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Homochirality is a feature of life, but its origin is still disputed. Recent theories indicate that the origin of homochirality coincided with that of the RNA world, but proteins have not yet been incorporated into the story. Ribosome is considered a living fossil that survived the RNA world and records the oldest interaction between RNA and proteins. Inspired by several ribosome-related findings, we propose a hypothesis as follows: the substrate chirality preference of some primitive peptide synthesis ribozymes can mediate the chirality transmission from RNA to protein. In return, the chiral preference of protective peptide-RNA interaction can bring these ribozymes an evolutionary advantage and facilitate the expansion of enantiomeric excess in peptides. Monte Carlo simulation results show that this system's chemistry model is plausible. This model can be further tested through investigation of the chirality preference for the interactions between d/l-ribose-composed rRNA homologs and l/d-amino acid-composed peptides.

The origin of life has long baffled scientists, trying to shed some light on the universe of the unknown we live in. The RNA world hypothesis is merely an idea that tries to grasp the root of life by going beyond phylogenetic trees, and the ‘Drawinian threshold'. The birth of this hypothesis came with the discovery of ribozymes and certain relic molecules left behind by an RNA ruled world about -3.8 billion years ago. These primitive cells were the most minimal forms of life and experiments are trying to show this by mimicking primitive earth environments. Nucleotides have been shown to polymerize into random chains easily on clay or in ice and the chemical synthesis of RNA is possible although extremely challenging without the modern cellular machinery. The RNA world is untraceable because of horizontal gene transfer, which is highly criticized by researches, and still remains a widely researched and studied topic as it could be the heart of life on other earth like planets in the universe. The state of the model needs improvements in analytical techniques and experiments for the rate of Horizontal Gene Transfer on loosely bound components, and continued comparison of the different types of phylogenetic trees to widen the evolution of the genetic core. Furthermore the development of analytical techniques used for the monitoring of the Donan effect may show more insight into the division and growth of primitive cellular membranes and the continued research and exploration in the fields of Ribozymes, with a goal to reach a higher catalytic range with high fidelity and rate.

The modern version of the RNA World Hypothesis begins with activated ribonucleotides condensing (nonenzymatically) to make RNA molecules, some of which possess (perhaps slight) catalytic activity. We propose that noncanonical ribonucleotides, which would have been inevitable under prebiotic conditions, might decrease the RNA length required to have useful catalytic function by allowing short RNAs to possess a more versatile collection of folded motifs. We argue that modified versions of the standard bases, some with features that resemble cofactors, could have facilitated that first moment in which early RNA molecules with catalytic capability began their evolutionary path toward self-replication.

In recent years, the role of non-coding RNAs (ncRNAs) in regulating cell physiology has begun to be better understood. Recent discoveries in viral molecular biology have revealed that such cellular functions are disturbed during viral infections mainly due to host cell ncRNAs, cellular factors, and virus-derived ncRNAs. Apart from the interplay between those molecules, other interactions derive from the specific folding of RNA virus genomes. These fulfill canonical regulation functions such as replication, translation, and viral packaging. In some cases, folds serve as precursors of small viral RNAs whose biogenesis is not yet clearly understood. Since ncRNAs and RNA viral genomes modulate complex molecular and cellular processes in viral infections, a new taxonomy is being proposed here overarching three main categories, considering the current information about ncRNA interactions in some well-known viral infections. The first category shows examples of host ncRNAs associated with the trigger of the immune response under viral infections. The second category describes interactions between the virus and host ncRNAs. The last category shows how the shape of the RNA viral genome is essential in processing RNAs derived from viruses. Finally, we introduce evidence of how these three categories can also work as a framework in order to organize known interactions of ncRNAs and cellular factors under DENV infection. This new taxonomy of interactions provides a comprehensive framework for organizing the ncRNA regulatory roles in the context of viral interactions and an RNA world.

The encapsulation of genetic material inside compartments together with the creation and sustenance of functionally diverse internal components are likely to have been key steps in the formation of ‘live’, replicating protocells in an RNA world. Several experiments have shown that RNA encapsulated inside lipid vesicles can lead to vesicular growth and division through physical processes alone. Replication of RNA inside such vesicles can produce a large number of RNA strands. Yet, the impact of such replication processes on the emergence of the first ribozymes inside such protocells and on the subsequent evolution of the protocell population remains an open question. In this paper, we present a model for the evolution of protocells with functionally diverse ribozymes. Distinct ribozymes can be created with small probabilities during the error-prone RNA replication process via the rolling circle mechanism. We identify the conditions that can synergistically enhance the number of different ribozymes inside a protocell and allow functionally diverse protocells containing multiple ribozymes to dominate the population. Our work demonstrates the existence of an effective pathway towards increasing complexity of protocells that might have eventually led to the origin of life in an RNA world.

