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Adaptive changes in bacteria: a consequence of nonlinear transitions in chromosome topology?
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Journal of Theoretical Biology 229 (2004) 361–369
Adaptive changes in bacteria: a consequence of nonlinear transitions in chromosome topology? G.N. Amzallag* The Judea Center for Research and Development, Carmel 90404, Israel Received 19 March 2003; received in revised form 11 January 2004; accepted 6 April 2004
Abstract Adaptive changes in bacteria are generally considered to result from random mutations selected by the environment. This interpretation is challenged by the non-randomness of genomic changes observed following ageing or starvation in bacterial colonies. A theory of adaptive targeting of sequences for enzymes involved in DNA transactions is proposed here. It is assumed that the sudden leakage of cAMP consecutive to starvation induces a rapid drop in the ATP/ADP ratio that inactivates the homeostasis in control of the level of DNA supercoiling. This phase change enables the emergence of local modifications in chromosome topology in relation to the missing metabolites, a first stage in expression of an adaptive status in which DNA transactions are induced. The nonlinear perspective proposed here is homologous to that already suggested for adaptation of pluricellular organisms during their development. In both cases, phases of robustness in regulation networks for genetic expression are interspaced by critical periods of breakdown of the homeostatic regulations during which, through isolation of nodes from a whole network, specific changes with adaptive value may locally occur. r 2004 Elsevier Ltd. All rights reserved. Keywords: Adaptive mutations; cAMP; Cell differentiation; DNA supercoiling; Critical period; Nonlinear dynamics; Phase transition; Genome modifications; Lamarckian evolution
1. Introduction According to the neo-Darwinian paradigm, an organism exposed to a perturbation may only strengthen the homeostatic mechanisms for conservation of its initial equilibrium, or stimulate the expression of genes coding for stress proteins, or even compensate the deformation through induction of an alternative pathway. In this context, novelty results only from random ‘accidents’ in genome duplication lately selected for their contribution to fitness. Common responses to stresses have been described at the cellular level. In bacteria, the specific reprogramming of the protein synthesis patterns observed following stress exposure is regarded as general stress/starvation response (Bernhardt et al., 2003). Also in yeast, the expression of a pool of about 900 genes is modified following exposure to various perturbations (Gasch and *Tel./fax: +972-2-9960061. E-mail address: [email protected] (G.N. Amzallag). 0022-5193/$ - see front matter r 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.jtbi.2004.04.001
Werner-Washburne, 2002). At first sight, these findings confirm the idea that the environment acts as a trigger for expression of a pre-existing response to stress. However, the above-cited authors noticed that ‘‘cells respond independently to each feature of the new environment to provide a composite genomic expression program unique to the combined characteristics of the new conditions’’ (Gasch and Werner-Washburne, 2002). Uniqueness of the modifications observed in genome expression suggests that the adaptive response should not be restricted to combination of expression of a preexisting program and emergence of random mutations. A finely tuned response is generally interpreted as a consequence of a series of feedback regulation for gene expression. This mode of regulation may be effective when expression is tuned independently for each gene, but this situation is rarely encountered. Rather, genes are frequently linked in their regulation, generating a very stable network of expression (Thieffry et al., 1998; Thieffry and Romero, 1999; Kremling et al., 2000; Ravasz et al., 2002). This complex reality challenges the
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classical representation of the genotype–phenotype link, in which each gene may be considered separately for its regulation and its contribution to the phenotype’s fitness (Kuile and Westerhoff, 2001). Networks do not evolve in a linear manner. Exposed to an increasing level of perturbation, they remain stable until a threshold for which the structure is suddenly broken (Gardner and Ashby, 1970; May, 1972; Barkai and Leibler, 1997). This suggests the occurrence of short critical periods during which, despite their constitutive stability, networks may be adaptively restructured. Identified as a fundamental component of harmonious development of pluricellular organisms (Amzallag, 2001, 2004), this phenomenon probably exist at many scales of biological organization (Zhirmunsky and Kuzmin, 1988). This study is an attempt to elaborate a new framework in which, in regard to other scales of organization, the adaptive response in bacteria may emerge from a sudden breakdown in homeostatic regulations of the DNA supercoiling. It is suggested that, after breakdown of the homeostatic mechanisms of regulation, local anisotropies in DNA supercoiling related to gene expression generate hotspots for enzymes involved in DNA metabolism, linking genome modifications to environmentally induced perturbations in the bacterial physiology.
2. The problem of novelty in bacterial adaptation The paradigm assuming that mutations occur before exposure to the selecting milieu (Luria and Delbruck, 1943) has been revisited after identification of postexposure adapted individuals (Shapiro, 1984; Cairns et al., 1988; Foster, 1994). In order to explain this phenomenon, induction of an hypermutable state in which some sequences are amplified has been suggested (Hall, 1990; Sniegowski, 1995), followed by selection of the fittest sequences and their integration back to the genome (Foster, 1993; Lombardo et al., 1999; Radman, 1999). According to this interpretation, the level of random mutations may be enhanced by stress, but the ‘adaptive mutations’ do not challenge the paradigm of independency of genetic changes from the environment. 2.1. Adaptation and punctual mutations In Salmonella exposed to a new environment, the genetic modifications of pre-adapted mutants differ from those observed on individuals adapted few days following stress exposure (Prival and Cebula, 1992). Confirmed in Escherichia coli (Heidenreich and Wintersberger, 2001; Powel and Wartell, 2001), this observation suggests that ‘‘induced’’ and ‘‘pre-existing’’ mutants have not the same origin. Moreover, the
mutations observed on post-exposure adapted individuals are not randomly dispersed in the genome. Rather, they seem to occur in relation to the environmental constraint. For example, the rate of reversions in Trp mutants was increased by tryptophan but not by another amino acid starvation (Hall, 1990, 1995). Frequency of genetic changes is extremely high around the nucleotide artificially inserted (Rosenberg et al., 1994) or within sequences modifying activity of the gene product (Hall, 1997). In mutants of E. coli deprived of the galactose operon, an ability to use galactose has been detected within few days following exposure to a medium in which galactose remains the main source of carbohydrates (Hall, 1982). A de novo emergence of such an ability (including membrane transport of the sugar, its metabolism and a function of regulation of the whole operon) cannot be easily explained through accumulation of a series of random mutations with cumulative adaptive value. As suggested (Opadia-Kadima, 1987), it seems that the genetic modifications occurring after exposure to a new source of carbon are not completely random. 2.2. Large-scale modifications of the genome and ageing The mechanisms underlying adaptive changes are generally investigated through analysis of ‘‘revertant mutants’’. For this reason, the attention has been focused on the mechanisms enabling to compensate a punctual mutation. However, nucleotide substitutions are not the main modifications endured by a genome during the adaptive response. As Galitski and Roth (1996) concluded, ‘‘adaptive mutability should be a more general phenomenon. It should be easily detectable without resorting to complex genetic systems that require transposon or conjugation functions’’. In parallel, the rate of adaptive reversions is reduced in E. coli when enzymes involved in genetic recombination (RecA or LexA) (Foster and Cairns, 1991) or conjugation (Harris et al., 1994, 1996; Rosenberg et al., 1995; Foster and Trimarchi, 1995) are altered. Observations on ageing colonies indicated that largescale DNA modifications represent the most widespread response to environmental changes in bacteria (Naas et al., 1994). Indeed, it seems that site-specific recombination or transposition of mobile elements represent the first adaptive response to perturbation in bacteria (Arber, 1995; Charlebois and St. Jean, 1995). Also in this case, transposition of mobile elements does not occur randomly. This point is confirmed by the strong parallel in modifications of genome expression induced in different lines of E. coli grown in a glucose-limited medium for 20 000 generations (Cooper et al., 2003). A differentiation of bacterial types also occurs in colonies of E. coli grown on agar (Shapiro and Higgins, 1989). The structural organization consecutive to ageing
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seems to reflect a sequential coordination of transposition events according to the environmental conditions (starvation and density of the population). For all these reasons, and as suggested by Hall (1999), adaptive mutations should be integrated in a wider context, in which genome modifications induced by recombination and conjugation become an integrative part of the response to stress.
