Coevolution of reproducers and replicators at the origin of life and the conditions for the origin of genomes.

There are two fundamentally distinct but inextricably linked types of biological evolutionary units, reproducers and replicators. Reproducers are cells and organelles that reproduce via various forms of division and maintain the physical continuity of compartments and their content. Replicators are genetic elements (GE), including genomes of cellular organisms and various autonomous elements, that both cooperate with reproducers and rely on the latter for replication. All known cells and organisms comprise a union between replicators and reproducers. We explore a model in which cells emerged via symbiosis between primordial "metabolic" reproducers (protocells) which evolved, on short time scales, via a primitive form of selection and random drift, and mutualist replicators. Mathematical modeling identifies the conditions, under which GE-carrying protocells can outcompete GE-less ones, taking into account that, from the earliest stages of evolution, replicators split into mutualists and parasites. Analysis of the model shows that, for the GE-containing protocells to win the competition and to be fixed in evolution, it is essential that the birth-death process of the GE is coordinated with the rate of protocell division. At the early stages of evolution, random, high-variance cell division is advantageous compared with symmetrical division because the former provides for the emergence of protocells containing only mutualists, preventing takeover by parasites. These findings illuminate the likely order of key events on the evolutionary route from protocells to cells that involved the origin of genomes, symmetrical cell division, and antiparasite defense systems.

Self-Sorting in Dynamic Combinatorial Libraries Leads to the Co-Existence of Foldamers and Self-Replicators.

Nature segregates fundamental tasks such as information storage/transmission and catalysis between two different compound classes (e.g. polynucleotides for replication and folded polyamides for catalysis). This division of labor is likely a product of evolution, raising the question of how simpler systems in which replicators and folded macromolecules co-exist may emerge in the transition from chemistry to biology. In synthetic systems, achieving co-existence of replicators and foldamers in a single molecular network remains an unsolved problem. Previous work on dynamic molecular networks has given rise to either self-replicating fibers or well-defined foldamer structures (or completely un-sorted complex systems). We report a system in which two cross-reactive dithiol (nucleobase- and peptide-based) building blocks self-sort into a replicator fiber and foldamer that both emerge spontaneously and co-exist. The self-sorting behavior remains prevalent across different building block ratios as two phases of emergence occur: replicator growth followed by foldamer formation. This is attributed to the autocatalytic formation of the replicator fiber, followed by enrichment of the system in the remaining building block, which is subsequently incorporated into a foldamer.

Prebiotic competition and evolution in self-replicating polynucleotides can explain the properties of DNA/RNA in modern living systems.

