Streptococcus mutans

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Streptococcus mutans
Gram stain of S. mutans in thioglycollate broth culture.
Gram stain of S. mutans in thioglycollate broth culture.
Scientific classification
Kingdom: Bacteria
Phylum: Firmicutes
Class: Cocci
Order: Lactobacillales
Family: Streptococcaceae
Genus: Streptococcus
Species: S. mutans
Binomial name
Streptococcus mutans
Clarke 1924

Streptococcus mutans is a Gram-positive, facultatively anaerobic bacteria commonly found in the human oral cavity and is a significant contributor to tooth decay.[1][2] The microbe was first described by Clarke in 1924.[3]

Contents

[edit] Role in tooth decay

Along with S. sobrinus, S. mutans plays a major role in tooth decay, metabolizing sucrose to lactic acid.[2] The acidic environment created in the mouth by this process is what causes the highly mineralized tooth enamel to be vulnerable to decay. S. mutans is one of a few specialized organisms equipped with receptors that help for better adhesion to the surface of teeth. Sucrose is utilized by S. mutans to produce a sticky, extracellular, dextran-based polysaccharide that allows them to cohere to each other forming plaque. S. mutans produces dextran via the enzyme dextransucrase (a hexosyltransferase) using sucrose as a substrate in the following reaction:

n sucrose → (glucose)n + n fructose

Sucrose is the only sugar that S. mutans can use to form this sticky polysaccharide.[1]

Conversely, many other sugars—glucose, fructose, lactose—can be digested by S. mutans, but they produce lactic acid as an end product. It is the combination of plaque and acid that leads to dental decay.[4] Due to the role the S. mutans plays in tooth decay, there have been many attempts to make a vaccine for the organism. So far, such vaccines have not been successful in humans.[5] Recently, proteins involved in the colonization of teeth by S. mutans have been shown to produce antibodies that inhibit the cariogenic process.[6]

[edit] Genome

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The S. mutans genome sequence was determined using a shotgun high-throughput sequencing approach as described [7]. The genome of S. mutans UA159, a serotype c strain, has been completely sequenced and is composed of 2,030,936 base pairs. It contains 1,963 ORFs, 63% of which have been assigned putative functions. The genome analysis provides further insight into how S. mutans has adapted to surviving the oral environment through resource acquisition, defense against host factors, and use of gene products that maintain its niche against microbial competitors. S. mutans metabolizes a wide variety of carbohydrates via nonoxidative pathways and all of these pathways have been identified, along with the associated transport systems whose genes account for almost 15% of the genome. Virulence genes associated with extracellular adherent glucan production, adhesins, acid tolerance, proteases, and putative hemolysins have been identified. Strain UA159 is naturally competent and contains all of the genes essential for competence and quorum sensing. Mobile genetic elements in the form of IS elements and transposons are prominent in the genome and include a previously uncharacterized conjugative transposon and a composite transposon containing genes for the synthesis of antibiotics of the gramicidin bacitracin family. However, no bacteriophage genomes are present.

[edit] Genomic insights

The complete genome sequence of S. mutans enables a better understanding of the complexity and genetic specificity of this organism. This Streptococcus, unlike the related pathogens S.pyogenes and S. pneumoniae, is part of the human oral flora, and only incidentally an oral pathogen. As such, it differs from the pathogenic streptococci in several aspects of its basic physiology and in its adaptations to maintain an ecological niche. As the genome analysis shows, S. mutans is able to metabolize a wider variety of carbohydrates than any other Gram-positive organism sequenced to date and can synthesize all of its required amino acids. To complement the number of carbohydrates it can use, S. mutans devotes a large portion of its coding potential (almost 15%) to various transport mechanisms. The number of proteases, peptidases, and other exoenzymes produced by S. mutans clearly suggests that it derives resources from host tissues. The analysis of the genome sequence showed that around 16% of the predicted ORFs specified unique genes and revealed the presence of many previously uncharacterized genes predicted to be involved in virulence, transport, and gene regulation. These discoveries provide a basis for future drug development and new approaches in prevention and treatment of dental caries.