3. DNA supercoiling: an environment–bacteria interface 3.1. Environmental influence on DNA topology The bacterial chromosome is organized in discrete domains of supercoiling (Rebollo et al., 1988). About 50 domains were identified in the chromosome of E. coli grown in optimal conditions (Sinden and Pettijohn, 1981). Within each domain, the DNA topology creates a supralevel of genome organization linking gene expression to their sequential order (Charlebois and St. Jean, 1995). The ‘gene expression network’ is not a fixed structure. It is, first of all, conditioned by counteracting activities of the DNA gyrase (an ATP dependent enzyme generating the negative supercoiling) and the topoisomerase I (an enzyme relaxing the supercoiling) (Pruss et al., 1982; DiNardo et al., 1982). The supercoiling-dependent activity and regulation of expression of these antagonistic enzymes (Menzel and Gellert, 1983; Tse-Dinh and Beran, 1988; Liebart et al., 1989) generates homeostasis in regulation of the DNA topology. The level of supercoiling is also influenced by physical factors, such as temperature, mono and divalent ions, as well as a large range of organic compounds (Higgins et al., 1988; Kanaar and Cozzarelli, 1992) and by the level of gene expression. Separating the two strands during gene transcription generates a negative supercoiling behind and a positive supercoiling ahead the RNA polymerase (Liu and Wang, 1987; Wu et al., 1988; Pruss and Drlica, 1989; Rahmouni and Wells, 1992). These local changes in topology are stabilized by the large structures generated through the dual link of the transcripted mRNA, both with the template DNA strand and ribosomes (Spirito et al., 1994; Mojica and Higgins, 1996). Moreover, simultaneous transcription and translation (also termed a transertion process) of membrane (or secreted) proteins anchors DNA to the membrane, generating local supercoiling proportional to the level of gene transcription (Lynch and Wang, 1993; Binenbaum et al., 1999). Accordingly, gene transcription influences supercoiling proportionally to the number of nascent mRNA strands, the size of the encoded protein, and difference between the rate of mRNA and protein synthesis, while all these factors are themselves modulated by the concentration of ATP, nucleotides and loaded tRNA
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in the cell. For all these reasons, DNA topology represents a dynamic interface between the environment (direct influence or through expression of specific proteins) and the genome. 3.2. Adaptive changes and DNA topology Gene transcription induces local changes in supercoiling (Cook et al., 1992). In parallel, amplitude of the genome modifications during adaptive response has been related to the level of gene expression in bacteria (Mellon and Hanawalt, 1989) and in yeast (Natsoulis et al., 1989; Datta and Jinks-Roberston, 1995). This is why local supercoiling may serve as a marker for DNA transactions. An analysis of the mutation spectrum in lactose operon of E. coli reveals specific hotspots for deletion, base substitution, duplication and insertion mutations (Schaaper et al., 1986). A large variability is observed in localization of the hotspots, suggesting that they are linked to local modifications in supercoiling (Kazic and Berg, 1990). In parallel, a perturbation in regulation of DNA supercoiling induced by caffeine prevents expression of an adaptive response in bacteria (Grigg and Stuckey, 1966). Indeed, hotspots for genome modifications are identified as palindrome or quasi-palindrome (Collins et al., 1982; Glickman and Ripley, 1984), the sequences the most influenced by changes in supercoiling (Ching et al., 1988). Through a capacity to modify their conformation, they buffer local variations in supercoiling (Young and Ames, 1988). Negative supercoiling regulates the B–Z transition in palindromes (Vologodskii et al., 1992), while only one of the conformation is recognized by promoters or repressors of gene expression (Mojica and Higgins, 1996), or by enzymes of DNA metabolism (Kanaar and Cozzarelli, 1992). These evidences suggest that, through changes in configuration of palindromes, hotspots for genome transaction are generated by local supercoiling constraints. However, homeostasis in regulation of DNA supercoiling does not enable stabilization of local variations. This is why a breakdown of the homeostasis mechanisms of regulation of the DNA supercoiling is required for emergence of an adaptive targeting the DNA sequences.
