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1.  Gene-specific selective sweeps in bacteria and archaea caused by negative frequency-dependent selection 
BMC Biology  2015;13:20.
Fixation of beneficial genes in bacteria and archaea (collectively, prokaryotes) is often believed to erase pre-existing genomic diversity through the hitchhiking effect, a phenomenon known as genome-wide selective sweep. Recent studies, however, indicate that beneficial genes spread through a prokaryotic population via recombination without causing genome-wide selective sweeps. These gene-specific selective sweeps seem to be at odds with the existing estimates of recombination rates in prokaryotes, which appear far too low to explain such phenomena.
We use mathematical modeling to investigate potential solutions to this apparent paradox. Most microbes in nature evolve in heterogeneous, dynamic communities, in which ecological interactions can substantially impact evolution. Here, we focus on the effect of negative frequency-dependent selection (NFDS) such as caused by viral predation (kill-the-winner dynamics). The NFDS maintains multiple genotypes within a population, so that a gene beneficial to every individual would have to spread via recombination, hence a gene-specific selective sweep. However, gene loci affected by NFDS often are located in variable regions of microbial genomes that contain genes involved in the mobility of selfish genetic elements, such as integrases or transposases. Thus, the NFDS-affected loci are likely to experience elevated rates of recombination compared with the other loci. Consequently, these loci might be effectively unlinked from the rest of the genome, so that NFDS would be unable to prevent genome-wide selective sweeps. To address this problem, we analyzed population genetic models of selective sweeps in prokaryotes under NFDS. The results indicate that NFDS can cause gene-specific selective sweeps despite the effect of locally elevated recombination rates, provided NFDS affects more than one locus and the basal rate of recombination is sufficiently low. Although these conditions might seem to contradict the intuition that gene-specific selective sweeps require high recombination rates, they actually decrease the effective rate of recombination at loci affected by NFDS relative to the per-locus basal level, so that NFDS can cause gene-specific selective sweeps.
Because many free-living prokaryotes are likely to evolve under NFDS caused by ubiquitous viruses, gene-specific selective sweeps driven by NFDS are expected to be a major, general phenomenon in prokaryotic populations.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-015-0131-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4410459  PMID: 25928466
2.  Horizontal Gene Transfer Can Rescue Prokaryotes from Muller’s Ratchet: Benefit of DNA from Dead Cells and Population Subdivision 
G3: Genes|Genomes|Genetics  2013;4(2):325-339.
Horizontal gene transfer (HGT) is a major factor in the evolution of prokaryotes. An intriguing question is whether HGT is maintained during evolution of prokaryotes owing to its adaptive value or is a byproduct of selection driven by other factors such as consumption of extracellular DNA (eDNA) as a nutrient. One hypothesis posits that HGT can restore genes inactivated by mutations and thereby prevent stochastic, irreversible deterioration of genomes in finite populations known as Muller’s ratchet. To examine this hypothesis, we developed a population genetic model of prokaryotes undergoing HGT via homologous recombination. Analysis of this model indicates that HGT can prevent the operation of Muller’s ratchet even when the source of transferred genes is eDNA that comes from dead cells and on average carries more deleterious mutations than the DNA of recipient live cells. Moreover, if HGT is sufficiently frequent and eDNA diffusion sufficiently rapid, a subdivided population is shown to be more resistant to Muller’s ratchet than an undivided population of an equal overall size. Thus, to maintain genomic information in the face of Muller’s ratchet, it is more advantageous to partition individuals into multiple subpopulations and let them “cross-reference” each other’s genetic information through HGT than to collect all individuals in one population and thereby maximize the efficacy of natural selection. Taken together, the results suggest that HGT could be an important condition for the long-term maintenance of genomic information in prokaryotes through the prevention of Muller’s ratchet.
PMCID: PMC3931566  PMID: 24347631
environmental DNA; evolution of transformation; competence; structured population; soil bacteria
3.  Evolutionary Dynamics of RNA-like Replicator Systems: A Bioinformatic Approach to the Origin of Life✩ 
Physics of life reviews  2012;9(3):219-263.