Various self-cleaving ribozymes appearing in nature catalyze the sequence-specific intramolecular cleavage of RNA and can be engineered to catalyze cleavage of appropriate substrates in an intermolecular fashion, thus acting as true catalysts. The mechanisms of the small, self-cleaving ribozymes have been extensively studied and reviewed previously. Self-cleaving ribozymes can possess high catalytic activity and high substrate specificity; however, substrate specificity is also engineerable within the constraints of the ribozyme structure. While these ribozymes share a common fundamental catalytic mechanism, each ribozyme family has a unique overall architecture and active site organization, indicating that several distinct structures yield this chemical activity. The multitude of catalytic structures, combined with some flexibility in substrate specificity within each family, suggests that such catalytic RNAs, taken together, could access a wide variety of substrates. Here, we give an overview of 10 classes of self-cleaving ribozymes and capture what is understood about their substrate specificity and synthetic applications. Evolution of these ribozymes in an RNA world might be characterized by the emergence of a new ribozyme family followed by rapid adaptation or diversification for specific substrates., Self-cleaving ribozymes have become important tools of synthetic biology. Here we summarize the substrate specificity and applications of the main classes of these ribozymes.

In this paper the hypothesis that prions and prion-like molecules could have initiated the chemical evolutionary process which led to the eventual emergence of life is reappraised. The prions first hypothesis is a specific application of the protein-first hypothesis which asserts that protein-based chemical evolution preceded the evolution of genetic encoding processes. This genetics-first hypothesis asserts that an “RNA-world era” came before protein-based chemical evolution and rests on a singular premise that molecules such as RNA, acetyl-CoA, and NAD are relics of a long line of chemical evolutionary processes preceding the Last Universal Common Ancestor (LUCA). Nevertheless, we assert that prions and prion-like molecules may also be relics of chemical evolutionary processes preceding LUCA. To support this assertion is the observation that prions and prion-like molecules are involved in a plethora of activities in contemporary biology in both complex (eukaryotes) and primitive life forms. Furthermore, a literature survey reveals that small RNA virus genomes harbor information about prions (and amyloids). If, as has been presumed by proponents of the genetics-first hypotheses, small viruses were present during an RNA world era and were involved in some of the earliest evolutionary processes, this places prions and prion-like molecules potentially at the heart of the chemical evolutionary process whose eventual outcome was life. We deliberate on the case for prions and prion-like molecules as the frontier molecules at the dawn of evolution of living systems.

Parasitism emerges readily in models and laboratory experiments of RNA world and would lead to extinction unless prevented by compartmentalisation or spatial patterning. Modelling replication as an active computational process opens up many degrees of freedom that are exploited to meet environmental challenges, and to modify the evolutionary process itself. Here we use automata chemistry models and spatial RNA world models to study the emergence of parasitism and the complexity that evolves in response. The system is initialised with a hand-designed replicator that copies other replicators with a small chance of point mutation. Almost immediately, short parasites arise; these are copied more quickly, and so have an evolutionary advantage. The replicators also become shorter, and so are replicated faster; they evolve a mechanism to slow down replication, which reduces the difference of replication rate of replicators and parasites. They also evolve explicit mechanisms to discriminate copies of self from parasites; these mechanisms become increasingly complex. New parasite species continually arise from mutated replicators, rather than from evolving parasite lineages. Evolution itself evolves, eg by effectively increasing point mutation rates, and by generating novel emergent mutational operators. Thus, parasitism drives the evolution of complex replicators and complex ecosystems.

Summary The ribosome is the most complex molecular machine shared by all cellular life forms. Details of its evolution from an RNA world precursor are still encrypted in its molecular sequences, which are gradually yielding information beyond the reach of phylogenetic trees. Meanwhile, researchers can now study the assembly of the structure in real time, yielding further insights into the origins of complexity. Michael Gross reports.

Based on the RNA world hypothesis, we outline a possible evolutionary route from infrabiological systems to early protocells. To assess the scientific merits of the different models of prebiotic evolution and to suggest directions for future research, we investigate the diversity-maintaining ability, evolutionary/ecological stability, and evolvability criteria of existing RNA world model systems for the origin of life. We conclude that neither of the studied systems satisfies all of the aforementioned criteria, although some of them are more convincing than the others. Furthermore, we found that the most conspicuous features of the proposed prebiotic evolutionary scenarios are their increasing spatial inhomogeneity along with increasing plasticity, evolvability, and functional diversity. All of these characteristics change abruptly with the emergence of the protocells.