4. The nonlinear response to starvation in bacteria The adaptive response has sometime been regarded as an integrative part of the reaction to starvation (Shapiro, 1984; Cairns et al., 1988; Mittler and Lenski, 1992; Sniegowski, 1995; Prival and Cebula, 1996). This is confirmed by the fact that starvation stimulates the emergence of adaptive modifications in E. coli (Hall, 1995) and Pseudomonas (Kasak et al., 1997). Adaptive
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mutations and ‘starvation associated mutagenesis’ both include activation of mobile elements (Pfeifer and Blaseio, 1990; Naas et al., 1994; Hall, 1999), punctual mutations (Bridges et al., 1996; McKenzie et al., 2001), and induction of the SOS DNA-repair system (Taddei et al., 1995; McKenzie et al., 2000; Bridges, 2001). The starvation response has been related to cellular capacity to switch on a new physiological state (Weichart et al., 1993; Bouvier et al., 1998; Storchova and Vondrejs, 1999), though the gradual decrease in nutrients concentration. This nonlinear response implies first a breakdown of initial network of regulation of gene expression. 4.1. Homeostatic regulation of DNA supercoiling In E. coli, a sudden transfer to salinity or anaerobic conditions decreases the ATP/ADP ratio. However, the concomitant decrease in negative supercoiling (drop in activity of the ATP-dependent gyrase) is rapidly compensated for (Hsieh et al., 1991a, b). This confirms the active regulation of the level of chromosome supercoiling, isolating the gene expression from shortterm environmental influences on the chromosome topology. For a bacteria, this homeostasis enables to ‘ignore’ transient fluctuations. However, permanency of the perturbation generates a progressive bias between the gene expression pattern and the cellular metabolism. Being a source of abnormal accumulation of secondary metabolites, this homeostatic response progressively represents, by itself, a source of perturbation. When the bias between gene expression and cellular metabolism reaches a critical level, it may induce the stringent response. 4.2. Breakdown of the homeostatic regulations The stringent response is characterized by the rapid degradation of proteins and RNA (Matin et al., 1989) and an enhanced expression of transporters for aminoacid or carbohydrates (Notley and Ferenci, 1995). In contrast, genes coding for enzymes involved in anabolic reactions are inhibited in their expression (Wright, 1996). The stringent response is induced by starvation but its expression depends on changes in supercoiling (Wright, 1996) and accumulation of endoinducers such as cAMP and ppGpp (Haseltine and Block, 1973). Beyond a threshold level of carbon starvation, a sudden increase (30 fold) in production and secretion of cyclic AMP is observed (Buettner et al., 1973). This phenomenon remains enigmatic when consider that 99.9% of the cAMP produced is leaked. Dissipating a significant part of energy of the cell (about 9% of the total ATP at the induction of the stringent response, see Matin and Matin, 1982), this phenomenon has been interpreted as
a ‘suicide response’. However, the sudden drop in the pool of ATP reduces abruptly the negative supercoiling (through a decrease in activity of the DNA gyrase and the rate of transcription/translation). In this perspective, the sudden drop in ATP concentration represents a breakdown of the network of regulation of gene expression. This abrupt changes enable emergence of a new physiological status. For example, the drop in supercoiling is required for the stress-provoked change in transcription protein induced by sigmaS, a proteic factor accumulated during stress exposure (Bordes et al., 2003). Moreover, the cAMP receptor protein (CRP) may act as coactivator or corepressor of the same gene, as a function of the level of DNA supercoiling (Rasmussen et al., 1996). Scale-free networks are characterized by a high degree of robustness in regard to perturbations, but a sudden change in the mostly connected nodes induces a fragmentation of the whole network in isolated parts (Albert et al., 2000). In E. coli, the cAMP receptor protein (CRP) represents the mostly connected node of the scale-free transcription network (Herrgard et al., 2003). For this reason, the sudden modification of the CRP regulation functions also provokes a dismantlement of the initial transcription network concomitant to that generated by the decrease in supercoiling.
5. The adaptive status In starved Salmonella, a new physiological status is induced 72 hours after expression of the stringent response (Kenyon et al., 2002). Similarly, a new phase transition in the DNA structure and conformation have been described for E. coli following expression of the stringent response (Frenkiel-Krispin et al., 2001). These findings suggest that the adaptive response is not a simple extension of the stringent response (Balke and Gralla, 1987). Rather, the stringent response represents the first of a series of discrete changes following starvation. 5.1. Overproduction of cAMP and its effect Overproduction of cAMP is not restricted to the short period of transition towards the stringent physiological status. Rather, the release of cAMP may even increase after its expression (Matin and Matin, 1982). Being leaked out, the endogenous cAMP concentration remains quite constant in bacteria. For this reason, the significance of such an extended overproduction of cAMP remains obscure. In fact, the internal cAMP concentration remains low if the metabolites are released in a large volume in regard to the cell volume. This is the case for bacteria grown in a liquid medium. However, for bacteria living on solid substrates, biotic
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surfaces or colonies or at very high density, a concentration gradient of the leaked metabolite is generated around the cell. In this situation, the cAMP concentration in the starved bacteria increases rapidly and may influence physiological processes. Such a phenomenon has been observed in Pseudomonas, in which cell density interfered with starvation and cAMP on induction of the developmental switch towards virulence (van Delden et al., 2001). Adaptive mutations in bacteria have been especially observed on bacteria grown on a structured (solid) environment (Taddei et al., 1997a, b). The link between adaptive status and increase in internal cAMP concentration is suggested in yeast (Storchova and Vondrejs, 1999). In E. coli, cAMP is also required for expression of the mechanisms involved in adaptive mutations (the LexA-dependent SOS system of mutation repair) (Taddei et al., 1995; Janion et al., 2002). Internal concentration of cAMP modulates gene expression during starvation (Notley and Ferenci, 1995). However, the effect of cAMP depends on its concentration. In Streptomyces griseus, for example, an exogenous supply of high concentration of cAMP inhibits production of ppGpp, a factor involved in expression of the stringent response (Honirouchi et al., 2001). The phenomenon is confirmed by the negative regulation of the cAMP receptor protein by ppGpp in E. coli (Johansson et al., 2000). This antagonism in signals promoting/inhibiting the stringent response suggests that a sudden increase in internal concentration of cAMP is able to provoke a new nonlinear transition from the stringent status. 5.2. Adaptive targeting of the DNA sequences In bacteria grown on agar, ageing generates specific patterns of differentiation in initially homogeneous populations. Regularity of the ‘‘rings of differentiation’’ reveals the occurrence of similar genomic changes at each stage of ageing (Shapiro and Higgins, 1989). Kuan and Tessman (1992) emphasized the importance of cAMP in control of these non-random processes. A similar spectrum of genome modifications was identified in adaptive mutations, long term starvation and activation of the SOS DNA repair system in absence of DNA lesions (Taddei et al., 1995), suggesting that cAMP is also involved in adaptive mutations. In a starved bacteria, the overproduction of cAMP affects activity of the ATP-dependent DNA gyrase. In this context, the level of DNA supercoiling depends mainly on local factors, especially the rate of gene expression (and especially the number of nascent mRNA on the DNA sequence, and the rate of translation of the mRNA before achievement of transcription). By reducing the level of supercoiling, the level of transcription becomes itself mainly regulated
