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The origin of replication and translation and the RNA World

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The origin of replication and translation and the RNA World

http://reasonandscience.heavenforum.org/t2234-the-origin-of-replication-and-translation-and-the-rna-world

The very origin of the first organisms presents at least an appearance of a paradox because a certain minimum level of complexity is required to make self-replication possible at all; high-fidelity replication requires additional functionalities that need even more information to be encoded (Penny, 2005).

The crucial question in the study of the origin of life is how the Darwin-Eigen cycle started—how was the minimum complexity that is required to achieve the minimally acceptable replication fidelity attained? In even the simplest modern systems, such as RNA viruses with the replication fidelity of only about 10^3 and viroids that replicate with the lowest fidelity among the known replicons (about 10^2; Gago, et al., 2009), replication is catalyzed by complex protein polymerases. The replicase itself is produced by translation of the respective mRNA(s), which is mediated by the immensely complex ribosomal apparatus. Hence, the dramatic paradox of the origin of life is that, to attain the minimum complexity required for a biological system to start on the Darwin-Eigen spiral, a system of a far greater complexity appears to be required. How such a system could evolve is a  puzzle that defeats conventional evolutionary thinking, all of which is about biological systems moving along the spiral; the solution is bound to be unusual. 


from the book: The Logic of Chance: The Nature and Origin of Biological Evolution
By Eugene V. Koonin

The primary incentive behind the theory of self-replicating systems that Manfred Eigen outlined was to develop a simple model explaining the origin of biological information and, hence, of life itself. Eigen’s theory revealed the existence of the fundamental limit on the fidelity of replication (the Eigen threshold): If the product of the error (mutation) rate and the information capacity (genome size) is below the Eigen threshold, there will be stable inheritance and hence evolution; however, if it is above the threshold, the mutational meltdown and extinction become inevitable (Eigen, 1971). The Eigen threshold lies somewhere between 1 and 10 mutations per round of replication (Tejero, et al., 2011); regardless of the exact value, staying above the threshold fidelity is required for sustainable replication and so is a prerequisite for the start of biological evolution
(see Figure 12-1A).



Indeed, the very origin of the first organisms presents at least an appearance of a paradox because a certain minimum level of complexity is required to make self-replication possible at all; high-fidelity replication requires additional functionalities that need even more information to be encoded (Penny, 2005). However, the replication fidelity at a given point in time limits the amount of information that can be encoded in the genome. What turns this seemingly vicious circle into the (seemingly) unending spiral of increasing complexity—the Darwin-Eigen cycle, following the terminology introduced by David Penny (Penny, 2005)—is a combination of natural selection with genetic drift. Even small gains in replication fidelity are advantageous to the system, if only because of the decrease of the reproduction cost as a result of the increasing yield of viable copies of the genome. In itself, a larger genome is more of a liability than an advantage because of higher replication costs. However, moderate genome increase, such as by duplication of parts of the genome or by recombination, can be fixed via genetic drift in small populations. Replicators with a sufficiently high fidelity can take advantage of such randomly fixed and initially useless genetic material by evolving new functions, without falling off the “Eigen cliff” (see Figure 12-1B). Among such newly evolved, fitness-increasing functions will be those that increase replication fidelity, which, in turn, allows a further increase in the amount of encoded information. And so the Darwin- Eigen cycle recapitulates itself in a spiral progression, leading to a steady increase in genome complexity (see Figure 12-1A). The crucial question in the study of the origin of life is how the Darwin-Eigen cycle started—how was the minimum complexity that is required to achieve the minimally acceptable replication fidelity attained? In even the simplest modern systems, such as RNA viruses with the replication fidelity of only about 10^3 and viroids that replicate with the lowest fidelity among the known replicons (about 10^2; Gago, et al., 2009), replication is catalyzed by complex protein polymerases. The replicase itself is produced by translation of the respective mRNA(s), which is mediated by the immensely complex ribosomal apparatus. Hence, the dramatic paradox of the origin of life is that, to attain the minimum complexity required for a biological system to start on the Darwin-Eigen spiral, a system of a far greater complexity appears to be required. How such a system could evolve is a  puzzle that defeats conventional evolutionary thinking, all of which is about biological systems moving along the spiral; the solution is bound to be unusual. 
 