[edit] General Findings

General Findings. The genome of S. mutans strain UA159 is organized in one circular chromosome of 2,030,936 base pairs. The average GC content of 36.82% is similar to that of other low GC organisms. It possesses 65 tRNAs and five rRNA operons. The protein-coding sequences represent 85.66% of the genome and are organized in 1,963 ORFs, with an average gene length of 885 bases. The ORFs are arranged so that transcription is biased in the direction of DNA replication with 78% of the genes encoded on the leading strand. The average GC content of the gene-coding sequences is 37.54%.. Of the total number of predicted ORFs, 63% have assigned putative function, 21% have homologs from different species, although their function is unknown, and 16% are unique to S. mutans. This distribution of ORFs is similar to that found in other bacterial genomes sequenced to date. Comparison of all S. mutans UA159 ORFs with the coding regions of several other Gram-positive organisms showed the greatest extent of similarity to S. pneumoniae and S. pyogenes. [8]

[edit] Cell Division and Cell Wall Synthesis

Several clusters of genes involved in cell division were found in the UA159 genome, including those conserved in most bacteria. Additionally, there are more than 60 proteins responsible for cell envelope biogenesis, including 5 penicillin-binding proteins, 3 ABC transporters, 10 glycosyltransferases, and 6 autolysins. Autolysins are responsible for the selective removal of cell wall peptidoglycan and can be classified in different groups according to the type of peptidoglycan bond they hydrolyze [9]. S. mutans shows enormous variability in chain length, which suggests that it has autolysins and that they are regulated. In fact, Clark named this organism ‘‘mutans’’ because of the observed changes in cell shape (probably due to wall remodeling) depending on growth conditions.[10]. Four types of predicted autolysins were found in UA159 including muramidase (amidase 4; SMU.76), amidase 2 (SMU.704) that is similar to the autolysins from Listeria monocytogenes, Listeria innocua, and Staphylococcus caprae, an endolysin (SMU.707) homologous to one associated with a bacteriophage from S. pyogenes, and the LrgB family protein (SMU.574) similar to the putative autolysin of S. aureus. Two more ORFs that encode a potential lytic transglycosylase (SMU.2147) and an additional LrgB family protein (SMU.1700) were also identified. However, autolysins that belong to the LytC, LytD, endopeptidase II, and lysostaphin families characteristic of bacillus and staphylococcus species were not present in UA159.