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by the concentration of metabolites in the cell. In such a situation, the level of supercoiling increases for sequences involved in synthesis of the missing metabolites, while it remains low for sequences coding for enzymes producing the metabolites in excess. Thus, the sequences involved in expression of the missing metabolites become a target for genome modifications. The expression of genes involved in anabolic reactions is inhibited in the stringent status (Schultz et al., 1988). This reduces the emergence of local increases in level of supercoiling of sequences coding for anabolism. In the perspective presented here, this process becomes important for two reasons: (i) it increases efficiency of the targeting on sequences coding for enzymes involved in the stimulated catabolic reactions, (ii) it decreases to the maximum the probability of genetic transactions on sequences coding for structural proteins or anabolic processes. Such a protection of sequences coding for anabolic and structural proteins would not be possible through a one-step transition from active growth to adaptive status. But the differences in levels of supercoiling between sequences with adaptive and nonadaptive value is probably increased with time, even after induction of the adaptive status. This may explain why the emergence of adaptive reversion of highly specific modifications is a long-term process, in which bacteria are in a pre-apoptotic status (Janion, 2000). 5.3. The topologically oriented DNA transactions In yeast, activation of mobile elements is preferentially targeted towards the actively transcribed genes (Natsoulis et al., 1989; Adams et al., 1992), so that a direct relationship between hotspots for transposition and local supercoiling has been suggested (Lodge and Berg, 1990). A similar result is observed in E. coli (Kazic and Berg, 1990). The coincidence between hotspots for punctual mutations and sites for DNA-gyrase affinity (Marvo et al., 1983; Saing et al., 1988) confirms this link between topology and DNA transactions. Moreover, the fact that DNA gyrase is required for transposition of mobile elements (Isberg and Syvanen, 1982; Ikeda et al., 1984) and amplification of specific DNA sequences (Kim and Wang, 1989) links these processes to modified structures induced by supercoiling (Glickman and Ripley, 1984). All these observations emphasize the role of the residual DNA supercoiling (proportional to the level of gene expression) in emergence of hotspots with adaptive potential. Many adaptive mutations depend on expression of the RecA gene product (Foster and Cairns, 1991), which is stimulated by a global decrease in level of negative supercoiling (Menzel and Gellert, 1983). This suggests that the expression of enzymes involved in genome transactions coincides with the drop of homeostasis in regulation of the DNA supercoiling, bringing to the ‘adaptive targeting’ described above.
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5.4. Imprinting the adaptive DNA topology The rate of transcription and translation decreases progressively during starvation. For this reason, the local variations in DNA supercoiling issued from gene expression are expected to disappear progressively with time. However, the adaptive response is generally characterized by continuous emergence of growing cells throughout the first 3–7 days of the experiment (Cairns et al., 1988). If adaptation is really conditioned by local variations in supercoiling, this observation implies that the DNA topology generated by transition towards the adaptive status remains stabilized. During normal growth, the HU proteins stabilize a part of the DNA supercoiling independently from gyrase activity (Drlica, 1992; Steck et al., 1993; Tanaka et al., 1995; Malik et al., 1996). Through this influence, the HU proteins strengthen stability of the DNA topology by buffering minor variations in the ATP/ ADP ratio, gene expression and gyrase activity. Affinity of the DNA–HU complex decrease with reduction of the level of supercoiling (Tanaka et al., 1995). This phenomenon seems counteracted by overproduction of HU proteins, and change of their composition (homoor heterodimer) in starved bacteria (Claret and Rouviere-Yaniv, 1997). Such a modification enables first a dissipation of the initial HU–DNA link, followed by stabilization of local topological variations in spite of a decrease in the ATP/ADP ratio, consecutive to the synthesis of new HU proteins following starvation. Another type of histone-like proteins, H-NS, is specifically expressed during the stationary phase (Afflerbach et al., 1999). This protein is known to interact with non-expressed genes by decreasing their level of supercoiling (McGovern et al., 1994). Interestingly, a decrease in the rate of adaptive mutations was observed in E. coli for which the H-NS proteins are overexpressed (Gomez et al., 1997). Accordingly, it is likely that both HU and H-NS proteins are involved in amplifying the topological differences between expressed and non-expressed sequences by eliminating the ‘residual supercoiling’ structures (H-NS proteins) and by stabilizing the local supercoiling modifications related to gene expression (HU proteins). Maintained by non-covalent bonds, this ‘adaptive topology’ is progressively dissipated. This may explain the progressive decrease in adaptive value of the mutations occurring in E. coli cells surviving the 8th day of starvation (Powell and Wartell, 2001).
6. Conclusion The theory proposed here is illustrated mainly by observations issued from experiments performed in another context. This situation does not result from
experimental difficulties, since most of the parts of this theory are testable with the tools currently available. Rather than technical, the problem remains conceptual: there is no room for ‘oriented DNA transactions’ in the linear representation of bacterial response to a perturbation: blind mutations selected by the resulting fitness remain the unique explanation. Reinterpreting observations performed in another context, the current theory suggests that a disruption of the regulation network below the critical level of its spontaneous breakdown (lethality) generates the emergence of an ‘adaptive targeting’ on the bacterial chromosome. This theory has been elaborated from the assumption of homology in basic patterns of adaptation response of cells and multicellular organisms. In plants, for example, the adaptive response to a NaCl-induced perturbation has been related to a sudden, endogenously regulated breakdown of the between-meristem network of relationships (Amzallag, 2002). This phenomenon occurs during specific critical periods, linking adaptive plasticity to the development (Amzallag, 2000, 2004). In both cases, the nonlinear dynamics is generated by a breakdown of the homeostasis regulations, an event required for adaptive modification of the linkages between nodules generating the network. This similarity in response may be understood as a consequence of the primacy of homeostatic regulations in both scales, when exposed to optimal conditions. In both cases, adaptation requires a nonlinear approach of the response to a perturbation, in which adaptation emerges from breakdown of the initially existing network of relationships. Being dependent on the external concentration of cAMP, the nonlinear transition to adaptation depends on the bacterial environment, and especially on bacterial density of the population. This observation suggests to reconsider the linkage between adaptation, ageing, conjugation, quorum sensing and cell differentiation in prokaryotes.