The evolutionary origin of the genome remains elusive. Here, I hypothesize that its first iteration, the protogenome, was a multi-ribozyme RNA. It evolved, likely within liposomes (the protocells) forming in dry-wet cycling environments, through the random fusion of ribozymes by a ligase and was amplified by a polymerase. The protogenome thereby linked, in one molecule, the information required to seed the protometabolism (a combination of RNA-based autocatalytic sets) in newly forming protocells. If this combination of autocatalytic sets was evolutionarily advantageous, the protogenome would have amplified in a population of multiplying protocells. It likely was a quasispecies with redundant information, e.g., multiple copies of one ribozyme. As such, new functionalities could evolve, including a genetic code. Once one or more components of the protometabolism were templated by the protogenome (e.g., when a ribozyme was replaced by a protein enzyme), and/or addiction modules evolved, the protometabolism became dependent on the protogenome. Along with increasing fidelity of the RNA polymerase, the protogenome could grow, e.g., by incorporating additional ribozyme domains. Finally, the protogenome could have evolved into a DNA genome with increased stability and storage capacity. I will provide suggestions for experiments to test some aspects of this hypothesis.

The early history of life on Earth likely included a stage in which life existed as self-replicating protocells with single-stranded RNA (ssRNA) genomes. In this RNA world, genome damage from a variety of sources (spontaneous hydrolysis, UV, etc.) would have been a problem for survival. Selection pressure for dealing with genome damage would have led to adaptive strategies for mitigating the damage. In today’s world, RNA viruses with ssRNA genomes are common, and these viruses similarly need to cope with genome damage. Thus ssRNA viruses can serve as models for understanding the early evolution of genome repair. As the ssRNA protocells in the early RNA world evolved, the RNA genome likely gave rise, through a series of evolutionary stages, to the double-stranded DNA (dsDNA) genome. In ssRNA to dsDNA evolution, genome repair processes also likely evolved to accommodate this transition. Some of the basic features of ssRNA genome repair appear to have been retained in descendants with dsDNA genomes. In particular, a type of strand-switching recombination occurs when ssRNA replication is blocked by a damage in the template strand. Elements of this process appear to have a central role in recombinational repair processes during meiosis and mitosis of descendant dsDNA organisms.

Nine distinct classes of self-cleaving ribozymes are known to date, of which the pistol ribozyme class was discovered only 5 years ago. Self-cleaving ribozymes are able to cleave their own phosphodiester backbone at a specific site with rates much higher than those of spontaneous RNA degradation. Our study focuses on a bioinformatically predicted pistol ribozyme from the bacterium Paenibacillus polymyxa. We provide a biochemical characterization of this ribozyme, which includes an investigation of the effect of various metal ions on ribozyme cleavage and a kinetic analysis of ribozyme activity under increasing Mg2+ concentrations and pH. Based on the obtained results, we discuss a possible catalytic role of divalent metal ions. Moreover, we investigated the ligation activity of the P. polymyxa pistol ribozyme – an aspect that has not been previously analysed for this ribozyme class. We determined that the P. polymyxa pistol ribozyme is almost fully cleaved at equilibrium with the ligation rate constant being nearly 30-fold lower than the cleavage rate constant. In summary, we have characterized an additional representative of this recently discovered ribozyme class isolated from P. polymyxa. We expect that our biochemical characterization of a pistol representative in a cultivatable, genetically tractable organism will support our future investigation of the biological roles of this ribozyme class in bacteria. Read the transcript Watch the video on Vimeo

The Metabolically Coupled Replicator System (MCRS) model of early chemical evolution offers a plausible and efficient mechanism for the self-assembly and the maintenance of prebiotic RNA replicator communities, the likely predecessors of all life forms on Earth. The MCRS can keep different replicator species together due to their mandatory metabolic cooperation and limited mobility on mineral surfaces, catalysing reaction steps of a coherent reaction network that produces their own monomers from externally supplied compounds. The complexity of the MCRS chemical engine can be increased by assuming that each replicator species may catalyse more than a single reaction of metabolism, with different catalytic activities of the same RNA sequence being in a trade-off relation: one catalytic activity of a promiscuous ribozyme can increase only at the expense of the others on the same RNA strand. Using extensive spatially explicit computer simulations we have studied the possibility and the conditions of evolving ribozyme promiscuity in an initial community of single-activity replicators attached to a 2D surface, assuming an additional trade-off between replicability and catalytic activity. We conclude that our promiscuous replicators evolve under weak catalytic trade-off, relatively strong activity/replicability trade-off and low surface mobility of the replicators and the metabolites they produce, whereas catalytic specialists benefit from very strong catalytic trade-off, weak activity/replicability trade-off and high mobility. We argue that the combination of conditions for evolving promiscuity are more probable to occur for surface-bound RNA replicators, suggesting that catalytic promiscuity may have been a significant factor in the diversification of prebiotic metabolic reaction networks., Author summary Complex biochemical machineries responsible for maintaining the correct ratio of enzymes and genes were highly unlikely to exist at the wake of life. Individual genes must have been subject to competition for resources of replication leading to the competitive exclusion between them, and thus to the loss of genetic information. A feasible scenario that avoids competitive exclusion requires the assumption of mandatory cooperation between the enzymes. A potentially dynamically important but mostly neglected feature of RNA enzymes (ribozymes) is their capacity to catalyse more than a single reaction. Here, we analyse the possibility that this “promiscous” nature of prebiotic ribozymes could have helped the maintenance of early replicator communities cooperating in running a simple metabolism. To do so, we have implemented a spatially explicit computer model simulating the dynamics of replicating entities on a mineral surface–an extension of the Metabolically Coupled Replicator System including the possibility of multiple catalytic activities within the same replicator. Our results suggest that under realistic assumptions of replicator and metabolite mobility and feasible trade-off relations between different catalytic activities of the same RNA replicator molecule, catalytic promiscuity may have indeed helped booting up life through supporting the assembly of minimal metabolisms.