BACKGROUND: We hypothesize prebiotic evolution of self-replicating macro-molecules (Alberts, Molecular biology of the cell, 2015; Orgel, Crit Rev Biochem Mol Biol 39:99-123, 2004; Hud, Nat Commun 9:5171) favoured the constituent nucleotides and biophysical properties observed in the RNA and DNA of modern organisms. Assumed initial conditions are a shallow tide pool, containing a racemic mix of diverse nucleotide monomers (Barks et al., Chembiochem 11:1240-1243, 2010; Krishnamurthy, Nat Commun 9:5175, 2018; Hirao, Curr Opin Chem Biol 10:622-627), subject to day/night thermal fluctuations (Piccirilli et al., Nature 343:33-37, 1990). Self-replication, like Polymerase Chain Reactions, followed as higher daytime thermal energy "melted" inter-strand hydrogen bonds causing strand separation while solar UV radiation increased prebiotic nucleobase formation (Szathmary, Proc Biol Sci 245:91-99, 1991; Materese et al., Astrobiology 17:761-770, 2017; Bera et al., Astrobiology 17:771-785, 2017). Lower night energies allowed free monomers to form hydrogen bonds with their template counterparts leading to daughter strand synthesis (Hirao, Biotechniques 40:711, 2006). RESULTS: Evolutionary selection favoured increasing strand length to maximize auto-catalytic function in RNA and polymer stability in double stranded DNA (Krishnamurthy, Chemistry 24:16708-16715, 2018; Szathmary, Nat Rev Genet 4:995-1001, 2003). However, synthesis of the full daughter strand before daytime temperatures produced strand separation, longer polymer length required increased speed of self-replication. Computer simulations demonstrate optimal polynucleotide autocatalytic speed is achieved when the constituent nucleotides possess a left-right asymmetry that decreases the hydrogen bond kinetic barrier for the free nucleotide attachment to the template on one side and increases bond barrier on the other side preventing it from releasing prior to covalent bond formation. This phenomenon is similar to asymmetric kinetics observed during polymerization of the front and the back ends of linear cytoskeletal proteins such as actin and microtubules (Orgel, Nature 343:18-20, 1990; Henry, Curr Opin Chem Biol 7:727-733, 2003; Walker et al., J Cell Biol 108:931-937, 1989; Crevenna et al., J Biol Chem 288:12102-12113, 2013). Since rotation of the nucleotide would disrupt the asymmetry, the optimal nucleotides must form two or more hydrogen bonds with their counterpart on the template strand. All nucleotides in modern RNA and DNA have these predicted properties. Our models demonstrate these constraints on the properties of constituent monomers result in biophysical properties found in modern DNA and RNA including strand directionality, anti-parallel strand orientation, homochirality, quadruplet alphabet, and complementary base pairing. Furthermore, competition between RNA and DNA auto-replicators for 3 nucleotides in common permit states coexistence and possible cooperative interactions that could be incorporated into nascent living systems. CONCLUSION: Our findings demonstrate the molecular properties of DNA/RNA could have emerged from Darwinian competition among macromolecular replicators that selected nucleotide monomers that maximized the speed of autocatalysis.

Nonequilibrium Entropic Bounds for Darwinian Replicators.

Life evolved on our planet by means of a combination of Darwinian selection and innovations leading to higher levels of complexity. The emergence and selection of replicating entities is a central problem in prebiotic evolution. Theoretical models have shown how populations of different types of replicating entities exclude or coexist with other classes of replicators. Models are typically kinetic, based on standard replicator equations. On the other hand, the presence of thermodynamical constraints for these systems remain an open question. This is largely due to the lack of a general theory of statistical methods for systems far from equilibrium. Nonetheless, a first approach to this problem has been put forward in a series of novel developements falling under the rubric of the extended second law of thermodynamics. The work presented here is twofold: firstly, we review this theoretical framework and provide a brief description of the three fundamental replicator types in prebiotic evolution: parabolic, malthusian and hyperbolic. Secondly, we employ these previously mentioned techinques to explore how replicators are constrained by thermodynamics. Finally, we comment and discuss where further research should be focused on.

The evolution of cooperation in simple molecular replicators.

In order for the first genomes to evolve, independent replicators had to act cooperatively, with some reducing their own replication rate to help copy others. It has been argued that limited diffusion explains this early cooperation. However, social evolution models have shown that limited diffusion on its own often does not favour cooperation. Here we model early replicators using social evolution tools. We show that: (i) replicators can be considered to be cooperating as a result of kin selection; (ii) limited diffusion on its own does not favour cooperation; and (iii) the addition of overlapping generations, probably a general trait of molecular replicators, promotes cooperation. These results suggest key life-history features in the evolution of the genome and that the same factors can favour cooperation across the entire tree of life.

Viroids and Viroid-like Circular RNAs: Do They Descend from Primordial Replicators?