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Adaptive changes in bacteria: a consequence of nonlinear transitions in chromosome topology? G.N. Amzallag* The Judea Center for Research and Development, Carmel 90404, Israel Received 19 March 2003; received in revised form 11 January 2004; accepted 6 April 2004
Abstract Adaptive changes in bacteria are generally considered to result from random mutations selected by the environment. This interpretation is challenged by the non-randomness of genomic changes observed following ageing or starvation in bacterial colonies. A theory of adaptive targeting of sequences for enzymes involved in DNA transactions is proposed here. It is assumed that the sudden leakage of cAMP consecutive to starvation induces a rapid drop in the ATP/ADP ratio that inactivates the homeostasis in control of the level of DNA supercoiling. This phase change enables the emergence of local modifications in chromosome topology in relation to the missing metabolites, a first stage in expression of an adaptive status in which DNA transactions are induced. The nonlinear perspective proposed here is homologous to that already suggested for adaptation of pluricellular organisms during their development. In both cases, phases of robustness in regulation networks for genetic expression are interspaced by critical periods of breakdown of the homeostatic regulations during which, through isolation of nodes from a whole network, specific changes with adaptive value may locally occur. r 2004 Elsevier Ltd. All rights reserved. Keywords: Adaptive mutations; cAMP; Cell differentiation; DNA supercoiling; Critical period; Nonlinear dynamics; Phase transition; Genome modifications; Lamarckian evolution
1. Introduction According to the neo-Darwinian paradigm, an organism exposed to a perturbation may only strengthen the homeostatic mechanisms for conservation of its initial equilibrium, or stimulate the expression of genes coding for stress proteins, or even compensate the deformation through induction of an alternative pathway. In this context, novelty results only from random ‘accidents’ in genome duplication lately selected for their contribution to fitness. Common responses to stresses have been described at the cellular level. In bacteria, the specific reprogramming of the protein synthesis patterns observed following stress exposure is regarded as general stress/starvation response (Bernhardt et al., 2003). Also in yeast, the expression of a pool of about 900 genes is modified following exposure to various perturbations (Gasch and *Tel./fax: +972-2-9960061. E-mail address: [email protected] (G.N. Amzallag). 0022-5193/$ - see front matter r 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.jtbi.2004.04.001
Werner-Washburne, 2002). At first sight, these findings confirm the idea that the environment acts as a trigger for expression of a pre-existing response to stress. However, the above-cited authors noticed that ‘‘cells respond independently to each feature of the new environment to provide a composite genomic expression program unique to the combined characteristics of the new conditions’’ (Gasch and Werner-Washburne, 2002). Uniqueness of the modifications observed in genome expression suggests that the adaptive response should not be restricted to combination of expression of a preexisting program and emergence of random mutations. A finely tuned response is generally interpreted as a consequence of a series of feedback regulation for gene expression. This mode of regulation may be effective when expression is tuned independently for each gene, but this situation is rarely encountered. Rather, genes are frequently linked in their regulation, generating a very stable network of expression (Thieffry et al., 1998; Thieffry and Romero, 1999; Kremling et al., 2000; Ravasz et al., 2002). This complex reality challenges the
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classical representation of the genotype–phenotype link, in which each gene may be considered separately for its regulation and its contribution to the phenotype’s fitness (Kuile and Westerhoff, 2001). Networks do not evolve in a linear manner. Exposed to an increasing level of perturbation, they remain stable until a threshold for which the structure is suddenly broken (Gardner and Ashby, 1970; May, 1972; Barkai and Leibler, 1997). This suggests the occurrence of short critical periods during which, despite their constitutive stability, networks may be adaptively restructured. Identified as a fundamental component of harmonious development of pluricellular organisms (Amzallag, 2001, 2004), this phenomenon probably exist at many scales of biological organization (Zhirmunsky and Kuzmin, 1988). This study is an attempt to elaborate a new framework in which, in regard to other scales of organization, the adaptive response in bacteria may emerge from a sudden breakdown in homeostatic regulations of the DNA supercoiling. It is suggested that, after breakdown of the homeostatic mechanisms of regulation, local anisotropies in DNA supercoiling related to gene expression generate hotspots for enzymes involved in DNA metabolism, linking genome modifications to environmentally induced perturbations in the bacterial physiology.
2. The problem of novelty in bacterial adaptation The paradigm assuming that mutations occur before exposure to the selecting milieu (Luria and Delbruck, 1943) has been revisited after identification of postexposure adapted individuals (Shapiro, 1984; Cairns et al., 1988; Foster, 1994). In order to explain this phenomenon, induction of an hypermutable state in which some sequences are amplified has been suggested (Hall, 1990; Sniegowski, 1995), followed by selection of the fittest sequences and their integration back to the genome (Foster, 1993; Lombardo et al., 1999; Radman, 1999). According to this interpretation, the level of random mutations may be enhanced by stress, but the ‘adaptive mutations’ do not challenge the paradigm of independency of genetic changes from the environment. 2.1. Adaptation and punctual mutations In Salmonella exposed to a new environment, the genetic modifications of pre-adapted mutants differ from those observed on individuals adapted few days following stress exposure (Prival and Cebula, 1992). Confirmed in Escherichia coli (Heidenreich and Wintersberger, 2001; Powel and Wartell, 2001), this observation suggests that ‘‘induced’’ and ‘‘pre-existing’’ mutants have not the same origin. Moreover, the
mutations observed on post-exposure adapted individuals are not randomly dispersed in the genome. Rather, they seem to occur in relation to the environmental constraint. For example, the rate of reversions in Trp mutants was increased by tryptophan but not by another amino acid starvation (Hall, 1990, 1995). Frequency of genetic changes is extremely high around the nucleotide artificially inserted (Rosenberg et al., 1994) or within sequences modifying activity of the gene product (Hall, 1997). In mutants of E. coli deprived of the galactose operon, an ability to use galactose has been detected within few days following exposure to a medium in which galactose remains the main source of carbohydrates (Hall, 1982). A de novo emergence of such an ability (including membrane transport of the sugar, its metabolism and a function of regulation of the whole operon) cannot be easily explained through accumulation of a series of random mutations with cumulative adaptive value. As suggested (Opadia-Kadima, 1987), it seems that the genetic modifications occurring after exposure to a new source of carbon are not completely random. 2.2. Large-scale modifications of the genome and ageing The mechanisms underlying adaptive changes are generally investigated through analysis of ‘‘revertant mutants’’. For this reason, the attention has been focused on the mechanisms enabling to compensate a punctual mutation. However, nucleotide substitutions are not the main modifications endured by a genome during the adaptive response. As Galitski and Roth (1996) concluded, ‘‘adaptive mutability should be a more general phenomenon. It should be easily detectable without resorting to complex genetic systems that require transposon or conjugation functions’’. In parallel, the rate of adaptive reversions is reduced in E. coli when enzymes involved in genetic recombination (RecA or LexA) (Foster and Cairns, 1991) or conjugation (Harris et al., 1994, 1996; Rosenberg et al., 1995; Foster and Trimarchi, 1995) are altered. Observations on ageing colonies indicated that largescale DNA modifications represent the most widespread response to environmental changes in bacteria (Naas et al., 1994). Indeed, it seems that site-specific recombination or transposition of mobile elements represent the first adaptive response to perturbation in bacteria (Arber, 1995; Charlebois and St. Jean, 1995). Also in this case, transposition of mobile elements does not occur randomly. This point is confirmed by the strong parallel in modifications of genome expression induced in different lines of E. coli grown in a glucose-limited medium for 20 000 generations (Cooper et al., 2003). A differentiation of bacterial types also occurs in colonies of E. coli grown on agar (Shapiro and Higgins, 1989). The structural organization consecutive to ageing
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seems to reflect a sequential coordination of transposition events according to the environmental conditions (starvation and density of the population). For all these reasons, and as suggested by Hall (1999), adaptive mutations should be integrated in a wider context, in which genome modifications induced by recombination and conjugation become an integrative part of the response to stress.