We review computational studies on prebiotic evolution, focusing on informatic processes in RNA-like replicator systems. In particular, we consider the following processes: the maintenance of information by replicators with and without interactions, the acquisition of information by replicators having a complex genotype-phenotype map, the generation of information by replicators having a complex genotype-phenotype-interaction map, and the storage of information by replicators serving as dedicated templates. Focusing on these informatic aspects, we review studies on quasi-species, error threshold, RNA-folding genotype-phenotype map, hypercycle, multilevel selection (including spatial self-organization, classical group selection, and compartmentalization), and the origin of DNA-like replicators. In conclusion, we pose a future question for theoretical studies on the origin of life.
PMCID: PMC3466355  PMID: 22727399
RNA world; early evolution; mathematical modeling; computational modeling; cellular automata; phenotypic information threshold; parasite; traveling wave; protocell; multilevel evolution; division of labor between templates and catalysts; What is life?
4.  Nature and Intensity of Selection Pressure on CRISPR-Associated Genes 
Journal of Bacteriology  2012;194(5):1216-1225.
The recently discovered CRISPR-Cas adaptive immune system is present in almost all archaea and many bacteria. It consists of cassettes of CRISPR repeats that incorporate spacers homologous to fragments of viral or plasmid genomes that are employed as guide RNAs in the immune response, along with numerous CRISPR-associated (cas) genes that encode proteins possessing diverse, only partially characterized activities required for the action of the system. Here, we investigate the evolution of the cas genes and show that they evolve under purifying selection that is typically much weaker than the median strength of purifying selection affecting genes in the respective genomes. The exceptions are the cas1 and cas2 genes that typically evolve at levels of purifying selection close to the genomic median. Thus, although these genes are implicated in the acquisition of spacers from alien genomes, they do not appear to be directly involved in an arms race between bacterial and archaeal hosts and infectious agents. These genes might possess functions distinct from and additional to their role in the CRISPR-Cas-mediated immune response. Taken together with evidence of the frequent horizontal transfer of cas genes reported previously and with the wide-spread microscale recombination within these genes detected in this work, these findings reveal the highly dynamic evolution of cas genes. This conclusion is in line with the involvement of CRISPR-Cas in antiviral immunity that is likely to entail a coevolutionary arms race with rapidly evolving viruses. However, we failed to detect evidence of strong positive selection in any of the cas genes.
PMCID: PMC3294813  PMID: 22178975
5.  On the Origin of DNA Genomes: Evolution of the Division of Labor between Template and Catalyst in Model Replicator Systems 
PLoS Computational Biology  2011;7(3):e1002024.
The division of labor between template and catalyst is a fundamental property of all living systems: DNA stores genetic information whereas proteins function as catalysts. The RNA world hypothesis, however, posits that, at the earlier stages of evolution, RNA acted as both template and catalyst. Why would such division of labor evolve in the RNA world? We investigated the evolution of DNA-like molecules, i.e. molecules that can function only as template, in minimal computational models of RNA replicator systems. In the models, RNA can function as both template-directed polymerase and template, whereas DNA can function only as template. Two classes of models were explored. In the surface models, replicators are attached to surfaces with finite diffusion. In the compartment models, replicators are compartmentalized by vesicle-like boundaries. Both models displayed the evolution of DNA and the ensuing division of labor between templates and catalysts. In the surface model, DNA provides the advantage of greater resistance against parasitic templates. However, this advantage is at least partially offset by the disadvantage of slower multiplication due to the increased complexity of the replication cycle. In the compartment model, DNA can significantly delay the intra-compartment evolution of RNA towards catalytic deterioration. These results are explained in terms of the trade-off between template and catalyst that is inherent in RNA-only replication cycles: DNA releases RNA from this trade-off by making it unnecessary for RNA to serve as template and so rendering the system more resistant against evolving parasitism. Our analysis of these simple models suggests that the lack of catalytic activity in DNA by itself can generate a sufficient selective advantage for RNA replicator systems to produce DNA. Given the widespread notion that DNA evolved owing to its superior chemical properties as a template, this study offers a novel insight into the evolutionary origin of DNA.