As a mental framework for the transition of self-replicating biological forms, the RNA world concept stipulates a dual function of RNAs as genetic substance and catalyst. The chaperoning function is found intrinsic to ribozymes involved in protein synthesis and tRNA maturation, enriching the primordial RNA world with proteins of biological relevance. The ribozyme-resident protein folding activity, even before the advent of protein-based molecular chaperone, must have expedited the transition of the RNA world into the present protein theatre.

The RNA World theory encompasses the hypothesis that sophisticated ribozymes and riboswitches were the primary drivers of metabolic processes in ancient organisms. Several types of catalytic RNAs and many classes of ligand-sensing RNA switches still exist in modern cells. Curiously, allosteric ribozyme formed by the merger of RNA enzyme and RNA switch components are largely absent in today’s biological systems. This is true despite the striking abundances of various classes of both self-cleaving ribozymes and riboswitch aptamers. Herein we present the known types of ligand-controlled ribozymes and riboswitches and discuss the possible reasons why fused ribozyme-aptamer constructs have been disfavored through evolution.

LncRNAs (long non-coding RNAs) are pervasively transcribed in the human genome and also extensively involved in a variety of essential biological processes and human diseases. The comprehensive annotation of human lncRNAs is of great significance in navigating the functional landscape of the human genome and deepening the understanding of the multi-featured RNA world. However, the unique characteristics of lncRNAs as well as their enormous quantity have complicated and challenged the annotation of lncRNAs. Advances in high-throughput sequencing technologies give rise to a large volume of omics data that are generated at an unprecedented rate and scale, providing possibilities in the identification, characterization and functional annotation of lncRNAs. Here, we review the recent important discoveries of human lncRNAs through analysis of various omics data and summarize specialized lncRNA database resources. Moreover, we highlight the multi-omics integrative analysis as a powerful strategy to efficiently discover and characterize the functional lncRNAs and elucidate their potential molecular mechanisms.

Life emerging in an RNA world is expected to propagate RNA as hereditary information, requiring some form of primitive replication without enzymes. Nonenzymatic template-directed RNA primer extension is a model of the polymerisation step in this posited form of replication. The sequence space accessed by primer extension dictates potential pathways to self-replication and, eventually, ribozymes. Which sequences can be accessed? What is the fidelity of the reaction? Does the recently-illuminated mechanism of primer extension affect the distribution of sequences that can be copied? How do sequence features respond to experimental conditions and prebiotically relevant contexts? To help answer these and related questions, we here introduce a deep-sequencing methodology for studying RNA primer extension. We have designed and vetted special RNA constructs for this purpose, honed a protocol for sample preparation and developed custom software that sorts and analyses raw sequencing data. We apply this new methodology to proof-of-concept controls, and demonstrate that it works as expected and reports on key features of the sequences accessed by primer extension.

The origins of life on Earth have been the subject of inquiry since the early days of philosophical thought and are still intensively investigated by the researchers around the world. One of the theories explaining the life emergence, that gained the most attention recently is the RNA World hypothesis, which assumes that life on Earth was sparked by replicating RNA chains. Since wet lab analysis is time-consuming, many mathematical and computational approaches have been proposed that try to explain the origins of life. Recently proposed one, based on the work by Takeuchi and Hogeweg, addresses the problem of interplay between RNA replicases and RNA parasitic species, which is crucial for understanding the first steps of prebiotic evolution. In this paper, the aforementioned model has been extended and modified by introducing RNA sequence (structure) information and mutation rate close to real one. It allowed to observe the simple evolution mechanisms, which could have led to the more complicated systems and eventually, to the formation of the first cells. The main goal of this study was to determine the conditions that allowed the spontaneous emergence and evolution of the prebiotic replicases equipped with simple functional domains within a large population. Here we show that polymerase ribozymes could have appeared randomly and then quickly started to copy themselves in order for the system to reach equilibrium. It has been shown that evolutionary selection works even in the simplest systems.