[edit] Metabolic Pathways

Carbohydrate metabolism is a key survival strategy for S. mutans, and current knowledge about sugar metabolism of this organism combined with genome data suggests that S. mutans is capable of metabolizing a wider variety of carbohydrates than any other Gram-positive organism sequenced to date. Genes for transport and metabolism of glucose, fructose, sucrose, lactose, galactose (via Leloir and tagatose 6-phosphate pathways), mannose, cellobiose,glucosides, trehalose, Maltose/maltodextrin, raffinose, ribulose, melibiose starch, isomaltosaccharides, and possibly sorbose are found in the genome. In addition to sugars, S. mutans is able to convert several sugar-alcohols to glycolytic intermediates, and the genes for metabolism of mannitol and sorbitol (glucitol) are also present. Among the newly identified gene clusters is one responsible for the synthesis and degradation of starch (SMU.1535– 1541) that includes pullulanase. Further, two key enzymes of the nonoxidative branch of the pentose-phosphate pathway , ribose-phosphate epimerase (rpe), and ribose-phosphate isomerase (rpiA) are found in UA159. This finding, in conjunction with the presence of a phosphotransferase system (PTS) transporter for pentose, suggests that S. mutans is able to synthesize and use certain pentoses. A second copy of sugar-phosphate isomerase with sequence similarity to rpiB from Escherichia coli was also found (SMU.2142). The fermentation of carbohydrates by S. mutans is the principal source of energy production for the organism. A complete glycolytic pathway was found in UA159, leading to the production of pyruvate that is then reduced to various fermentation products (lactic acid, formate, ethanol, and acetate). These metabolic processes are important for oxidation of NADH, as well as synthesis of an additional ATP due to conversion of pyruvate to acetate. The enzymes responsible for pyruvate metabolism found in S. mutans include pyruvate dehydrogenase, pyruvate formate/lyase (the anaerobic counterpart of pyruvate dehydrogenase), phosphotransacetylase, acetate kinase, lactate dehydrogenase, alcohol dehydrogenase, and a newly identified acetoin dehydrogenase. Streptococci are incapable of aerobic respiratory metabolism [11], and the genes required for the aerobic electron transport chain were not present. S. mutans possesses an incomplete tricarboxylic acid (TCA) cycle and the primary role of the existing TCA enzymes is most likely synthesis of amino acid precursors [12]. Because most S. mutans strains can grow in vitro on minimal medium supplemented with only a few amino acids [13], and because some strains can be cultured anaerobically with ammonia as the sole nitrogen source [14], it was not surprising that all amino acid biosynthetic pathways were identified in the genome. Indeed, UA159 can grow on minimal medium devoid of amino acids if thiosulfate is provided for cysteine biosynthesis (data not shown). Analysis of the histidine operon organization revealed that in addition to eight his genes, two other ORFs were present, one that encodes a protein of unknown function, and another that has sequence similarity to phosphoserine phosphatase (SerB) from several organisms. Although the presence of unrelated ORFs in the his operon is not unusual for Gram-positive bacteria [15], the presence of a gene for the synthesis of another amino acid was not expected, and might indicate regulation of serB and his genes. The acidification of the local environment by the end products of metabolism inhibits many competing bacterial species, enabling S. mutans to maintain its niche, and incidentally causing dental caries in the host. Acid tolerance of S. mutans is based primarily on the presence of a membrane-bound, acid-stable, proton-translocating F0F1 ATPase that can maintain the intracellular pH at 7.5 [16], and all genes encoding components of this ATPase are present in the genome. In addition to this mechanism, some oral streptococci use the arginine deiminase pathway to survive a decrease in environmental pH. Although the enzyme arginine deiminase was not found in the genome, the other enzymes of this pathway, including ornithine carbamoyltransferase and carbamate kinase, were identified. Moreover, an amino acid antiporter different from that described for other arginine deiminase operons is a component of the same gene cluster (SMU.262–265), indicating that UA159 may utilizes an unknown amino acid (possibly agmatine) in this pathway. In addition to acid, other environmental changes can trigger a variety of adaptive responses in this organism, and the expression of numerous genes is affected following exposure to oxidative, osmotic, heat, or starvation stress [17]. Genes previously demonstrated to be involved in general stress responses of S. mutans were all identified in UA159. In addition, several proteases possibly involved in the stress response and more than 30 other stress-related proteins are present, including cold-shock (SMU.957) and alkaline-shock (SMU.228) protein homologs. S. mutans lacks cytochromes, heme-containing proteins, and catalases [18], but is able to grow in the presence of oxygen, and all genes previously reported to be involved in oxidative stress were present in UA159. In addition, a previously uncharacterized glutathione reductase (SMU.140), two thioredoxin reductases (SMU.463 and SMU.869), a glutaredoxin (SMU.669), and a thiol peroxidase (SMU.924) were also found.

[edit] Transport

S. mutans UA159 contains more then 280 genes associated with various transport systems, accounting for almost 15% of the total ORFs. Most of the identified transporters are ATP dependent, a characteristic observed in other organisms lacking an electron transport chain. Three types of solute transporting ATPases are present: P-type, F-type, and ABC-type. The P-type ATPases are predicted to be responsible for the transport of calcium and potassium, as well as bacterial resistance to the toxic metals copper and cadmium. F-type ATPases (F0F1 ATPases)use an electrochemical gradient of H+ or Na+ to synthesize ATP, or they hydrolyze ATP to reverse an electrochemical gradient [19]. As mentioned earlier, one H_-transporting ATP synthase- ATPase was found in the S. mutans genome. ABC-type ATPases are the most abundant, with more than 60 ABC transporters in the genome, which accounts for almost 10% of the total number of S. mutans ORFs. About one-third of all ABC transporters are categorized as importers, whereas the rest are exporters, suggesting that this organism is capable of actively exporting excess and harmful molecules. ABC transporters exhibit specificity for different substrates: amino acids, carbohydrates, oligopeptides, osmoprotectants (proline_glycine betaine, choline), inorganic ions (Fe3+, Co2+, Mn2+, Zn2+, phosphate, nitrate, sulfate, and molybdenum), bacteriocins, and DNA. Despite the fact that S. mutans synthesizes glutamine, it also possesses five predicted glutamineABC transporters, emphasizing the importance of this amino acid as a principal source of nitrogen and a substrate for amino acid biosynthesis in S. mutans. Three types of transport facilitators are also found in UA159. The first type specifies a pore-type mechanism known to facilitate glycerol uptake in prokaryotes [20]. A second type of facilitator is represented by several solute–cation symporters with a common characteristic that Na+ is used for generation of membrane potential for solute (usually amino acid) transport. A third type involves solute–solute antiporters, present in virtually all living organisms, and the UA159 strain possesses at least one amino acid antiporter of this type (SMU.263). In addition to these transport mechanisms, putative transport proteins have been identified for the uptake of essential inorganic nutrients (K+, Fe2+, Mn2+, nitrite, Mg2+, and Co2+), efflux of toxic metal ions (Co2+, Zn2+, Cd2+, and Tl+), and undefined molecules. In some cases, both uptake systems and efflux transporters are present for ions that are both essential and toxic (Co2+ and Zn2+). The uptake of sugars from the environment is a key component of S. mutans carbohydrate metabolism. Although at least five sugar ABC transport systems exist, including the well described multiple sugar metabolism (MSM) system [21], most sugars are transported by phosphoenolpyruvate sugar PTSs, the apparent primary sugar transport systems of Gram-positive bacteria sequenced to date. They consist of two nonspecific energy coupling components, enzyme I (SMU.675) and a heatstable protein (HPr; SMU.674), and several sugar-specific multiprotein permeases known as enzyme II. The UA159 genome contains 14 PTSs with a variety of enzyme II domains and specificity for different sugars. This strain also possesses putative carbohydrate efflux proteins , presumably for actively transporting sugar intermediates that need to be excreted.