Author Summary
At the core of all biological systems lies the division of labor between the storage of genetic information and its phenotypic implementation, in other words, the functional differentiation between templates (DNA) and catalysts (proteins). This fundamental property of life is believed to have been absent at the earliest stages of evolution. The RNA world hypothesis, the most realistic current scenario for the origin of life, posits that, in primordial replicating systems, RNA functioned both as template and as catalyst. How would such division of labor emerge through Darwinian evolution? We investigated the evolution of DNA-like molecules in minimal computational models of RNA replicator systems. Two models were considered: one where molecules are adsorbed on surfaces and another one where molecules are compartmentalized by dividing cellular boundaries. Both models exhibit the evolution of DNA and the ensuing division of labor, revealing the simple governing principle of these processes: DNA releases RNA from the trade-off between template and catalyst that is inevitable in the RNA world and thereby enhances the system's resistance against parasitic templates. Hence, this study offers a novel insight into the evolutionary origin of the division of labor between templates and catalysts in the RNA world.
PMCID: PMC3063752  PMID: 21455287
6.  Multilevel Selection in Models of Prebiotic Evolution II: A Direct Comparison of Compartmentalization and Spatial Self-Organization 
PLoS Computational Biology  2009;5(10):e1000542.
Multilevel selection has been indicated as an essential factor for the evolution of complexity in interacting RNA-like replicator systems. There are two types of multilevel selection mechanisms: implicit and explicit. For implicit multilevel selection, spatial self-organization of replicator populations has been suggested, which leads to higher level selection among emergent mesoscopic spatial patterns (traveling waves). For explicit multilevel selection, compartmentalization of replicators by vesicles has been suggested, which leads to higher level evolutionary dynamics among explicitly imposed mesoscopic entities (protocells). Historically, these mechanisms have been given separate consideration for the interests on its own. Here, we make a direct comparison between spatial self-organization and compartmentalization in simulated RNA-like replicator systems. Firstly, we show that both mechanisms achieve the macroscopic stability of a replicator system through the evolutionary dynamics on mesoscopic entities that counteract that of microscopic entities. Secondly, we show that a striking difference exists between the two mechanisms regarding their possible influence on the long-term evolutionary dynamics, which happens under an emergent trade-off situation arising from the multilevel selection. The difference is explained in terms of the difference in the stability between self-organized mesoscopic entities and externally imposed mesoscopic entities. Thirdly, we show that a sharp transition happens in the long-term evolutionary dynamics of the compartmentalized system as a function of replicator mutation rate. Fourthly, the results imply that spatial self-organization can allow the evolution of stable folding in parasitic replicators without any specific functionality in the folding itself. Finally, the results are discussed in relation to the experimental synthesis of chemical Darwinian systems and to the multilevel selection theory of evolutionary biology in general. To conclude, novel evolutionary directions can emerge through interactions between the evolutionary dynamics on multiple levels of organization. Different multilevel selection mechanisms can produce a difference in the long-term evolutionary trend of identical microscopic entities.
Author Summary
The origin of life has ever been attracting scientific inquiries. The RNA world hypothesis suggests that, before the evolution of DNA and protein, primordial life was based on RNA-like molecules both for information storage and chemical catalysis. In the simplest form, an RNA world consists of RNA molecules that can catalyze the replication of their own copies. Thus, an interesting question is whether a system of RNA-like replicators can increase its complexity through Darwinian evolution and approach the modern form of life. It is, however, known that simple natural selection acting on individual replicators is insufficient to account for the evolution of complexity due to the evolution of parasite-like templates. Two solutions have been suggested: compartmentalization of replicators by membranes (i.e., protocells) and spatial self-organization of a replicator population. Here, we make a direct comparison of the two suggestions by computer simulations. Our results show that the two suggestions can lead to unanticipated and contrasting consequences in the long-term evolution of replicating molecules. The results also imply a novel advantage in the spatial self-organization for the evolution of complexity in RNA-like replicator systems.