Life might have originated in an ‘RNA world’ yet until a few years ago, RNA was perceived just as a transient intermediate that ferried genetic information from DNA to protein [1]. With the advent of -omics, the rather pervasive nature of transcription came to the fore, suggesting non protein coding functions of RNA. Today there are numerous species of RNA known to us and varied methods of studying them have been established. We start this chapter with a brief introduction to the classical and contemporary protocols of RNA extraction from sources ranging from monolayer cells to tissues and 3D organoids. Since the premise is to familiarize the reader with the different experimental methods in the field that are routinely employed to study RNA, we have attempted to arrange these techniques chronologically. We conclude with a discussion on single cell (sc)RNA-seq and epitranscriptomics.

Ribonucleic acid or RNA is an essential bio-macromolecule, having a variety of functions like gene coding & decoding, regulation of gene expression, etc., in all domains of life like viruses, microbes, fungus, plants and animals. RNA has been considered a primordial biomolecule possibly played a vital role in the evolution of life and playing significant function in almost all cellular processes. Not only as a major component of cellular machinery, microbial and viral RNA’s are widely used as a diagnostic or prognostic markers for a number of human diseases. The omnipresence of RNA molecules either as genetic elements or expression element, possible primitive nature, functional and regulatory unit of the cellular molecular machinery, features of molecular marker, allowed this molecule to fetch the attention of worldwide researchers. Advances in molecular tools enabled in depth exploration of the RNA world of viruses, microbes and plants and made breakthrough discoveries about the role if RNA in cellular bioprocesses. Current chapter is focused to summarize these breakthrough discoveries about the functional role of RNA in modulating or defining physiology of plants, microbes and viruses is complied to enhance the knowledge base of the readers about the RNA world.

In the RNA world, enrichment of self-replicating RNAs would have been beneficial to their survival, amplification, and evolution. Self-assembly of RNAs may be a strategy by which they enrich themselves. We examined the effects of molecular crowding on the activity of a bimolecular group I ribozyme and its derivative that self-assembles to form ribozyme oligomers. In a comparative activity assay using PEG as a molecular crowder, PEG rescued mutations in the parent bimolecular ribozyme more effectively than those in the oligomeric form.

The emergence of cellular compartmentalization was a crucial step in the hypothetical RNA world and its evolution because it would not only prevent the extinction of RNA self-replication systems due to dispersion/diffusion of their components but also facilitate ribozyme reactions by molecular crowding effects. Here, we proposed and examined self-assembly of RNA components as a primitive cellular-like environment, which may have the ability to mimic cellular compartmentalization and crowding effects. We engineered a bimolecular group I ribozyme to form a one-dimensional (1D)-ribozyme assembly. In the 1D assembly form, severe mutations that inactivated the parent bimolecular ribozyme were modestly rescued resulting in weak catalytic ability.

A recent revolution in RNA biology has led to the identification of new RNA classes with unanticipated functions, new types of RNA modifications, an unexpected multiplicity of alternative transcripts and widespread transcription of extragenic regions. This development in basic RNA biology has spawned a corresponding revolution in RNA-based strategies to generate new types of therapeutics. Here, I review RNA-based drug design and discuss barriers to broader applications and possible ways to overcome them. Because they target nucleic acids rather than proteins, RNA-based drugs promise to greatly extend the domain of ‘druggable’ targets beyond what can be achieved with small molecules and biologics.

Science is facing a new RNA world that is shaping our knowledge, and we are discovering a new horizon in molecular biology. New technologies revealed thousands and thousands of new RNAs, most of them located in what was once known as the "dark matter of DNA". They are functional regulatory RNAs and do not code for proteins, and they orchestrate the cellular function according to the changes needed. These noncoding RNAs are ubiquitous, and they are present from viruses to humans. In this Virtual Issue, The FEBS Journal features a collection of recent articles on long noncoding RNAs, microRNAs, and circular RNAs. It gives a broad perspective regarding their role in vascular diseases, ocular diseases, immune cell development and homeostasis, inflammation, production of extracellular matrix, and cancer. Furthermore, review-type articles highlight the potential use of noncoding RNAs in a wide range of applications.