Or the solution might be outside the realm of philosophical  naturalism, that is, intelligent design ?!!  Very Happy

In the next sections, we first examine the potential of a top-down approach based on the analysis of extant genes, to obtain clues on possible origins of replicator systems. We then discuss the bottom-up approach. The case for a complex RNA World from protein domain evolution: The top-down view As pointed out earlier, the translation system is the only complex ensemble of genes that is conserved in all extant cellular life forms. With about 60 protein-coding genes and some 40 structural RNA genes universally conserved, the modern translation system is the best-preserved relic of the LUCA(S) and the strongest available piece of evidence that some form of LUCA(S) actually existed . Given this extraordinary conservation of the translation system, comparison of orthologous sequences reveals very little, if anything, about its origins: The emergence of the
translation system is beyond the horizon of the comparison of extant life forms. Indeed, comparative genomic reconstructions of the gene repertoire of LUCA(S) point to a complex translation system that includes at least 18 of the 20 aminoacyl-tRNA synthetases (aaRS), several translation factors, at least 40 ribosomal proteins, and several enzymes involved in rRNA and tRNA modification. It appears that the core of the translation system was already fully shaped in LUCA(S) (Anantharaman, et al., 2002). Fortunately, sequence and structure comparisons of protein and RNA components within the translation system itself are informative, thanks to the extensive paralogy among the respective genes. Whenever a pair of paralogous genes is assigned to LUCA(S), the respective duplication must have been a more ancient event, so reconstruction of the series of ancient duplications opens a window into very early stages of evolution. The story of the paralogous aaRS is particularly revealing. The aaRS form two distinct classes of ten specificities each (that is, each class is responsible for the recognition and activation of ten amino acids), with unrelated catalytic domains and distinct sets of accessory domains. The catalytic domains of the Class I and Class II aaRS belong to the Rossmann fold and the biotin synthase fold, respectively. The analysis of the evolutionary histories of these protein folds has far-reaching implications for the early evolution of the translation system and beyond (Aravind, et al., 2002). The catalytic domains of Class I aaRS form but a small twig in the evolutionary tree of the Rossmann fold domains (see Figure 12-2A).


Figure 12-2A

Diversification of protein domains, crystallization of the translation system, and the LUCA(S): Evolution of the Rossmann fold–like nucleotide-binding domains. Based on data from Aravind, et al., 2002. Only the better-known proteins are indicated. USPA = Universal stress protein A; ETFP = electron transfer flavoprotein; vWA = Von Willebrand A factor; Toprim = catalytic domain of topoisomerases, primases, and some nucleases; Receiver = a component of prokaryotic two-component signaling systems; TIR = a widespread protein-protein interaction domain in prokaryotic and eukaryotic signaling systems; Sir2 = protein (in particular, histone) deacetylase; Methylase = diverse methyltransferases. For details, see (Aravind, et al., 2002) and references therein.


Thus, the appearance of the common ancestor of the aaRS is preceded by a number of nodes along the evolutionary path from the primitive, ancestral domain to the highly diversified state that corresponds to LUCA(S). So a substantial diversity of Rossmann fold domains evolved prior to the series of duplications that led to the emergence of the aaRS of different specificities, which itself antedates LUCA(S) (see Figure 12-2A). A similar evolutionary pattern is implied by the analysis of the biotin synthase domain that gave
rise to Class II aaRS. Thus, even within these two folds alone, remarkable structural and functional complexity of protein domains had evolved before the full-fledged RNA-protein machinery of translation resembling the modern system was in place.