PMCID: PMC2757730  PMID: 19834556
7.  The evolution of strand preference in simulated RNA replicators with strand displacement: Implications for the origin of transcription 
Biology Direct  2008;3:33.
The simplest conceivable example of evolving systems is RNA molecules that can replicate themselves. Since replication produces a new RNA strand complementary to a template, all templates would eventually become double-stranded and, hence, become unavailable for replication. Thus the problem of how to separate the two strands is considered a major issue for the early evolution of self-replicating RNA. One biologically plausible way to copy a double-stranded RNA is to displace a preexisting strand by a newly synthesized strand. Such copying can in principle be initiated from either the (+) or (-) strand of a double-stranded RNA. Assuming that only one of them, say (+), can act as replicase when single-stranded, strand displacement produces a new replicase if the (-) strand is the template. If, however, the (+) strand is the template, it produces a new template (but no replicase). Modern transcription exhibits extreme strand preference wherein anti-sense strands are always the template. Likewise, replication by strand displacement seems optimal if it also exhibits extreme strand preference wherein (-) strands are always the template, favoring replicase production. Here we investigate whether such strand preference can evolve in a simple RNA replicator system with strand displacement.
We first studied a simple mathematical model of the replicator dynamics. Our results indicated that if the system is well-mixed, there is no selective force acting upon strand preference per se. Next, we studied an individual-based simulation model to investigate the evolution of strand preference under finite diffusion. Interestingly, the results showed that selective forces "emerge" because of finite diffusion. Strikingly, the direction of the strand preference that evolves [i.e. (+) or (-) strand excess] is a complex non-monotonic function of the diffusion intensity. The mechanism underlying this behavior is elucidated. Furthermore, a speciation-like phenomenon is observed under certain conditions: two extreme replication strategies, namely replicase producers and template producers, emerge and coexist among competing replicators.
Finite diffusion enables the evolution of strand preference, the direction of which is a non-monotonic function of the diffusion intensity. By identifying the conditions under which strand preference evolves, this study provides an insight into how a rudimentary transcription-like pattern might have emerged in an RNA-based replicator system.
This article was reviewed by Eugene V Koonin, Rob Kinght and István Scheuring (nominated by David H Ardell). For the full reviews, please go to the Reviewers' comments section.
PMCID: PMC2648946  PMID: 18694481
8.  Evolution of complexity in RNA-like replicator systems 
Biology Direct  2008;3:11.
The evolution of complexity is among the most important questions in biology. The evolution of complexity is often observed as the increase of genetic information or that of the organizational complexity of a system. It is well recognized that the formation of biological organization – be it of molecules or ecosystems – is ultimately instructed by the genetic information, whereas it is also true that the genetic information is functional only in the context of the organization. Therefore, to obtain a more complete picture of the evolution of complexity, we must study the evolution of both information and organization.
Here we investigate the evolution of complexity in a simulated RNA-like replicator system. The simplicity of the system allows us to explicitly model the genotype-phenotype-interaction mapping of individual replicators, whereby we avoid preconceiving the functionality of genotypes (information) or the ecological organization of replicators in the model. In particular, the model assumes that interactions among replicators – to replicate or to be replicated – depend on their secondary structures and base-pair matching. The results showed that a population of replicators, originally consisting of one genotype, evolves to form a complex ecosystem of up to four species. During this diversification, the species evolve through acquiring unique genotypes with distinct ecological functionality. The analysis of this diversification reveals that parasitic replicators, which have been thought to destabilize the replicator's diversity, actually promote the evolution of diversity through generating a novel "niche" for catalytic replicators. This also makes the current replicator system extremely stable upon the evolution of parasites. The results also show that the stability of the system crucially depends on the spatial pattern formation of replicators. Finally, the evolutionary dynamics is shown to significantly depend on the mutation rate.