Viroids are a unique class of plant pathogens that consist of small circular RNA molecules, between 220 and 450 nucleotides in size. Viroids encode no proteins and are the smallest known infectious agents. Viroids replicate via the rolling circle mechanism, producing multimeric intermediates which are cleaved to unit length either by ribozymes formed from both polarities of the viroid genomic RNA or by coopted host RNAses. Many viroid-like small circular RNAs are satellites of plant RNA viruses. Ribozyviruses, represented by human hepatitis delta virus, are larger viroid-like circular RNAs that additionally encode the viral nucleocapsid protein. It has been proposed that viroids are direct descendants of primordial RNA replicons that were present in the hypothetical RNA world. We argue, however, that much later origin of viroids, possibly, from recently discovered mobile genetic elements known as retrozymes, is a far more parsimonious evolutionary scenario. Nevertheless, viroids and viroid-like circular RNAs are minimal replicators that are likely to be close to the theoretical lower limit of replicator size and arguably comprise the paradigm for replicator emergence. Thus, although viroid-like replicators are unlikely to be direct descendants of primordial RNA replicators, the study of the diversity and evolution of these ultimate genetic parasites can yield insights into the earliest stages of the evolution of life.

Open Prebiotic Environments Drive Emergent Phenomena and Complex Behavior.

We have been studying simple prebiotic catalytic replicating networks as prototypes for modeling replication, complexification and Systems Chemistry. While living systems are always open and function far from equilibrium, these prebiotic networks may be open or closed, dynamic or static, divergent or convergent to a steady state. In this paper we review the properties of these simple replicating networks, and show, via four working models, how even though closed systems exhibit a wide range of emergent phenomena, many of the more interesting phenomena leading to complexification and emergence indeed require open systems.

Parsimonious Scenario for the Emergence of Viroid-Like Replicons De Novo.

Viroids are small, non-coding, circular RNA molecules that infect plants. Different hypotheses for their evolutionary origin have been put forward, such as an early emergence in a precellular RNA World or several de novo independent evolutionary origins in plants. Here, we discuss the plausibility of de novo emergence of viroid-like replicons by giving theoretical support to the likelihood of different steps along a parsimonious evolutionary pathway. While Avsunviroidae-like structures are relatively easy to obtain through evolution of a population of random RNA sequences of fixed length, rod-like structures typical of Pospiviroidae are difficult to fix. Using different quantitative approaches, we evaluated the likelihood that RNA sequences fold into a rod-like structure and bear specific sequence motifs facilitating interactions with other molecules, e.g., RNA polymerases, RNases, and ligases. By means of numerical simulations, we show that circular RNA replicons analogous to Pospiviroidae emerge if evolution is seeded with minimal circular RNAs that grow through the gradual addition of nucleotides. Further, these rod-like replicons often maintain their structure if independent functional modules are acquired that impose selective constraints. The evolutionary scenario we propose here is consistent with the structural and biochemical properties of viroids described to date.

Entropic Analysis of Mirror Symmetry Breaking in Chiral Hypercycles.

Replicators are fundamental to the origin of life and evolvability. Biology exhibits homochirality: only one of two enantiomers is used in proteins and nucleic acids. Thermodynamic studies of chemical replicators able to lead to homochirality shed valuable light on the origin of homochirality and life in conformity with the underlying mechanisms and constraints. In line with this framework, enantioselective hypercyclic replicators may lead to spontaneous mirror symmetry breaking (SMSB) without the need for additional heterochiral inhibition reactions, which can be an obstacle for the emergence of evolutionary selection properties. We analyze the entropy production of a two-replicator system subject to homochiral cross-catalysis which can undergo SMSB in an open-flow reactor. The entropy exchange with the environment is provided by the input and output matter flows, and is essential for balancing the entropy production at the non-equilibrium stationary states. The partial entropy contributions, associated with the individual elementary flux modes, as defined by stoichiometric network analysis (SNA), describe how the system's internal currents evolve, maintaining the balance between entropy production and exchange, while minimizing the entropy production after the symmetry breaking transition. We validate the General Evolution Criterion, stating that the change in the chemical affinities proceeds in a way as to lower the value of the entropy production.

Five Misunderstandings About Cultural Evolution.