Ribozymes and the RNA World

The Central Dogma of molecular biology (Crick, 1970) states that, in biological systems, information is transferred from DNA to protein through an RNA intermediate (Francis Crick added the possibility of reverse information flow from RNA to DNA after the discovery of RT): DNA ↔️ RNA protein Obviously, when considering the origin of the first life forms, one faces the proverbial chicken-and egg problem: What came first, DNA or protein, the gene or the product? In that form, the problem might be outright unsolvable due to the Darwin-Eigen paradox: To replicate and transcribe DNA, functionally active proteins are required, but production of these proteins requires accurate replication, transcription, and translation of nucleic acids. If one sticks to the triad of the Central Dogma, it is impossible to envisage what could be the starting material for the Darwin-Eigen cycle. Even removing DNA from the triad and postulating that the original genetic material consisted of RNA (thus reducing the triad to a dyad), although an important idea, does not help much because the paradox remains. For the evolution toward greater complexity to take off, the system needs to somehow get started on the Darwin-Eigen cycle before establishing the feedback between the (RNA) templates (the information component of the replicator system) and proteins (the executive component). The brilliantly ingenious and perhaps only possible solution was independently proposed by Carl Woese, Francis Crick, and Leslie Orgel in 1967–68 (Crick, 1968; Orgel, 1968; Woese, 1967): neither the chicken nor the egg, but what is in the middle—RNA alone. The unique property of RNA that makes it a credible—indeed, apparently, the best—candidate for the central role in the primordial replicating system is its ability to combine informational and catalytic functions. Thus, it was extremely tempting to propose that the first replicator systems—the first life forms—consisted solely of RNA molecules that functioned both as information carriers (genomes and genes) and as catalysts of diverse reactions, including, in particular, their own replication and precursor synthesis. This bold speculation has been spectacularly boosted by the discovery and subsequent study of ribozymes (RNA enzymes), which was pioneered by the discovery by Thomas Cech and colleagues in 1982 of the autocatalytic cleavage of the Tetrahymena rRNA intron, and by the demonstration in 1983 by Sydney Altman and colleagues that RNAse P is a ribozyme. Following these seminal discoveries, the study of ribozymes has evolved into a vast, expanding research area (Cech, 2002; Doudna and Cech, 2002; Fedor and Williamson, 2005). The discovery of ribozymes made the idea that the first replicating systems consisted solely of RNA molecules, which catalyzed their own replication, enormously attractive. In 1986, Walter Gilbert coined the term “RNA World” to designate this hypothetical stage in the evolution of life, and theRNA World hypothesis caught on in a big way; it became the leading and most popular hypothesis on the early stages of evolution. (The diverse aspects of the RNA World hypothesis and the supporting data are thoroughly covered in the eponymous book that in 2010 appeared in its fourth edition: Atkins, et al., 2010.) The popularity of the RNA World hypothesis has further stimulated ribozyme research aimed at testing the feasibility of various RNA-based catalytic activities—above all, perhaps, an RNA replicase. It is noteworthy that the main experimental approach employed to develop ribozymes with desired activities is in vitro selection that, at least conceptually, mimics the Darwinian evolution of ribozymes thought to have occurred in the primeval RNA World (Ellington, et al., 2009). The directed selection experiments are designed in such a way that, from a random population of RNA sequences, only those are amplified that catalyze the target reaction. In multiple-round selection
experiments, ribozymes have been evolved to catalyze an extremely broad variety of reactions. Box 12-1 lists some of the most biologically relevant ribozyme-catalyzed reactions.



Notably, all three elementary reactions that are required for translation—namely (i) amino acid activation through the formation of aminoacyl-AMP, (ii) (t)RNA aminoacylation, and (iii) transpeptidation (the peptidyltransferase reaction)—have been successfully modeled with ribozymes. The selfaminoacylation reaction that is key to the origin of the primordial RNA-only adaptors (the RNA analog of aaRS) has been selected in vitro with relative ease. Strikingly, the best of the resulting ribozymes catalyze this reaction with a rate and specificity greater than those of the respective aaRS, and very short oligonucleotides possessing this activity have been selected (Turk, et al., 2010). Understandably, major effort has focused on the demonstration of nucleotide polymerization and, ultimately, RNA replication catalyzed by ribozymes, the central processes in the hypothetical primordial RNA World. The outcome of the experiments aimed at the creation of ribozyme replicases so far has been mixed (Cheng and Unrau, 2010). Ribozymes have been obtained that are capable of extending a primer annealed to a template (Johnston, et al., 2001); initially, the ribozymes with this activity could function only by specific base-pairing to the template, but subsequently general ribozyme polymerases of this class have been evolved through additional selection (Lincoln and Joyce, 2009). The latest breakthrough in the field of polymerase ribozymes has been published at the time of the final editing of this chapter: an active endonuclease ribozyme was produced using a
ribozyme polymerase that itself was constructed by recombining two pre-existing ribozymes, potentially, a plausible route for pre-biological evolution (Wochner, et al., 2011). All this progress notwithstanding, the ribozyme polymerases that are currently available are a far cry from processive, sufficiently accurate (in terms of the Eigen threshold) replicases, capable of catalyzing the replication of exogenous templates and themselves. Enzymes with such properties appear to be a conditio sine qua non for the evolution of the hypothetical RNA World. Besides, even the available ribozymes with the limited RNA polymerase capacity are rather complex molecules that consist of some 200 nucleotides and could be nontrivial to evolve in the prebiotic setting.