The interdependence of information and organization can play an important role for the evolution of complexity. Namely, the emergent ecosystem supplies a context in which a novel phenotype gains functionality. Realizing such a phenotype, novel genotypes can evolve, which, in turn, results in the evolution of more complex ecological organization. Hence, the evolutionary feedback between information and organization, and thereby the evolution of complexity.
This article was reviewed by Eugene V Koonin, Eörs Szathmáry (nominated by Anthony M Poole), and Chris Adami. For the full reviews, please go to the Reviewers' comments section.
PMCID: PMC2390529  PMID: 18371199
9.  Error-threshold exists in fitness landscapes with lethal mutants 
One of the important insights of quasi-species theory is an error-threshold. The error-threshold is the error rate of replication above which the sudden onset of the population delocalization from the fittest genotype occurs despite Darwinian selection; i.e., the break down of evolutionary optimization. However, a recent article by Wilke in this journal, after reviewing the previous studies on the error-threshold, concluded that the error-threshold does not exist if lethal mutants are taken into account in a fitness landscape. Since lethal mutants obviously exist in reality, this has a significant implication about biological evolution. However, the study of Wagner and Krall on which Wilke's conclusion was based considered mutation-selection dynamics in one-dimensional genotype space with the assumption that a genotype can mutate only to an adjoining genotype in the genotype space. In this article, we study whether the above conclusion holds in high-dimensional genotype space without the assumption of the adjacency of mutations, where the consequences of mutation-selection dynamics can be qualitatively different.
To examine the effect of mutant lethality on the existence of the error-threshold, we extend the quasi-species equation by taking the lethality of mutants into account, assuming that lethal genotypes are uniformly distributed in the genotype space. First, with the simplification of neglecting back mutations, we calculate the error-threshold as the maximum allowable mutation rate for which the fittest genotype can survive. Second, with the full consideration of back mutations, we study the equilibrium population distribution and the ancestor distribution in the genotype space as a function of error rate with and without lethality in a multiplicative fitness landscape. The results show that a high lethality of mutants actually introduces an error-threshold in a multiplicative fitness landscape in sharp contrast to the conclusion of Wilke. Furthermore, irrespective of the lethality of mutants, the delocalization of the population from the fittest genotype occurs for an error rate much smaller than random replication. Finally, the results are shown to extend to a system of finite populations.
High lethality of mutants introduces an error-threshold in a multiplicative fitness landscape. Furthermore, irrespective of the lethality of mutants, the break down of evolutionary optimization happens for an error rate much smaller than random replication.
PMCID: PMC1805495  PMID: 17286853
10.  Phenotypic error threshold; additivity and epistasis in RNA evolution 
The error threshold puts a limit on the amount of information maintainable in Darwinian evolution. The error threshold was first formulated in terms of genotypes. However, if a genotype-phenotype map involves redundancy ("mutational neutrality"), the error threshold should be formulated in terms of phenotypes since there is no unique fittest genotype. A previous study formulated the error threshold in terms of phenotypes, and their results showed that a rather low degree of mutational neutrality can increase the error threshold unlimitedly.
We obtain an analytical formulation of the phenotypic error threshold by considering the "additive assumption", in which base substitutions do not influence each other (no epistasis). Our formulation shows that an increase of the error threshold due to mutational neutrality is limited. Computer simulations of RNA evolution are conducted to verify our formulation, and the results show a good agreement between the analytical prediction and the simulations. The comparison with the previous formulation illustrates that it is important for the prediction of the error threshold to consider that the number of base substitutions per replication is rather large near the error threshold. To examine the additive assumption, a detailed analysis of additivity and epistasis in RNA folding of a particular sequence is performed. The results show a high degree of epistasis in RNA folding; furthermore, the analysis also elucidates the reason of the success of the additive assumption.
We conclude that an increase of the error threshold by mutational neutrality is limited, and that the additive assumption achieves a good prediction of the error threshold in spite of a high degree of epistasis in RNA folding because the average number of base substitutions of sequences retaining the phenotype per replication is sufficiently small to avoid of the effect of epistasis.
PMCID: PMC550645  PMID: 15691379

Results 1-10 (10)