The ability of the ribonucleic acid (RNA) to self-replicate, combined with a unique cocktail of chemical properties, suggested the existence of an RNA world at the origin of life. Nowadays, this hypothesis is supported by innovative high-throughput and biochemical approaches, which definitively revealed the essential contribution of RNA-mediated mechanisms to the regulation of fundamental processes of life. With the recent development of SARS-CoV-2 mRNA-based vaccines, the potential of RNA as a therapeutic tool has received public attention. Due to its intrinsic single-stranded nature and the ease with which it is synthesized in vitro, RNA indeed represents the most suitable tool for the development of drugs encompassing every type of human pathology. The maximum effectiveness and biochemical versatility is achieved in the guise of non-coding RNAs (ncRNAs), which are emerging as multifaceted regulators of tissue specification and homeostasis. Here, we report examples of coding and ncRNAs involved in muscle regeneration and discuss their potential as therapeutic tools. Small ncRNAs, such as miRNA and siRNA, have been successfully applied in the treatment of several diseases. The use of longer molecules, such as lncRNA and circRNA, is less advanced. However, based on the peculiar properties discussed below, they represent an innovative pool of RNA biomarkers and possible targets of clinical value.

The structural flexibility of RNA and its ability to store genetic information has led scientists to postulate that RNA could be the key molecule for the development of life on Earth, further leading to formulate the RNA world hypothesis that received a lot of success and acceptance after the discoveries of the last thirty-five years. Despite its highly structural and functional significance, the difficulty in synthesizing the four nucleobases that form the RNA polymer from the same primordial soup, its low stability, and limited catalytic repertoire, make the RNA world hypothesis less convincing even though it remains the best explanation for the origin of life. An increasing number of scientists are becoming more supportive of a more realistic approach explaining the appearance of life. In this review, I propose an enhanced explanation for the appearance of life supported by recent discoveries and theories. Accordingly, amino acids and peptides associated with RNA (e.g., ribonucleopeptides) might have existed at the onset of RNA and might have played an important role in the continuous development of self-sustaining biological systems. Therefore, in this review, I cover the most recent and relevant scientific investigations that propose a better understanding of the ribonucleopeptide world hypothesis and the appearance of life. Finally, I propose two hypotheses for a primitive translation machinery (PTM) that might have been formed of either a T box ribozyme or a ribopolymerase.

The central dogma of molecular biology rests on two kinds of asymmetry between genomes and enzymes: informatic asymmetry, where information flows from genomes to enzymes but not from enzymes to genomes; and catalytic asymmetry, where enzymes provide chemical catalysis but genomes do not. How did these asymmetries originate? Here we show that these asymmetries can spontaneously arise from conflict between selection at the molecular level and selection at the cellular level. We developed a model consisting of a population of protocells, each containing a population of replicating catalytic molecules. The molecules are assumed to face a trade-off between serving as catalysts and serving as templates. This trade-off causes conflicting multilevel selection: serving as catalysts is favoured by selection between protocells, whereas serving as templates is favoured by selection between molecules within protocells. This conflict induces informatic and catalytic symmetry breaking, whereby the molecules differentiate into genomes and enzymes, establishing the central dogma. We show mathematically that the symmetry breaking is caused by a positive feedback between Fisher’s reproductive values and the relative impact of selection at different levels. This feedback induces a division of labour between genomes and enzymes, provided variation at the molecular level is sufficiently large relative to variation at the cellular level, a condition that is expected to hinder the evolution of altruism. Taken together, our results suggest that the central dogma is a logical consequence of conflicting multilevel selection.

Owing to their ability to encapsulate biomolecules, complex coacervates formed by associative phase separation of oppositely charged polyelectrolytes have been postulated as prebiotic nonmembranous compartments (NMCs). Recent studies show that NMCs sequester RNA and enhance ribozyme reactions, a critical tenet of the RNA World Hypothesis. As RNA is negatively charged, it is expected to interact with polycationic coacervate components. The molecular basis for how identity and concentration of polyanionic components of complex coacervates affect ribozyme catalysis remains unexplored. We report here a general mechanism wherein diverse polyanions enhance ribozyme catalysis in complex coacervates. By competing for unproductive RNA-polycation interactions, polyanions enhance ribozyme reaction more than 12-fold. The generality of our findings is supported by similar behavior in three polyanions-polycarboxylates, polysulfates, and polysulfates/carboxylates-as well as two different ribozymes, the hammerhead and hairpin. These results reveal potential roles for polyanions in prebiotic chemistry and extant biology.