3. DNA supercoiling: an environment–bacteria interface 3.1. Environmental influence on DNA topology The bacterial chromosome is organized in discrete domains of supercoiling (Rebollo et al., 1988). About 50 domains were identified in the chromosome of E. coli grown in optimal conditions (Sinden and Pettijohn, 1981). Within each domain, the DNA topology creates a supralevel of genome organization linking gene expression to their sequential order (Charlebois and St. Jean, 1995). The ‘gene expression network’ is not a fixed structure. It is, first of all, conditioned by counteracting activities of the DNA gyrase (an ATP dependent enzyme generating the negative supercoiling) and the topoisomerase I (an enzyme relaxing the supercoiling) (Pruss et al., 1982; DiNardo et al., 1982). The supercoiling-dependent activity and regulation of expression of these antagonistic enzymes (Menzel and Gellert, 1983; Tse-Dinh and Beran, 1988; Liebart et al., 1989) generates homeostasis in regulation of the DNA topology. The level of supercoiling is also influenced by physical factors, such as temperature, mono and divalent ions, as well as a large range of organic compounds (Higgins et al., 1988; Kanaar and Cozzarelli, 1992) and by the level of gene expression. Separating the two strands during gene transcription generates a negative supercoiling behind and a positive supercoiling ahead the RNA polymerase (Liu and Wang, 1987; Wu et al., 1988; Pruss and Drlica, 1989; Rahmouni and Wells, 1992). These local changes in topology are stabilized by the large structures generated through the dual link of the transcripted mRNA, both with the template DNA strand and ribosomes (Spirito et al., 1994; Mojica and Higgins, 1996). Moreover, simultaneous transcription and translation (also termed a transertion process) of membrane (or secreted) proteins anchors DNA to the membrane, generating local supercoiling proportional to the level of gene transcription (Lynch and Wang, 1993; Binenbaum et al., 1999). Accordingly, gene transcription influences supercoiling proportionally to the number of nascent mRNA strands, the size of the encoded protein, and difference between the rate of mRNA and protein synthesis, while all these factors are themselves modulated by the concentration of ATP, nucleotides and loaded tRNA
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in the cell. For all these reasons, DNA topology represents a dynamic interface between the environment (direct influence or through expression of specific proteins) and the genome. 3.2. Adaptive changes and DNA topology Gene transcription induces local changes in supercoiling (Cook et al., 1992). In parallel, amplitude of the genome modifications during adaptive response has been related to the level of gene expression in bacteria (Mellon and Hanawalt, 1989) and in yeast (Natsoulis et al., 1989; Datta and Jinks-Roberston, 1995). This is why local supercoiling may serve as a marker for DNA transactions. An analysis of the mutation spectrum in lactose operon of E. coli reveals specific hotspots for deletion, base substitution, duplication and insertion mutations (Schaaper et al., 1986). A large variability is observed in localization of the hotspots, suggesting that they are linked to local modifications in supercoiling (Kazic and Berg, 1990). In parallel, a perturbation in regulation of DNA supercoiling induced by caffeine prevents expression of an adaptive response in bacteria (Grigg and Stuckey, 1966). Indeed, hotspots for genome modifications are identified as palindrome or quasi-palindrome (Collins et al., 1982; Glickman and Ripley, 1984), the sequences the most influenced by changes in supercoiling (Ching et al., 1988). Through a capacity to modify their conformation, they buffer local variations in supercoiling (Young and Ames, 1988). Negative supercoiling regulates the B–Z transition in palindromes (Vologodskii et al., 1992), while only one of the conformation is recognized by promoters or repressors of gene expression (Mojica and Higgins, 1996), or by enzymes of DNA metabolism (Kanaar and Cozzarelli, 1992). These evidences suggest that, through changes in configuration of palindromes, hotspots for genome transaction are generated by local supercoiling constraints. However, homeostasis in regulation of DNA supercoiling does not enable stabilization of local variations. This is why a breakdown of the homeostasis mechanisms of regulation of the DNA supercoiling is required for emergence of an adaptive targeting the DNA sequences.