[edit] Virulence Factors

Virulence factors in S. mutans help protect the bacterium against possible host defenses and maintain its ecological niche in the oral cavity, while contributing to its ability to cause host damage. Probable virulence factors include adhesins, glucan-producing and -binding exoenzymes, proteases and cytokine-stimulating molecules. In addition to the factors described below, several other gene products were found in UA159 that may also contribute to the virulence of S. mutans, such are hemolysins, the myosin cross-reactive streptococcal antigen and its paralog, a coiled-coil myosin-like protein, and the genes for transport and assimilation of iron and phosphate.

[edit] Adhesins

S. mutans can adhere to salivary agglutinin, other plaque bacteria, extracellular matrix, and epithelial cell-surface receptors. Two major types of S. mutans adhesins mediate this attachment: cell-surface proteins and sucrose-derived glucans. The major S. mutans surface receptors SpaP (also known as Pac, antigen I/II, B, P1, SR, MSL-1, and IF) and wall associated antigen A (WapA) were found in UA159. In addition, a complete operon for synthesis of cell wall polysaccharides (rhamnose-glucose polymers, RGPs), previously suggested to be involved in adhesion [22], was also found. The SloC protein, an adhesin belonging to the lipoprotein receptor antigen I (LraI) family, was recently characterized [23]. Members of the LraI family were found in a range of bacteria, and have a dual role: transport and adhesion [24]. The presence of lraI operon was confirmed in UA159, and a previously uncharacterized protein was also found possessing the characteristics of a Zn-binding ABC transporter-type lipoprotein that is similar to adhesin AdcA from S. pneumoniae [25].Several genes encoding known and newly characterized proteins similar to streptococcal extracellular matrix-binding proteins were also identified, including the glucan-binding proteins A [26] and C [27] that enable cell aggregation in the presence of dextran. One newly characterized protein (SMU.1449) has sequence similarity to the fibronectin/fibrinogen-binding proteins from S. pneumoniae[28] and S. pyogenes[29] (66% identity and 77% similarity). Fibronectin binding of S. mutans has been reported recently[30], and therefore SMU.1449 might indeed be responsible for fibronectin binding in S. mutans. Another protein (SMU.360) was found in UA159 that showed 89% identity and 94% similarity to the S. pyogenes plasmin receptor[31]. This protein is also similar to glyceraldehyde-3-phosphate dehydrogenase, suggesting that this protein might be an enzyme with plasmin-binding activity.

[edit] Exoenzymes

S. mutans UA159 has the genes to produce many exoenzymes involved in extracellular sucrose metabolism, including well known glucosyltransferases I, SI, and S, fructanase, fructosyltransferase, and dextranase. The gbpB (also known as sagA) gene that encodes a putative peptidoglycan hydrolase [32] important for cell wall integrity [33] and glucan binding[34] is also present. In addition to these previously described gene products, a previously uncharacterized gene encoding putative exoenzyme was found and named gbpD. A motif search of the GbpD protein sequence showed the presence of a putative signal peptide with a predicted cleavage site and three tandem copies of the ‘‘A’’ repeat identified in the glucan-binding domain of glucosyltransferase [35] and other glucan-binding proteins [36] [37]. There is evidence that GbpD binds glucan (R. R. B. Russell, personal communication).