Is the evidence in support of any of these models and scenarios compelling? Of course, the question already implies a negative answer. We do have some strong hints, even if these are a far cry from a coherent scenario of the earliest stages of evolution of biological information transmission. First, consider the apparent logical inevitability of an RNA World: What other starting point for the evolution of the translation system could there be? Second, comparative analysis of the translation system components does point to a much greater role of RNA in ancestral translation, compared to the modern system—notably, the decisive function of RNA as the determinant of amino acid–codon specificity. Third, ribozymes are impressive (if in general far inferior to proteins) in their catalytic versatility and efficiency. Thirty years ago, no catalytic activity was reported for any RNA molecule to catalyze any reaction at all; now we are aware of dozens of ribozyme activities, including some, such as highly efficient aminoacylation, that get the translation system going. However, this is about all the good news; the rest is more like a sobering cold shower. For all the advances of “ribozymology,” no ribozyme polymerase comes close to what is required if we are to accept an RNA-only replicator system as a key intermediate stage in the evolution of life. Nor are any ribozymes capable of catalyzing the synthesis of nucleotides or even their sugar moieties. Even sweeping all these problems under the proverbial rug, the path from a putative RNA World to the translation system is incredibly steep. The general idea of a function(s) for abiogenic amino acids and possibly peptides in the RNA World, such as the role of ribozyme cofactors (see the discussion in the preceding sections), appears fruitful and is compatible with experimental data. Nevertheless, breaking the evolution of the translation system into incremental steps, each associated with a biologically plausible selective advantage, is extremely difficult even within a speculative scheme let alone experimentally. The triplicase/protoribosome hypothesis is attractive as an attempt to explain the origin of translation and replication in one sweep, but is this scenario realistic? The triplicase itself would have to be an extremely complex, elaborate molecular machine, leaving one with the suspicion that, all its attraction notwithstanding, the triplicase might not be the most likely solution to the origin of translation problem.

The overall situation in the origin of life field appears rather grim. Even under the (highly nontrivial) assumption that monomers such as NTP are readily available, the problem of the synthesis of sufficiently stable, structurally regular polymers (RNA) is formidable, and the origin of replication and translation from such primordial RNA molecules could be an even harder problem. As emphasized repeatedly in this book, evolution by natural selection and drift can begin only after replication with sufficient fidelity is established. Even at that stage, the evolution of translation remains highly problematic. The emergence of the first replicator system, which represented the “Darwinian breakthrough,” was inevitably preceded by a succession of complex, difficult steps for which biological evolutionary mechanisms were not accessible (see Figure 12-6).


Figure 12-6 The prebiological and biological stages of the origin of life: the transition from anthropic causality to biological evolution.

Even considering environments that could facilitate these processes, such as networks of inorganic compartments at hydrothermal vents, multiplication of the probabilities for these steps could make the emergence of the first replicators staggeringly improbable.

The ultimate enigma of the origin of life

The origin of life—or, to be more precise, the origin of the first replicator systems and the origin of translation—remains a huge enigma, and progress in solving these problems has been very modest—in the case of translation, nearly negligible. Some potentially fruitful observations and ideas exist, such as the discovery of plausible hatcheries for life, the networks of inorganic compartments at hydrothermal vents, and the chemical versatility of ribozymes that fuels the RNA World hypothesis. However, these advances remain only preliminaries, even if important ones, because they do not even come close to a coherent scenario for prebiological evolution, from the first organic molecules to the first replicator systems, and from these to bona fide biological entities in which information storage and function are partitioned between distinct classes of molecules (nucleic acids and proteins, respectively). In my view, all advances notwithstanding, evolutionary biology is and will remain woefully incomplete until there is at least a plausible, even if not compelling, origin of life scenario.

Under this replication-centered perspective, the emergence of complexity is an enigma: Why are there numerous life forms that are far more complex than the minimal, simplest device for replication? We cannot know “for sure” what these minimally complex devices are, but there are excellent candidates —namely, the simplest autotrophic bacteria and archaea, such as Pelagibacter ubique or Prochlorococcus sp. These organisms get by with about 1,300 genes without using any organic molecules, and generally without any dependence on other life forms. Incidentally, these are also the most “successful” organisms on Earth. They have the largest populations that have evolved under the strongest selection pressure—and consequently have the most “streamlined” genomes. A complete biosphere consisting of such highly effective unicellular organisms is easily imaginable; indeed, the Earth biota prior to the emergence of eukaryotes (that is, probably for the 2 billion years of the evolution of life or so) must have resembled this image much closer than today’s biosphere (although more complex prokaryotes certainly existed even at that time).

So why complex organisms?


One answer that probably appeared most intuitive to biologists and to everyone else interested in evolution over the centuries is that the more complex organisms are also the more fit. This view is demonstrably false. Indeed, to accentuate the paradox of complexity, the general rule is the opposite: The more complex a life form is, the smaller effective population size it has, and so the less successful it is, under the only sensible definition of evolutionary success. This pattern immediately suggests that the answer to the puzzle of complexity emergence could be startlingly simple: Just turn this trend around and posit that the smaller the effective population size, the weaker the selection intensity, hence the greater the chance of non-adaptive evolution of complexity. This is indeed the essence of the population-genetic non-adaptive concept that Lynch propounded.