Recent debates about memetics have revealed some widespread misunderstandings about Darwinian approaches to cultural evolution. Drawing from these debates, this paper disputes five common claims: (1) mental representations are rarely discrete, and therefore models that assume discrete, gene-like particles (i.e., replicators) are useless; (2) replicators are necessary for cumulative, adaptive evolution; (3) content-dependent psychological biases are the only important processes that affect the spread of cultural representations; (4) the "cultural fitness" of a mental representation can be inferred from its successful transmission; and (5) selective forces only matter if the sources of variation are random. We close by sketching the outlines of a unified evolutionary science of culture.

Sustainability of a Compartmentalized Host-Parasite Replicator System under Periodic Washout-Mixing Cycles.

The emergence and dominance of parasitic replicators are among the major hurdles for the proliferation of primitive replicators. Compartmentalization of replicators is proposed to relieve the parasite dominance; however, it remains unclear under what conditions simple compartmentalization uncoupled with internal reaction secures the long-term survival of a population of primitive replicators against incessant parasite emergence. Here, we investigate the sustainability of a compartmentalized host-parasite replicator (CHPR) system undergoing periodic washout-mixing cycles, by constructing a mathematical model and performing extensive simulations. We describe sustainable landscapes of the CHPR system in the parameter space and elucidate the mechanism of phase transitions between sustainable and extinct regions. Our findings revealed that a large population size of compartments, a high mixing intensity, and a modest amount of nutrients are important factors for the robust survival of replicators. We also found two distinctive sustainable phases with different mixing intensities. These results suggest that a population of simple host-parasite replicators assumed before the origin of life can be sustained by a simple compartmentalization with periodic washout-mixing processes.

The evolutionary dynamics of language.

The well-established framework of evolutionary dynamics can be applied to the fascinating open problems how human brains are able to acquire and adapt language and how languages change in a population. Schemas for handling grammatical constructions are the replicating unit. They emerge and multiply with variation in the brains of individuals and undergo selection based on their contribution to needed expressive power, communicative success and the reduction of cognitive effort. Adopting this perspective has two major benefits. (i) It makes a bridge to neurobiological models of the brain that have also adopted an evolutionary dynamics point of view, thus opening a new horizon for studying how human brains achieve the remarkably complex competence for language. And (ii) it suggests a new foundation for studying cultural language change as an evolutionary dynamics process. The paper sketches this novel perspective, provides references to empirical data and computational experiments, and points to open problems.

Inevitability of the emergence and persistence of genetic parasites caused by evolutionary instability of parasite-free states.

Genetic parasites, including viruses and mobile genetic elements, are ubiquitous among cellular life forms, and moreover, are the most abundant biological entities on earth that harbor the bulk of the genetic diversity. Here we examine simple thought experiments to demonstrate that both the emergence of parasites in simple replicator systems and their persistence in evolving life forms are inevitable because the putative parasite-free states are evolutionarily unstable. REVIEWERS: This article has been reviewed by Yitzhak Pilpel, Bojan Zagrovic, and Eric van Nimwegen.

Are viruses alive? The replicator paradigm sheds decisive light on an old but misguided question.

The question whether or not "viruses are alive" has caused considerable debate over many years. Yet, the question is effectively without substance because the answer depends entirely on the definition of life or the state of "being alive" that is bound to be arbitrary. In contrast, the status of viruses among biological entities is readily defined within the replicator paradigm. All biological replicators form a continuum along the selfishness-cooperativity axis, from the completely selfish to fully cooperative forms. Within this range, typical, lytic viruses represent the selfish extreme whereas temperate viruses and various mobile elements occupy positions closer to the middle of the range. Selfish replicators not only belong to the biological realm but are intrinsic to any evolving system of replicators. No such system can evolve without the emergence of parasites, and moreover, parasites drive the evolution of biological complexity at multiple levels. The history of life is a story of parasite-host coevolution that includes both the incessant arms race and various forms of cooperation. All organisms are communities of interacting, coevolving replicators of different classes. A complete theory of replicator coevolution remains to be developed, but it appears likely that not only the differentiation between selfish and cooperative replicators but the emergence of the entire range of replication strategies, from selfish to cooperative, is intrinsic to biological evolution.