4. The nonlinear response to starvation in bacteria The adaptive response has sometime been regarded as an integrative part of the reaction to starvation (Shapiro, 1984; Cairns et al., 1988; Mittler and Lenski, 1992; Sniegowski, 1995; Prival and Cebula, 1996). This is confirmed by the fact that starvation stimulates the emergence of adaptive modifications in E. coli (Hall, 1995) and Pseudomonas (Kasak et al., 1997). Adaptive
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mutations and ‘starvation associated mutagenesis’ both include activation of mobile elements (Pfeifer and Blaseio, 1990; Naas et al., 1994; Hall, 1999), punctual mutations (Bridges et al., 1996; McKenzie et al., 2001), and induction of the SOS DNA-repair system (Taddei et al., 1995; McKenzie et al., 2000; Bridges, 2001). The starvation response has been related to cellular capacity to switch on a new physiological state (Weichart et al., 1993; Bouvier et al., 1998; Storchova and Vondrejs, 1999), though the gradual decrease in nutrients concentration. This nonlinear response implies first a breakdown of initial network of regulation of gene expression. 4.1. Homeostatic regulation of DNA supercoiling In E. coli, a sudden transfer to salinity or anaerobic conditions decreases the ATP/ADP ratio. However, the concomitant decrease in negative supercoiling (drop in activity of the ATP-dependent gyrase) is rapidly compensated for (Hsieh et al., 1991a, b). This confirms the active regulation of the level of chromosome supercoiling, isolating the gene expression from shortterm environmental influences on the chromosome topology. For a bacteria, this homeostasis enables to ‘ignore’ transient fluctuations. However, permanency of the perturbation generates a progressive bias between the gene expression pattern and the cellular metabolism. Being a source of abnormal accumulation of secondary metabolites, this homeostatic response progressively represents, by itself, a source of perturbation. When the bias between gene expression and cellular metabolism reaches a critical level, it may induce the stringent response. 4.2. Breakdown of the homeostatic regulations The stringent response is characterized by the rapid degradation of proteins and RNA (Matin et al., 1989) and an enhanced expression of transporters for aminoacid or carbohydrates (Notley and Ferenci, 1995). In contrast, genes coding for enzymes involved in anabolic reactions are inhibited in their expression (Wright, 1996). The stringent response is induced by starvation but its expression depends on changes in supercoiling (Wright, 1996) and accumulation of endoinducers such as cAMP and ppGpp (Haseltine and Block, 1973). Beyond a threshold level of carbon starvation, a sudden increase (30 fold) in production and secretion of cyclic AMP is observed (Buettner et al., 1973). This phenomenon remains enigmatic when consider that 99.9% of the cAMP produced is leaked. Dissipating a significant part of energy of the cell (about 9% of the total ATP at the induction of the stringent response, see Matin and Matin, 1982), this phenomenon has been interpreted as
a ‘suicide response’. However, the sudden drop in the pool of ATP reduces abruptly the negative supercoiling (through a decrease in activity of the DNA gyrase and the rate of transcription/translation). In this perspective, the sudden drop in ATP concentration represents a breakdown of the network of regulation of gene expression. This abrupt changes enable emergence of a new physiological status. For example, the drop in supercoiling is required for the stress-provoked change in transcription protein induced by sigmaS, a proteic factor accumulated during stress exposure (Bordes et al., 2003). Moreover, the cAMP receptor protein (CRP) may act as coactivator or corepressor of the same gene, as a function of the level of DNA supercoiling (Rasmussen et al., 1996). Scale-free networks are characterized by a high degree of robustness in regard to perturbations, but a sudden change in the mostly connected nodes induces a fragmentation of the whole network in isolated parts (Albert et al., 2000). In E. coli, the cAMP receptor protein (CRP) represents the mostly connected node of the scale-free transcription network (Herrgard et al., 2003). For this reason, the sudden modification of the CRP regulation functions also provokes a dismantlement of the initial transcription network concomitant to that generated by the decrease in supercoiling.
5. The adaptive status In starved Salmonella, a new physiological status is induced 72 hours after expression of the stringent response (Kenyon et al., 2002). Similarly, a new phase transition in the DNA structure and conformation have been described for E. coli following expression of the stringent response (Frenkiel-Krispin et al., 2001). These findings suggest that the adaptive response is not a simple extension of the stringent response (Balke and Gralla, 1987). Rather, the stringent response represents the first of a series of discrete changes following starvation. 5.1. Overproduction of cAMP and its effect Overproduction of cAMP is not restricted to the short period of transition towards the stringent physiological status. Rather, the release of cAMP may even increase after its expression (Matin and Matin, 1982). Being leaked out, the endogenous cAMP concentration remains quite constant in bacteria. For this reason, the significance of such an extended overproduction of cAMP remains obscure. In fact, the internal cAMP concentration remains low if the metabolites are released in a large volume in regard to the cell volume. This is the case for bacteria grown in a liquid medium. However, for bacteria living on solid substrates, biotic
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surfaces or colonies or at very high density, a concentration gradient of the leaked metabolite is generated around the cell. In this situation, the cAMP concentration in the starved bacteria increases rapidly and may influence physiological processes. Such a phenomenon has been observed in Pseudomonas, in which cell density interfered with starvation and cAMP on induction of the developmental switch towards virulence (van Delden et al., 2001). Adaptive mutations in bacteria have been especially observed on bacteria grown on a structured (solid) environment (Taddei et al., 1997a, b). The link between adaptive status and increase in internal cAMP concentration is suggested in yeast (Storchova and Vondrejs, 1999). In E. coli, cAMP is also required for expression of the mechanisms involved in adaptive mutations (the LexA-dependent SOS system of mutation repair) (Taddei et al., 1995; Janion et al., 2002). Internal concentration of cAMP modulates gene expression during starvation (Notley and Ferenci, 1995). However, the effect of cAMP depends on its concentration. In Streptomyces griseus, for example, an exogenous supply of high concentration of cAMP inhibits production of ppGpp, a factor involved in expression of the stringent response (Honirouchi et al., 2001). The phenomenon is confirmed by the negative regulation of the cAMP receptor protein by ppGpp in E. coli (Johansson et al., 2000). This antagonism in signals promoting/inhibiting the stringent response suggests that a sudden increase in internal concentration of cAMP is able to provoke a new nonlinear transition from the stringent status. 5.2. Adaptive targeting of the DNA sequences In bacteria grown on agar, ageing generates specific patterns of differentiation in initially homogeneous populations. Regularity of the ‘‘rings of differentiation’’ reveals the occurrence of similar genomic changes at each stage of ageing (Shapiro and Higgins, 1989). Kuan and Tessman (1992) emphasized the importance of cAMP in control of these non-random processes. A similar spectrum of genome modifications was identified in adaptive mutations, long term starvation and activation of the SOS DNA repair system in absence of DNA lesions (Taddei et al., 1995), suggesting that cAMP is also involved in adaptive mutations. In a starved bacteria, the overproduction of cAMP affects activity of the ATP-dependent DNA gyrase. In this context, the level of DNA supercoiling depends mainly on local factors, especially the rate of gene expression (and especially the number of nascent mRNA on the DNA sequence, and the rate of translation of the mRNA before achievement of transcription). By reducing the level of supercoiling, the level of transcription becomes itself mainly regulated
