalate dehydratase, small subunit 3-Isopropylmalate dehydratase, large subunit
2-Isopropylmalate synthase (LeuA-1) 3-Isopropylmalate dehydrogenase (LeuB)
CAC3172 CAC3173 CAC3174 Archaea
3-Isopropylmalate dehydratase, small subunit 3-Isopropylmalate dehydratase, large subunit 2-Isopropylmalate synthase
Arginine biosynthesis TM1784
Carbohydrate metabolism (glycolysis, gluconeogenesis)
Mycoplasma pneumoniae Mycoplasma genitalium
Heat shock protein (groES)
Mycoplasma pneumoniae, Mycoplasma genitalium
DNA replication, recombination and repair
Holliday junction resolvasome helicase subunit
DNA replication, recombination and repair
Holliday junction resolvasome helicase subunit
Organic radical activating enzyme
Energy production and conversion
Cytochrome b subunit of the bc complex Cytochrome b subunit of the bc complex
dTDP-4-dehydrorhamnose 3,5-epimerase and related enzymes
MTH1789, MTH1790, MTH1791
Gram-positive bacteria Bacteria Bacteria
dTDP-D-glucose 4,6-dehydratase dTDP-4-dehydrorhamnose 3,5-epimerase dTDP-glucose pyrophosphorylase
Below we describe in greater detail several case studies of putative mosaic operons; in each of these cases, in addition to the basic set of 41 species, we included in the analysis the apparent orthologs of the respective proteins from all prokaryotic species in which they were detected, in order to control for possible effects of taxon sampling. We found that, although the details of tree topology inevitably depended on the set of species analyzed, the conclusions regarding HGT were not affected by the inclusion of additional species.
Case studies of mosaic operons
Ribosomal protein L29 gene
Kishino-Hasegawa test for the analyzed cases of apparent xenologous gene displacement in situ
The ruvBgene of Mycoplasma
Undecaprenyl pyrophosphate synthase gene in the lipid biosynthesis operon of Rickettsia
NADH:ubiquinone oxidoreductase subunits in Halobacteriumsp
Lipopolysaccharide biosynthesis operon in Methanothermobacter thermoautotrophicus and Deinococcus radiodurans
Another interesting case of mosaic structure of the same operon is seen in Deinococcus radiodurans (Figure 5a). Deinococcus RfbA shows clear affinity with proteobacteria (Figure 5d), whereas RfbD is of archaeal descent (Figure 5e), with RELL analysis revealing no competing topologies (Table 3). The remaining two genes of this operon in Deinococcus, rfbB (DRA0041) and rfbC (DRA0043), have uncertain phylogenetic affinities (Figure 5b,5c). Thus, as in the case of M. thermoautotrophicus, this operon in Deinococcus was apparently formed through at least two events of xenologous gene displacement in situ and gene shuffling.
Leucine/isoleucine biosynthesis operon
Given the apparent propensity of Thermotoga (and other hyperthermophilic bacteria) for acquisition of archaeal genes via HGT, it seems most likely that the archaeal version of the leuACD suboperon originally entered the bacterial domain via Thermotoga or a related thermophilic bacterium. Formally, in Thermotoga these events could be classified as a combination of paralogous (sub)operon acquisition (TM0554-TM0555 in addition to another paralogous archaeal gene pair TM0291-TM0292) and xenologous gene displacements (genes TM0553, TM0556). In Clostridium, xenologous operon displacement seems to have occurred because the ancestral operon of the Gram-positive type apparently had been lost. The subsequent evolution of this operon in the four organisms proceeded along different paths. Aquifex has lost the operon structure even for the two subunits of 3-isopropylmalate dehydratase (LeuB, LeuD). Different genes in the operons of P. abyssi and C. acetobutylicum have been translocated and several genes probably have been independently accrued (Figure 6a). In both P. abyssi and Thermotoga, the original leuA and leuB genes within the leuABDC core seem to have been independently displaced by bacterial orthologs without a clear affinity with any specific bacterial lineage (Figure 6a). The most likely scenario for evolution of this operon in Thermotoga is that it originated as a Gram-positive type operon and subsequently many genes (or sub-operons) have been displaced in situ through multiple horizontal transfers and a few additional genes have been inserted into the preexisting structure. The alternative but less likely hypothesis involves independent, de novo operon assembly from genes of different phylogenetic affinities. Several other apparent HGT events were detected during the analysis of the phylogenetic trees for leucine biosynthesis genes (DR1614 in LeuD tree, DR1610 in LeuC tree (Figure 6d,e)) but, in these cases, the acquired genes do not belong to conserved operons.