Acytota - associated kingdom of neglected life.

There is a huge variety of RNA- and DNA-containing entities that multiply within and propagate between cells across all kingdoms of life, having no cells of their own. Apart from cellular organisms, these entities (viroids, plasmids, mobile elements and viruses among others) are the only ones with distinct genetic identities but which are not included in any traditional tree of life. We suggest to introduce or, rather, revive the distinct category of acellular organisms, Acytota, as an additional, undeservedly ignored full-fledged kingdom of life. Acytota are indispensable players in cellular life and its evolution. The six traditional kingdoms (Cytota) and Acytota together complete the classification of the biological world (Biota), leaving nothing beyond.

Classification of prokaryotic genetic replicators: between selfishness and altruism.

Prokaryotes harbor a variety of genetic replicators, including plasmids, viruses, and chromosomes, each having different effects on the phenotype of the hosting cell. Here, we propose a classification for replicators of bacteria and archaea on the basis of their horizontal-transfer potential and the type of relationships (mutualistic, symbiotic, commensal, or parasitic) that they have with the host cell vehicle. Horizontal movement of replicators can be either active or passive, reflecting whether or not the replicator encodes the means to mediate its own transfer from one cell to another. Some replicators also have an infectious extracellular state, thus separating viruses from other mobile elements. From the perspective of the cell vehicle, the different types of replicators form a continuum from genuinely mutualistic to completely parasitic replicators. This classification provides a general framework for dissecting prokaryotic systems into evolutionarily meaningful components.

Nontrivial quantum and quantum-like effects in biosystems: Unsolved questions and paradoxes.

Non-trivial quantum effects in biological systems are analyzed. Some unresolved issues and paradoxes related to quantum effects (Levinthal's paradox, the paradox of speed, and mechanisms of evolution) are addressed. It is concluded that the existence of non-trivial quantum effects is necessary for the functioning of living systems. In particular, it is demonstrated that classical mechanics cannot explain the stable work of the cell and any over-cell structures. The need for quantum effects is generated also by combinatorial problems of evolution. Their solution requires a priori information about the states of the evolving system, but within the framework of the classical theory it is not possible to explain mechanisms of its storage consistently. We also present essentials of so called quantum-like paradigm: sufficiently complex bio-systems process information by violating the laws of classical probability and information theory. Therefore the mathematical apparatus of quantum theory may have fruitful applications to describe behavior of bio-systems: from cells to brains, ecosystems and social systems. In quantum-like information biology it is not presumed that quantum information bio-processing is resulted from quantum physical processes in living organisms. Special experiments to test the role of quantum mechanics in living systems are suggested. This requires a detailed study of living systems on the level of individual atoms and molecules. Such monitoring of living systems in vivo can allow the identification of the real potentials of interaction between biologically important molecules.

Evolution of functional diversification within quasispecies.

According to quasispecies theory, high mutation rates limit the amount of information genomes can store (Eigen's Paradox), whereas genomes with higher degrees of neutrality may be selected even at the expenses of higher replication rates (the "survival of the flattest" effect). Introducing a complex genotype to phenotype map, such as RNA folding, epitomizes such effect because of the existence of neutral networks and their exploitation by evolution, affecting both population structure and genome composition. We reexamine these classical results in the light of an RNA-based system that can evolve its own ecology. Contrary to expectations, we find that quasispecies evolving at high mutation rates are steep and characterized by one master sequence. Importantly, the analysis of the system and the characterization of the evolved quasispecies reveal the emergence of functionalities as phenotypes of nonreplicating genotypes, whose presence is crucial for the overall viability and stability of the system. In other words, the master sequence codes for the information of the entire ecosystem, whereas the decoding happens, stochastically, through mutations. We show that this solution quickly outcompetes strategies based on genomes with a high degree of neutrality. In conclusion, individually coded but ecosystem-based diversity evolves and persists indefinitely close to the Information Threshold.