Background It has long been suggested that Darwinian evolution may have started at the molecular level and subsequently proceeded to a level with membrane boundary, i.e., of protocells. The transformation has been referred to as “the first major transition leading to life”. However, so far, we actually have little knowledge about the relevant evolutionary mechanisms – and even about the plausibility – of such a transition. Here, based upon the scenario of the RNA world, we performed a computer simulation study to address this issue. Results First, it was shown that at the molecular level, after the spread of one ribozyme (RNA replicase), another ribozyme (nucleotide synthetase) may emerge naturally in the system, and the two ribozymes would cooperate to spread in the naked scene. Then, when empty vesicles absorb the two ribozymes via “cytophagy”, the resulting protocells may spread in the system and substitute the naked ribozymes. As for the driven power of such a transition, it was demonstrated that the membrane boundary’s roles to ensure the cooperation between the two ribozymes and to prevent invasion of parasites are important. Beyond that, remarkably, it was found that another two factors may also have been significant: a possibly higher mobility of the raw materials in the environment (free water) and the protocells’ potential capability to move around actively. Finally, the permeability of the membrane to raw materials was shown to be a major problem regarding the disadvantage for the cellular form. Conclusions The transition from the molecular level to the cellular level may have occurred naturally in early history of evolution. The evolutionary mechanisms for this process were complex. Besides the membrane boundary’s roles to guarantee the molecular cooperation and to resist parasites, the greater chance for the protocells to access raw materials – either due to the diffusion of raw materials outside or the protocells’ active movement, should also be highlighted, which may have at least to an extent compensated the disadvantage regarding the membrane’s blocking effect against raw materials. The present study represents an effort of systematical exploration on this significant transition during the arising of life.

The discovery of exoplanets within putative habitable zones revolutionized astrobiology in recent years. It stimulated interest in the question about the origin of life and its evolution. Here, we discuss what the roles of viruses might have been at the beginning of life and during evolution. Viruses are the most abundant biological entities on Earth. They are present everywhere, in our surrounding, the oceans, the soil and in every living being. Retroviruses contributed to about half of our genomic sequences and to the evolution of the mammalian placenta. Contemporary viruses reflect evolution ranging from the RNA world to the DNA-protein world. How far back can we trace their contribution? Earliest replicating and evolving entities are the ribozymes or viroids fulfilling several criteria of life. RNA can perform many aspects of life and influences our gene expression until today. The simplest structures with non-protein-coding information may represent models of life built on structural, not genetic information. Viruses today are obligatory parasites depending on host cells. Examples of how an independent lifestyle might have been lost include mitochondria, chloroplasts, Rickettsia and others, which used to be autonomous bacteria and became intracellular parasites or endosymbionts, thereby losing most of their genes. Even in vitro the loss of genes can be recapitulated all the way from coding to non-coding RNA. Furthermore, the giant viruses may indicate that there is no sharp border between living and non-living entities but an evolutionary continuum. Here, it is discussed how viruses can lose and gain genes, and that they are essential drivers of evolution. This discussion may stimulate the thinking about viruses as early possible forms of life. Apart from our view “viruses first”, there are others such as “proteins first” and “metabolism first.”

Thirty years ago, molecular biologist Walter Gilbert published his RNA world hypothesis, which posited that early in evolution living systems were composed entirely of RNA. Proposed in the immediate wake of the discovery that certain RNA molecules were capable of catalyzing biological reactions, the hypothesis ascribed both of life's essential functions, namely carrying information and catalysis-respectively, performed by DNA and proteins in most modern life systems-to RNA, which were labeled as ribozymes. In the years since its inception, the RNA world has been greeted with equal parts enthusiasm and opposition from the origins of life research community, of which Gilbert neither was, nor really became, a part. For this special historical issue of the Journal of Molecular Evolution, Gilbert agreed to revisit his hypothesis and share his memories about the theory's origins and his insights into its fate in the years since he first published his idea.

In this chapter, we discuss the role of RNA in the major transitions that could have occurred during the origin and early evolution of life on the Earth. The ability of RNA to be a catalyst and the existence of ribozymes are important clues to how life developed. We discuss the RNA world hypothesis, and then, with examples of modern-day and laboratory-derived ribozymes, we discuss how RNA can evolve and search sequence space to discover new functions. Because RNA is a linear polymer of consecutive nucleotides, a network of related sequences can exist for any genotype. We describe the evolutionary pressures that exist to move a population of RNAs through this network and consider how similar networks can interact. Both point mutations and recombination contribute to the means by which new genotypes can emerge and evolve. Overall, these considerations depict a series of transitions that retell the history of how chemistry became biology.

The origin of life has not been solved as yet, in spit of the time passage more than thirty years from publication of RNA world hypothesis by W. Gilbert (1986), which is based on the “gene/replicator--first” theory. On the contrary, I have proposed [GADV]-protein world hypothesis (GADV hypothesis), assuming that life emerged from [GADV]-protein world, which is grounded on the “protein/metabolism-first” theory. However, two weak points of protein world hypothesis, (i) protein cannot be produced without gene, and (ii) protein cannot be self-replicated, have been frequently pointed out by supporters of RNA world hypothesis. Then, I examined whether the two weak points could be overcome by GADV hypothesis or not. From the results, it was confirmed that (i) [GADV]-protein could be pseudo-replicated in the absence of gene owing to protein 0th-order structure or [GADV]-amino acids, and (ii) the replication ability is not always required from the beginning but it is sufficient to acquire it at some time point until the emergence of life. Thus, it was concluded that life emerged as [GADV]-protein world hypothesis, which is grounded on the “protein/metabolism-first” theory, expects.