Intragenomic plasticity and inter-species horizontal mobility of operons are thought to be important facets of prokaryotic genome evolution. Indeed, the results presented here indicate that horizontal transfer of entire operons is the most likely explanation for most of the findings of co-localized 'alien' genes in a genome, which is generally consistent with SOM. However, a substantial fraction - approximately 35% - of operons with indications of horizontal transfer events appear to consist of genes with different phylogenetic affinities. Barring artifacts of phylogenetic analysis, which can never be ruled out completely, but appear unlikely given the strong statistical support for the anomalous placement of the genes in question in phylogenetic trees, two evolutionary scenarios for the origin of such mosaic operons are conceivable. The first involves de novo assembly of operons, in part from genes acquired via HGT, whereas the second one postulates in situ xenologous displacement of genes within a resident operon. Analysis of mosaic operons suggested that both scenarios might apply, but in situ displacement is likely to be more frequent. In several cases, in situ displacement seems to have occurred between genomes of distantly related parasitic bacteria that might have shared a host. A sequence of events that is often considered as an alternative to HGT is an ancient duplication with subsequent differential loss of paralogs. However, in the cases analyzed here, this seems to be a particularly remote possibility because a tandem duplication followed by lengthy evolution of both paralogs within the operon would be required to mimic in situ displacement. Tandem pairs of paralogs are uncommon in operons and such a 'smoking gun' was not observed in any of the suspected cases of in situ displacement.
At first glance, in situ gene displacement seems highly unlikely: given the vast evolutionary distance separating the donor and recipient genomes, homologous recombination is out of the question. In cases when the displacing gene(s) is located on the periphery of an operon (for example, Figure 5a), a plausible mechanism could involve initial insertion of the invading gene in the vicinity of the resident operon, followed by deletion of intervening genes (provided these are non-essential). However, when the displacing gene is tucked between resident ones (for example, Figures 4a, 6a), displacement must have occurred with surgical precision. The only conceivable explanation seems to be that HGT is extremely common in the evolution of prokaryotes and so is intragenomic recombination, which provides for rare chance occurrences of in situ displacement. Conceivably, a horizontally acquired gene that displaces the resident ortholog without disruption of operon organization would have its chances of evolutionary fixation greatly increased, hence the apparent disproportional survival of the displacing genes. This explanation does not refute SOM as the conceptual framework explaining the origin of operons but emphasizes the 'altruistic' aspect of the evolution of operons whereby the operon integrity is maintained by strong purifying selection at the organism level.
Materials and methods
Amino acid sequences from 41 completely sequenced prokaryotic genomes were extracted from the Genome division of the Entrez retrieval system  and used as the master species set for this analysis. Bacterial species abbreviations: Aquifex aeolicus (Aae), Bacillus halodurans (Bha), Bacillus subtilis (Bsu), Streptococcus pyogenes (Spy), Staphylococcus aureus (Sau), Clostridium acetobutylicum (Cac), Borrelia burgdorferi (Bbu), Campylobacter jejunii (Cje), Chlamydia trachomatis (Ctr), Chlamydophila pneumoniae (Cpn), Deinococcus radiodurans (Dra), Escherichia coli (Eco), Haemophilus influenzae (Hin), Helicobacter pylori (Hpy), Lactococcus lactis (Lla), Mesorhizobium loti (Mlo), Mycoplasma genitalium (Mge), Mycoplasma pneumoniae (Mpn), Mycobacterium tuberculosis (Mtu), Mycobacterium leprae (Mle), Pasteurella multocida (Pmu), Neisseria meningitidis (Nme), Pseudomonas aeruginosa (Pae), Rickettsia prowazekii (Rpr), Rickettsia conorii (Rco), Synechocystis PCC6803 (Ssp), Thermotoga maritima (Tma), Treponema pallidum (Tpa), Vibrio cholerae (Vch), Xylella fastidiosa (Xfa), Buchnera sp. (Bsp), Caulobacter crescentus (Ccr), and Ureaplasma urealyticum (Uur). Archaeal species abbreviations: Aeropyrum pernix (Ape), Archaeoglobus fulgidus (Afu), Halobacterium sp. (Hsp), Methanothermobacter thermoautotrophicum (Mth), Methanococcus jannaschii (Mja), Pyrococcus horikoshii (Pho), Pyrococcus abyssi (Pab), Thermoplasma