[edit] Proteases

S. mutans proteases contribute to virulence and are involved in the breakdown of host proteins for bacterial nutrition [38] and the direct degradation of host structural proteins [39]. These streptococcal proteases might also be involved in the destruction of some components of the host immune system because a previously uncharacterized putative C3-degrading protease homolog (SMU.399) was identified. Overall, strain UA159 possesses numerous proteases, including the ATPdependent Clp and FtsH proteases, and has at least 15 peptidases, indicating that it is capable of using the peptides generated by these proteases, as well as by those of other bacteria in plaque. Several proteases potentially involved in surface processing were also identified, including the serine protease HtrA, involved in bacterial stress responses [40], and a protease homologous to the HtpX protease from Streptococcus gordonii [41]. In addition, several previously uncharacterized predicted surface or extracellular proteases were identified, including three Zn-dependent proteases (SMU.160, SMU.1438, and SMU.1784), two proteases related to collagenase (SMU.759 and SMU.761), a serine protease RgpF, and a membrane protease (stomatin/prohibitin homolog; SMU.235). S. mutans lacks a homolog of the wall anchored cell-surface proteases (PrtP of L. lactis and C5a peptidase of S. pyogenes).

[edit] Other surface and extracellular proteins

Analysis of the genome ORFs revealed the presence of a large number of putative surface and extracellular proteins that are possibly involved in attachment and the stimulation of the immune system. Surface and secreted proteins of UA159 were detected using a search for specific motifs. There are 271 membrane, surface, and/or secreted proteins that have a predicted signal peptide, and of these, 135 have a possible cleavage site. In accordance with the large number of these proteins, five signal peptidases (type I and itshomologue, type II and IV, and lipoprotein signal peptidase) were found in the genome. Forty-seven putative lipoproteins were identified with a lipoprotein lipid attachment site motif . Further analysis using a revised lipoprotein motif [42] suggests that the actual number of S. mutans lipoproteins may be lower . In addition, five proteins were found with the tandem ‘‘A’’ repeats characteristic of glucan-binding domains . Four of these proteins were characterized before (GtfS, GtfSI, GtfI, and GbpA), and the fifth is the previously uncharacterized predicted extracellular protein, GbpD. The sortase target motif (LPxTG motif) was found in ten proteins, but is properly positioned at the C terminus in only six of the proteins: the previously reported FruA, SpaP, WapA, DexA, and GbpC, and a previously uncharacterized secreted protein, WapE, that appears to be wall associated (R. R. B. Russell, personal communication). The single S. mutans sortase responsible for anchoring of surface proteins was also identified and is an ortholog of the enzyme from several Gram-positive species [43][44].

[edit] Regulation and Signaling

The UA159 genome contains the major sigma factor (sigma70, RpoD) and as found in other sequenced streptococcal and L. lactis genomes, sigma B, a general stress transcription factor of B. subtilis and S. aureus, was not found. Another possible sigma factor is comX, a homologue of the alternate sigma factor found in S. pneumoniae and S. pyogenes [45]. However, unlike S. pneumoniae or S. pyogenes, only one copy of comX is present in the UA159 genome. Multiple sigma factors are characteristic of free-living bacteria and 18 were found in B. subtilis [46]. However, bacterial pathogens that are highly specialized for a particular environmental niche typically encode 1–4 sigma factors [47], a number consistent with that found in S. mutans. More than 100 transcriptional regulators, thirteen putative two-component regulatory systems (TCS) and one independent response regulator, five antiterminators, and homologs of the NusA and NusB proteins that are involved in termination in B. subtilis and E. coli [48] were identified. As with the other streptococci for which genome information is available, no homolog of the rho transcription terminator was found. Additionally, the genes encoding the global regulatory catabolite repressor protein CcpA [49] and a homologue of the stringent response protein RelA from S. pyogenes [50] were also found. A previously uncharacterized protein that is 54% similar to Rgg, a positive regulator of gtfG in S. oralis [51]and S. gordonii [52], was also found. Unlike these organisms, S. mutans rgg is not located upstream of the gtf gene. Whether this gene has a similar regulatory function in S. mutans remains to be determined.