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The Darwin-Eigen cycle, the emergence of biological complexity, and the continuity principle


As first outlined by Darwin [1], the evolution of life is based on the triad of heredity (the property of progeny to resemble their parent(s)), variation (generation of variants as a result of errors during reproduction), and selection (differential reproduction of variants). The theory of self-replicating systems that was developed, primarily, by Eigen and coworkers in the 1970ies [3] revealed an important limit (hereinafter the Eigen threshold) on the relationships between the reproduction fidelity and the amount of information contained in the system. Simply put, if the product of the error (mutation) rate and the information capacity (genome size) is safely below one (i.e., less then one error per genome is expected to occur per replication cycle), most of the progeny will be exact copies of the parent, and reproduction of the system will be sustainable. If, in contrast, this value is significantly greater than one, most of the progeny will differ from the parent, and the system will not possess sufficiently faithful heredity to reproduce itself; in other words, a system whose fidelity drops below the Eigen threshold is headed for collapse resulting from an error catastrophe (a term and idea traceable to the early hypothesis of Orgel on the possible contribution of translation errors to aging [4]). It appears that the product of the replication fidelity and the genome size of modern life forms, from RNA viruses to complex eukaryotes, is, typically, close to the Eigen threshold, indicating that evolution solves an optimization problem with respect to replication fidelity, information content of the genome, and, possibly, variation (evolvability) [5].


How does the author know that evolution was the providing force of replication fidelity ? Answer. He doesn't know. 