volcanium (Tvo), Thermoplasma acidophilum (Tac), Sulfolobus solfataricus (Sso). In addition, the following species were included in the case studies described in the text; bacteria: Agrobacterium tumefaciens (Atu), Bifidobacterium longum (Blo), Brucella melitensis (Rso), Chlorobium tepidum (Cte), Enterococcus faecalis (Efa), Fusobacterium nucleatum (Fnu), Lactobacillus plantarum (Lpl), Leptospira interrogans serovar (Lint), Listeria innocua (Lin), Listeria monocytogenes (Lmo), Nitrosomonas europaea (Neu), Nostoc sp. (Nsp), Oceanobacillus iheyensis (Oih), Ralstonia solanacearum (Rso), Sinorhizobium meliloti (Sme), Streptomyces coelicolor (Sco), Thermoanaerobacter tengcongensis (Tte), Thermosynechococcus elongatus (Tel), Xanthomonas campestris (Xca), Shewanella oneidensis (Son); archaea: Methanopyrus kandleri (Mka), Methanosarcina acetivorans (Mac), Pyrobaculum aerophilum (Pae), Pyrococcus furiosus (Pfu).
Reconstruction of gene neighborhoods
Gene neighborhoods for the 41 compared genomes were reconstructed as previously described . Briefly, the collection of clusters of orthologous groups of proteins from complete genomes (COGs)  was used as the source of information on orthologous relationships for detecting conserved gene pairs. For the purpose of this analysis only 'highly conserved' gene pairs were considered, that is, those formed by genes from two COGs that were present in the same orientation and separated by less than three genes in at least 10 of the compared genomes. This conservative approach was adopted in order to ensure that all analyzed gene pairs belong to the same operon. At the next step, overlapping gene pairs were joined in triplets; each triplet was required to exist in at least one genome. Overlapping triplets were used to construct gene arrays by run search in an oriented graph; a gene array may or may not be found in its entirety in any available genome. Finally, gene arrays that shared at least three COGs were clustered into neighborhoods by using a single-linkage clustering algorithm . Conserved gene pairs that did not belong to the reconstructed gene arrays were also analyzed.
Searching for candidate horizontally transferred genes
The protein sequences encoded by the genes of each neighborhood were searched against the non-redundant protein sequence database (NCBI, NIH, Bethesda) using the BLASTP program. The BLAST hits were analyzed to identify their potential phylogenetic affinity. For each protein, the best hits were identified to the taxon to which the given species belongs (hereinafter, reference taxon) and to other major taxa; hits to closely related species were disregarded (see Table 1S in the additional data file). Proteins that had more significant (lower E-value) hits to a non-reference taxon than to the reference taxon were considered candidates for horizontal transfer and the respective orthologous protein clusters were subject to further phylogenetic analysis as described in the next section. If phylogenetic analysis indicated that a particular gene was likely to be horizontally transferred, phylogenetic trees were built also for the genes predicted to belong to the same operon. When different phylogenetic affinities were found for genes of the same predicted operon, this operon was considered to be 'mosaic'.
Multiple protein sequence alignments were constructed using the T-Coffee program  and positions containing >70% gaps were excluded. Distance trees were constructed by using the least-square method as implemented in the FITCH program of the PHYLIP package [30, 31]. The least-square trees were subjected to maximum-likelihood local rearrangement using the ProtML program of the MOLPHY package, with the JTT-F model of amino acid substitutions [32, 33]. The resulting trees are a surrogate for maximum-likelihood phylogenies; exhaustive maximum-likelihood tree construction is impractical for the number of species analyzed here. Bootstrap analysis was performed for each maximum-likelihood tree using the Resampling of Estimated Log-Likelihoods (RELL) method as implemented in MOLPHY [32–34]. Alternative placements of selected clades in maximum-likelihood trees were compared by using the rearrangement optimization (Kishino-Hasegawa) method as implemented in the ProtML program .
Additional data file
We thank Jeffrey Lawrence for critical reading of the manuscript. Marina V. Omelchenko is supported by a grant from the US Department of Energy (Office of Biological and Environmental Research, Office of Science) grants DE-FG02 01ER63220 from the Genomes to Life Program.
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