Competence-mediated transformation is one of the mechanisms for horizontal gene transfer occurring between bacterial species. The UA159 strain is naturally competent and possesses an operon (comCDE) dedicated to quorum sensing and competence, composed of genes that encode a peptide pheromone precursor and an associated TCS responsible for regulation of pheromone production [53]. Secretion and processing of the peptide pheromone is accomplished using the ComAB secretion apparatus[54]. In addition to these two operons, the UA159 genome also contains the newly identified genes forDNAuptake (comYA and comYB) that are homologous to the same genes from S. gordonii [55]. Two other pheromone-like peptides and three characteristic peptide ABC transporters that may play some role in cell signaling were also found . The presence of a LuxS synthetase suggests that this strain is also able to synthesize autoinducer 2, a hormone-like molecule involved in cell–cell signaling and proposed to be responsible for crossspecies communication [56]. Therefore, the presence of this gene may be important for plaque formation. Clinically isolated strains of S. mutans often produce bacteriocins that exhibit a wide spectrum of antibacterial activity against competing strains in the oral cavity. Although UA159 is bacteriocin nonproducing strain [57], five bacteriocin-associated genes, similar to the regulatory (scnK and scnR) and immunity genes (scnG, scnE, and scnF) of the S. pyogenes streptococcin A-FF22 gene cluster are present in UA159. However, no genes similar to scnM and scnT, responsible for maturation and transport, were found, implying either a different processing and transport mechanism for this bacteriocin or an inability to produce it. ORFs homologous to mutacin I and lacticin 481 immunity genes [58] were found. Although these proteins may be remnants of lost systems, they probably provide protection from bacteriocins synthesized by other species.

[edit] Mobile Genetic Elements

Mobile genetic elements are prominent features of virtually all bacterial genomes, and in some organisms the associated genes may influence metabolism or pathogenic potential of the organisms. Now that the genomes of several lactic acid bacteria have been determined, the distribution and types of mobile elements found illustrates several important distinctions within this group. In contrast to the closely related low %G_C Gram-positive organisms S. pyogenes, L. monocytogenes, and L. lactis [59], no temperate bacteriophage genomes are detectable in strain UA159. The genomes of S. pneumoniae strains TIGR4 and R6 also had no prophage genomes, and like S. mutans, the pneumococci are naturally competent for transformation. Naturally competent bacteria typically have mechanisms in place to prevent the uptake or incorporation of foreign DNA, and these systems may incidentally prevent bacteriophages from becoming resident in these genomes. However, the presence or absence of prophages in a bacterial genome is not invariably linked to competence: B. subtilis and H. influenzae are both naturally transformable and harbor prophages in their genomes, whereas Neisseria gonorrhoeae resembles S. mutans in being competent but lacking prophages (D. Dyer, personal communication).

The IS3 family of insertion elements is widely distributed in Eubacteria, being found in over 40 Gram-positive and negative species. Seven complete IS3 family elements, as well as 15 fragments, are found in UA159. Six of the IS3 family members are closely related to IS861 from Streptococcus agalactiae [60] and are almost identical at the nucleotide level, suggesting a clonal origin. The seventh family member is a variant of the Streptococcus thermophilus IS1193 element (88% identity; Gen- Bank accession no. Y13713). Strain UA159 contains one probable conjugative transposon (TnSmu1) that is related to but distinct from the well known Tn916 from Enterococcus faecalis. Prominent in the genome is a large transposon-like region (TnSmu2) containing the genes similar to gramicidin and bacitracin synthetases; these genes include some of the largest ORFs found in the genome (one over 8 kb). This large region, over 40 kb, is flanked by remnants of transposases of the ISL3 family, arranged in inverted orientation relative to each other, whose reading frames are disrupted by frameshifts and contain several gene fragments from other IS element families. The nucleotide composition of this region markedly diverges from the genome average, having a %G_C of 28.9%. Such deviations may point to foreign origins of these elements. Although the transposons, IS elements, and fragments are distributed over the entire genome, there are several regions containing clusters of IS elements or remnants, suggesting that these regions may represent ‘‘hot spots’’ for integration.

[edit] See also

[edit] References

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