Taking the replication process over the Eigen threshold is required for sustainable replication and is, per force, a pre-requisite for the start of biological evolution (Fig. ​(Fig.1).). Indeed, the very origin of the first organisms presents, at least, an appearance of a paradox because a certain minimum level of complexity is required to make self-replication possible at all, and high-fidelity replication requires additional functionalities that need even more information to be encoded. At the same time, the existing level of replication fidelity limits the amount of information that can be encoded in the genome [3,6,7]. What turns this seemingly vicious circle into the (seemingly) unending spiral of increasing complexity (the Darwin-Eigen cycle, after Penny [8]) is a combination of natural selection with genetic drift. Even small gains in replication fidelity are advantageous to the system, if only due to the decrease of the reproduction cost as a result of the increasing yield of viable copies of the genome. In itself, a larger genome is more of a liability than an advantage due to higher replication costs. However, moderate genome increase, e.g., by duplication of parts of the genome, or by recombination, can be fixed via genetic drift in small populations [9]. Replicators with a sufficiently high fidelity can take advantage of such randomly fixed and, initially, useless genetic material by evolving new functions, without falling off the "Eigen cliff" (Fig. ​(Fig.1).). Among such newly evolved, fitness-increasing functions will be those that increase replication fidelity which, in turn, allows further increase in the amount of encoded information. And so the Darwin-Eigen cycle recapitulates itself in a spiral progression, leading to a steady increase in genome complexity (Fig. ​(Fig.2).
Figure 1
The Eigen threshold for replication fidelity. Fitness could potentially increase with the increase of the genome size and replication fidelity. However, exceeding the genome size limit, imposed by the fidelity that is attainable at the given point in ...
Figure 2
The Darwin-Eigen cycle. The Darwin-Eigen cycle, driven, in part, by selection and, in part, by drift, provides the path to the increasing complexity in course of the evolution of biological systems.
The crucial question on the origin of life is how did the Darwin-Eigen cycle start, i.e., how was the minimal complexity attained that is required to achieve the minimally acceptable replication fidelity. In even the simplest modern systems, such as RNA viruses with the replication fidelity of only ~10-3, replication is catalyzed by a complex protein replicase [10]. The replicase itself is produced by translation of the respective mRNA(s) which is mediated by a tremendously complex molecular machinery (see below). Hence the dramatic paradox of the origin of life: in order to attain the minimal complexity required for a biological system to get on the Darwin-Eigen spiral, a system of a far greater complexity appears to be required. How such a system could evolve, is a puzzle that defeats conventional evolutionary thinking, all of which is about biological systems moving along the spiral; the solution is bound to be unusual.
The origin of complex biological systems is a classical topic in evolutionary biology and, probably, the principal object of attacks of anti-darwinists of all ilk, including the notorious Intelligent Design movement. The gist of the criticisms is that many biological systems are not just complex but "irreducibly complex" and, as such, could never evolve via the Darwinian mechanism of gradual, stepwise adaptive change because intermediate stages of evolution would have no selective value and so could not be fixed. Darwin himself was perfectly aware of the problem and its dimensions and addressed it in one of the most famous passages of the Origin, the one on the evolution of the vertebrate eye [1]. The solution offered by Darwin and developed ever since in numerous works of evolutionary biology was straightforward in principle and extremely ingenious when it came to details. Darwin noticed that primitive eyes (or eye-like perceptive organs) were found in a variety of animals and outlined a hypothetical, multistage scenario for the evolution of the eye in which each simple, small step was selected for a particular advantage it conferred onto the evolving organism. Darwin depicted the gradual complexification of the organ of visual perception from a light-sensitive spot to a fully-fledged eye; in this example, the function of the organ, while evolving, remained, in principle, the same. When an evolutionary biologist strives to explain the origin of a truly novel system that is seen only in its elaborately complex state and, at face value, appears to be irreducibly complex, the task is much harder. Because evolution has no foresight, no system can evolve in anticipation of becoming useful once the requisite level of complexity is attained. Instead, the evolving system must have a selectable function(s) distinct from the modern one, a possibility recognized by Darwin [1] and emphasized by Gould in the concept of exaptation, that is, reassignment of function in the course of evolution [11,12]. In either case, the general Darwinian principle applies: evolution must proceed via consecutive, manageable steps, each one associated with a demonstrable increase in fitness. Darwin did not use a specific term for this crucial tenet of evolutionary biology; we will call it the Continuity Principle, following the recent insightful discussion of this issue by Penny [8]. The developments in the 150 years since Darwin taught us to be more flexible about this principle than he was. It is no longer prudent to demand, as Darwin did, that all evolutionary changes are "infinitesimal"; some genome modifications may have had a substantial one time effect on fitness, e.g., those that involve horizontal gene transfer, gene loss, or genome rearrangement [13]. Furthermore, it cannot be demanded that every change is selectively advantageous because neutral or even slightly deleterious mutations can be fixed by drift, especially, in small populations [9,14]. Nevertheless, these newly discovered factors of evolution, however important by themselves, are but modifications of the Continuity Principle – evolution of complex systems still needs to be deconstructed into successive steps and explained in a Darwinian way.
We discussed the principles of evolution of complex biological systems at some length because they are most pertinent to the fundamental problem we wish to address here: the origin of the translation system and the genetic code. Indeed, the translation system might appear to be the epitome of irreducible complexity because, although some elaborations of this machinery could be readily explainable by incremental evolution, the emergence of the basic principle of translation is not. Indeed, we are unaware of translation being possible without the involvement of ribosomes, the complete sets of tRNA and aminoacyl-tRNA synthetases (aaRS), and (at least, for translation to occur at a reasonable rate and accuracy) several translation factors. In other words, staggering complexity is inherent even in the minimally functional translation system. Thus, as outlined above, it appears that the evolutionary origin of translation is to be sought along the exaptation route, i.e., by retrodiction of the ancestral functions of various components of the translation system that would allow them to evolve functionalities enabling their recruitment for translation.
Even this, however, does not do the full justice to the difficulty of the problem. The origin of translation appears to be truly unique among all innovations in the history of life in that it involves the invention of a basic and highly non-trivial molecular-biological principle, the encoding of amino acid sequences in the sequences of nucleic acid bases via the triplet code[15,16]. This principle, although simple and elegant once implemented, is not immediately dictated by any known physics or chemistry (unlike, say, the Watson-Crick complementarity) and seems to be the utmost innovation of biological evolution.
The obvious common wisdom is that a system as complex as the translation machinery, even in its primitive state (let alone the modern version, with its hundreds of RNA and protein components – see below), could not have emerged in one sweep. Such an abrupt emergence would appear an outright miracle and an obvious violation of the Continuity Principle. Elsewhere, one of us considers a different worldview that might bring the chance emergence of complex (pre)biological systems, in particular, translation and replication, within the realm of the possible [17]. Here, however, we address the formidable problem of the origins of translation within the Continuity Principle, by harnessing evidence from comparative analysis of the translation system components, theoretical and experimental work on the hypothetical primordial RNA world, and the experimental study of interactions between amino acids and their codons and anticodons. After synthesizing the evidence from all these lines of enquiry, we embark on evolutionary modeling, with its unavoidable element of speculation, in an attempt to construct a sequence of plausible, incremental stages each of which is associated with a selective advantage to the evolving pre-biological entities – in accordance with the Continuity Principle.