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by the concentration of metabolites in the cell. In such a situation, the level of supercoiling increases for sequences involved in synthesis of the missing metabolites, while it remains low for sequences coding for enzymes producing the metabolites in excess. Thus, the sequences involved in expression of the missing metabolites become a target for genome modifications. The expression of genes involved in anabolic reactions is inhibited in the stringent status (Schultz et al., 1988). This reduces the emergence of local increases in level of supercoiling of sequences coding for anabolism. In the perspective presented here, this process becomes important for two reasons: (i) it increases efficiency of the targeting on sequences coding for enzymes involved in the stimulated catabolic reactions, (ii) it decreases to the maximum the probability of genetic transactions on sequences coding for structural proteins or anabolic processes. Such a protection of sequences coding for anabolic and structural proteins would not be possible through a one-step transition from active growth to adaptive status. But the differences in levels of supercoiling between sequences with adaptive and nonadaptive value is probably increased with time, even after induction of the adaptive status. This may explain why the emergence of adaptive reversion of highly specific modifications is a long-term process, in which bacteria are in a pre-apoptotic status (Janion, 2000). 5.3. The topologically oriented DNA transactions In yeast, activation of mobile elements is preferentially targeted towards the actively transcribed genes (Natsoulis et al., 1989; Adams et al., 1992), so that a direct relationship between hotspots for transposition and local supercoiling has been suggested (Lodge and Berg, 1990). A similar result is observed in E. coli (Kazic and Berg, 1990). The coincidence between hotspots for punctual mutations and sites for DNA-gyrase affinity (Marvo et al., 1983; Saing et al., 1988) confirms this link between topology and DNA transactions. Moreover, the fact that DNA gyrase is required for transposition of mobile elements (Isberg and Syvanen, 1982; Ikeda et al., 1984) and amplification of specific DNA sequences (Kim and Wang, 1989) links these processes to modified structures induced by supercoiling (Glickman and Ripley, 1984). All these observations emphasize the role of the residual DNA supercoiling (proportional to the level of gene expression) in emergence of hotspots with adaptive potential. Many adaptive mutations depend on expression of the RecA gene product (Foster and Cairns, 1991), which is stimulated by a global decrease in level of negative supercoiling (Menzel and Gellert, 1983). This suggests that the expression of enzymes involved in genome transactions coincides with the drop of homeostasis in regulation of the DNA supercoiling, bringing to the ‘adaptive targeting’ described above.
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5.4. Imprinting the adaptive DNA topology The rate of transcription and translation decreases progressively during starvation. For this reason, the local variations in DNA supercoiling issued from gene expression are expected to disappear progressively with time. However, the adaptive response is generally characterized by continuous emergence of growing cells throughout the first 3–7 days of the experiment (Cairns et al., 1988). If adaptation is really conditioned by local variations in supercoiling, this observation implies that the DNA topology generated by transition towards the adaptive status remains stabilized. During normal growth, the HU proteins stabilize a part of the DNA supercoiling independently from gyrase activity (Drlica, 1992; Steck et al., 1993; Tanaka et al., 1995; Malik et al., 1996). Through this influence, the HU proteins strengthen stability of the DNA topology by buffering minor variations in the ATP/ ADP ratio, gene expression and gyrase activity. Affinity of the DNA–HU complex decrease with reduction of the level of supercoiling (Tanaka et al., 1995). This phenomenon seems counteracted by overproduction of HU proteins, and change of their composition (homoor heterodimer) in starved bacteria (Claret and Rouviere-Yaniv, 1997). Such a modification enables first a dissipation of the initial HU–DNA link, followed by stabilization of local topological variations in spite of a decrease in the ATP/ADP ratio, consecutive to the synthesis of new HU proteins following starvation. Another type of histone-like proteins, H-NS, is specifically expressed during the stationary phase (Afflerbach et al., 1999). This protein is known to interact with non-expressed genes by decreasing their level of supercoiling (McGovern et al., 1994). Interestingly, a decrease in the rate of adaptive mutations was observed in E. coli for which the H-NS proteins are overexpressed (Gomez et al., 1997). Accordingly, it is likely that both HU and H-NS proteins are involved in amplifying the topological differences between expressed and non-expressed sequences by eliminating the ‘residual supercoiling’ structures (H-NS proteins) and by stabilizing the local supercoiling modifications related to gene expression (HU proteins). Maintained by non-covalent bonds, this ‘adaptive topology’ is progressively dissipated. This may explain the progressive decrease in adaptive value of the mutations occurring in E. coli cells surviving the 8th day of starvation (Powell and Wartell, 2001).
6. Conclusion The theory proposed here is illustrated mainly by observations issued from experiments performed in another context. This situation does not result from
experimental difficulties, since most of the parts of this theory are testable with the tools currently available. Rather than technical, the problem remains conceptual: there is no room for ‘oriented DNA transactions’ in the linear representation of bacterial response to a perturbation: blind mutations selected by the resulting fitness remain the unique explanation. Reinterpreting observations performed in another context, the current theory suggests that a disruption of the regulation network below the critical level of its spontaneous breakdown (lethality) generates the emergence of an ‘adaptive targeting’ on the bacterial chromosome. This theory has been elaborated from the assumption of homology in basic patterns of adaptation response of cells and multicellular organisms. In plants, for example, the adaptive response to a NaCl-induced perturbation has been related to a sudden, endogenously regulated breakdown of the between-meristem network of relationships (Amzallag, 2002). This phenomenon occurs during specific critical periods, linking adaptive plasticity to the development (Amzallag, 2000, 2004). In both cases, the nonlinear dynamics is generated by a breakdown of the homeostasis regulations, an event required for adaptive modification of the linkages between nodules generating the network. This similarity in response may be understood as a consequence of the primacy of homeostatic regulations in both scales, when exposed to optimal conditions. In both cases, adaptation requires a nonlinear approach of the response to a perturbation, in which adaptation emerges from breakdown of the initially existing network of relationships. Being dependent on the external concentration of cAMP, the nonlinear transition to adaptation depends on the bacterial environment, and especially on bacterial density of the population. This observation suggests to reconsider the linkage between adaptation, ageing, conjugation, quorum sensing and cell differentiation in prokaryotes.
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