Although we live in the remnants of an RNA world, the world of drug discovery and chemical probes is firmly protein-centric. Developing highly selective small molecules targeting RNA is often considered to be an insurmountable challenge. Our goal is to demystify the design of such compounds. In this review, we describe various approaches to design small molecules that target RNA from sequence and the application of these compounds in RNA biology, with a focus on inhibition of human RNA-protein complexes. We have developed a library-versus-library screening approach to define selective RNA-small-molecule binding partners and applied them to disease-causing RNAs, in particular noncoding oncogenic RNAs and expanded RNA repeats, to modulate their biology in cells and animals. We also describe the design of new types of small-molecule probes that could broadly decipher the mysteries of RNA in cells.

A primordial but still essential ribozyme co-opts proteins as it evolves

The past decades have witnessed tremendous developments in our understanding of RNA biology. At the core of these advances have been studies aimed at discerning RNA structure and at understanding the forces that influence the RNA folding process. It is easy to take the present state of understanding for granted, but there is much to be learned by considering the path to our current understanding, which has been tortuous, with the birth and death of models, the adaptation of experimental tools originally developed for characterization of protein structure and catalysis, and the development of novel tools for probing RNA. In this review we tour the stages of RNA folding studies, considering them as "epochs" that can be generalized across scientific disciplines. These epochs span from the discovery of catalytic RNA, through biophysical insights into the putative primordial RNA World, to characterization of structured RNAs, the building and testing of models, and, finally, to the development of models with the potential to yield generalizable predictive and quantitative models for RNA conformational, thermodynamic, and kinetic behavior. We hope that this accounting will aid others as they navigate the many fascinating questions about RNA and its roles in biology, in the past, present, and future.

The past decade has witnessed exciting breakthroughs that have contributed to the richness and complexity of a burgeoning modern RNA world, and one particular breakthrough—the competing endogenous RNA (ceRNA) hypothesis—has been described as the “Rosetta Stone” for decoding the RNA language used in regulating RNA crosstalk and modulating biological functions. The proposed far-reaching mechanism unites diverse RNA species and provides new insights into previously unrecognized RNA–RNA interactions and RNA regulatory networks that perhaps determine gene expression in an organized, hierarchical manner. The recently uncovered ceRNA regulatory loops and networks have emphasized the power of ceRNA regulation in a wide range of developmental stages and pathological contexts, such as in tumorigenesis and neurodegenerative disorders. Although the ceRNA hypothesis drastically enhanced our understanding of RNA biology, shortly after the hypothesis was proposed, disputes arose in relation mainly to minor discrepancies in the reported effects of ceRNA regulation under physiological conditions, and this resulted in ceRNA regulation becoming an extensively studied and fast-growing research field. Here, we focus on the evidence supporting ceRNA regulation in neurodegenerative disorders and address three critical points related to the ceRNA regulatory mechanism: the microRNA (miRNA) and ceRNA hierarchies in cross-regulations; the balance between destabilization and stable binding in ceRNA–miRNA interactions; and the true extent to which ceRNA regulatory mechanisms are involved in both health and disease, and the experimental shortcomings in current ceRNA studies.

RNA Biology and Parity at the Bench The 2018 Lasker–Koshland Special Achievement Award in Medical Science, announced September 11, goes to Joan A. Steitz for her pioneering discoveries in RNA biology and her work toward better representation of women and minorities in scientific research.

International audience; The origin of life is mostly divided into "genetics first" and "metabolism first" hypotheses. The former is based on spark-tube tests and organics from meteorites and comets and proposes a heterotrophic origin of life also consistent with the "RNA World" concept. The "metabolism first" hypothesis posits that life began autotrophically on minerals and/or hydrothermal vents. Due to the lack of direct evidence it is not possible to lend solid support to either hypothesis but the "metabolism first" option can be explored if a continuous geochemical, catalytically dynamic process is assumed. Using this approach, I speculate that purine and pyrimidine synthesis originated on a mineral surface, which was later replaced by ATP. The same applies to redox processes where metal bound hydrides could have been replaced by NAD.

An artificially evolved ribozyme can catalyse the synthesis of RNA by using trinucleotide triphosphates as building blocks.

The presumed RNA world was a time largely dominated by RNA and ribozymes before evolution of the tRNA cloverleaf, the ribosome and RNA-directed protein coding.