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Evolution of the translation system – the case for a complex RNA world


The design of the translation system in even the simplest modern cells (e.g., parasitic and endosymbiotic bacteria and archaea, such as Carsonella,Mycoplasma, or Nanoarchaeon) is extremely complex. At the heart of the system is the ribosome, a large complex of at least three RNA molecules and 60–80 proteins arranged in a precise spatial architecture and interacting with other components of the translation system in the most finely choreographed fashion [18-22]. These other essential components include the complete set of tRNAs for the 20 amino acids (~40 tRNA species considering the presence of isoacceptor tRNAs in all species), the set of 18–20 cognate aminoacyl-tRNA synthetases (aaRS), and a complement of at least 7–8 translation factors. An extraordinary feature of the translation system is the conservation of its core across all modern cellular life forms. Indeed, of all functional categories of proteins, translation is by far the most conserved one: among the ~60 proteins that are represented by an ortholog in every single cellular life form with a sequenced genome, over 50 are components of the translation machinery [23]. Together with the universal conservation of ~30 RNA species [three rRNAs, the signal recognition particle (SRP) RNA, and tRNAs of at least 18 specificities] and the virtual universality of the genetic code, this proves that, the substantial differences between the translation machineries of archaea (and the eukaryotic cytosol) and bacteria (and the eukaryotic organelles) notwithstanding, the modern translation system is the best preserved relic of the Last Common Universal Ancestor (LUCA) of modern cellular life forms. Put another way, the conservation of the core of the translation machinery is the strongest available evidence that some form of LUCA actually existed.
Given this extraordinary conservation of the translation system, comparison of orthologous sequences reveals very little, if anything, about its origins – because the emergence of the translation system is beyond the horizon of the comparison of extant life forms. Indeed, comparative-genomic reconstructions of the gene repertoire of LUCA point to a complex translation system including at least 18 of the 20 aaRS, several translation factors, at least 40 ribosomal proteins, and several enzymes involved in rRNA and tRNA modification; thus, it appears that the core of the translation system was already fully shaped in LUCA [24]. However, sequence and structure comparisons of protein and RNA components of the translation system itself are informative thanks to the extensive paralogy among the respective genes. Obviously, when the origin of each of a pair of paralogous genes antedates LUCA, the respective duplication must have been an even earlier event, so reconstruction of the scenario of such events opens a window into very early stages of evolution.
The story of the paralogous aaRS is particularly revealing. The aaRS form two distinct classes of 10 specificities each, with unrelated catalytic domains and distinct sets of accessory domains [25,26]. The catalytic domains of the class I and class II aaRS belong to the Rossmann fold and the biotin synthase fold, respectively. The analysis of the evolutionary histories of these protein folds has far-reaching implications for the early evolution of the translation system and beyond. It has been shown that the catalytic domains of the Class I aaRS form but a small twig in the evolutionary tree of the Rossmann fold proteins; the advent of the common ancestor of the aaRS is preceded by a number of nodes along the evolutionary path from the primitive, ancestral domain to the highly diversified state that corresponds to LUCA [27,28]. The striking corollary of this simple observation is that a substantial diversity of Rossmann fold domains has evolved prior to the series of duplications that led to the emergence of the aaRS of different specificities which, in turn, antedates LUCA. A very similar evolutionary pattern is implied by the analysis of the biotin synthase domain that gave rise to Class II aaRS [29]. Thus, even within these two folds alone, a remarkable structural and functional complexity had been attained before the fully-fledged RNA-protein machinery of translation resembling the modern one has evolved. The evolutionary analysis of the vast class of P-loop GTPases, in which a variety of translation factors comprise distinct, tight families, leads to essentially the same conclusions: in the succession of evolutionary bifurcations (tree branchings) that comprise the history of the GTPase domain, the translation factors are relatively late arrivals [30]; not to be forgotten that the GTPases are but one of the major branches of the P-loop fold [30]. This might strike one as counter-intuitive but it is an inevitable conclusion from the comparative analysis of ancient paralogous relationship between proteins within the translation system: with the interesting exception of the core ribosomal proteins, all proteins that play essential roles in modern translation are products of long and complex evolution of diverse protein domains. So here comes the Catch-22: for all this protein evolution to occur, an accurate and efficient translation system was required. This ancient translation system might not have been quite as accurate and efficient as the modern version but it will be a safe bet to infer that is must have been within an order of magnitude from the modern one in terms of fidelity and translation rates, to make protein evolution possible. However, from all we know about the modern translation system, this level of precision is unimaginable without a complex, dedicated protein apparatus [31].
Thus, the translation system presents us with the Darwin-Eigen paradox as clearly as it gets: for a modern-type, efficient and accurate translation system to function, many diverse proteins are needed, and for those proteins to evolve, a translation system almost as good as the modern one would be necessary. There is only one solution to this paradox, and it lies in an, at least, partial refutation of the first part of the above opposition: we are forced to conclude that a translation system comparable to the modern one in terms of accuracy and speed functioned without many proteins, possibly, without any proteins at all. Hence the very existence of a complex, elaborate RNA world (see the next section), in which a primitive version of the Darwin-Eigen cycle was already operating, can be conjectured from the comparative analysis of the translation system components (again, a different perspective on this issue is given elsewhere[17]).
This is not all the comparative analysis can do: comparison of RNAs themselves also yields important information and startling puzzles. The conservation of the structure, some sequence elements (e.g., the pseudouridine loop), and even modification sites of the tRNAs of all specificities (and, needless to say, all species) leaves no doubt that they all evolved from a single common ancestor [32-34]. Hence the second paradox of translation evolution ensuing from the comparison of modern sequences and structures: if, at some point in evolution, there was a single progenitor to tRNAs of all specificities, how could a translation system function – and, if there was no translation system at that stage, what would be the driving force of evolution of the amino-acid-specific tRNAs?

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Ribozymes and the RNA World


The famous central dogma of molecular biology [16] states that, in biological systems, information is transferred from DNA to protein through an RNA intermediate (the possibility of reverse information flow from RNA to DNA has been added after the discovery of reverse transcriptase):
DNA⇔RNA→protein
Obviously, when considering the origin of first life forms, one faces the proverbial chicken-and-egg problem: what came first, DNA or protein, the gene or the product? In that form, the problem might be outright unsolvable. Indeed, there is a crucial feedback in this system: to replicate and transcribe DNA, functionally active proteins are required, but production of these proteins requires accurate replication, transcription, and translation of nucleic acids. If one sticks to the triad of the Central Dogma, it is impossible to envisage what could serve as the starting material for the Darwin-Eigen cycle. Even removing DNA from the triad and postulating that the original genetic material consisted of RNA, while an important idea (see below), is not going to help much because the feedback remains as crucial as it is elusive. In order for evolution toward greater complexity to take off, the system needs to somehow get started on the Darwin-Eigen cycle prior to establishing this feedback.
The brilliantly ingenious and, perhaps, the only possible solution has been independently proposed by Woese [35], Crick [36], and Orgel [37] in 1967–68: neither the chicken nor the egg but what is in the middle, that is, RNA alone! The unique property of RNA that makes it a credible, indeed, apparently, the best candidate for the central role in the primordial replicating system is its ability to combine informational and catalytic functions. This notion has been greatly boosted by the study of ribozymes (RNA enzymes), which was pioneered by Cech and coworkers' discovery, in 1982, of the autocatalytic cleavage of theTetrahymena rRNA intron [38], and by the demonstration, in 1983, by Altman and coworkers, that RNAse P is a ribozyme [39]. Since the time of these seminal discoveries, the study of ribozymes has evolved into a vast, expanding research area (at the time of this writing, March 1, 2007, the keyword 'ribozyme' retrieves 4883 documents from the PubMed database; for recent reviews, see [40-43]).
The discovery of ribozymes made the idea that the first replicating systems consisted solely of RNA molecules, which catalyzed their own replication, extremely attractive. In 1986, Gilbert coined the term "RNA world" to designate this hypothetical stage in life's evolution [44], and the idea caught up big way, becoming the leading, in fact, almost universally accepted hypothesis on the early stages of life's evolution [45-48].
The popularity of the RNA World hypothesis has, in turn, further stimulated ribozyme research, aimed, in large part, at testing the feasibility of various RNA-based catalytic activities, above all, perhaps, an RNA replicase. It is noteworthy that the main approach to developing ribozymes with desired activities is in vitroselection that, at least conceptually, mimics the Darwinian evolution of ribozymes thought to occur in the primeval RNA world [49,50]. Essentially, these directed selection experiments are designed in such a fashion that, from a random population of RNA sequences, only those are amplified that catalyze the desired reaction. In such multiple-round selection experiments, ribozymes have been evolved to catalyze an extremely broad variety of reactions. Since here we are concerned with the problem of the origin of translation, Table ​Table1 lists only those of the ribozyme-catalyzed reactions that appear to be specifically relevant to this problem. Notably, all three elementary reactions required for translation, namely: i) amino acid activation through the formation of aminoacyl-AMP, ii) (t)RNA aminoacylation, and iii) transpeptidation (the peptidyltransferase reaction), have been successfully modeled with ribozymes (Table ​(Table1).). It is particularly remarkable that the key self-aminoacylation reaction has been selected in vitro with considerable ease such that the best of the resulting ribozymes catalyzed it with a rate and specificity greater than those of the respective aaRS [51].
Table 1
Ribozyme activities relevant for the emergence of the translation machinery from the RNA world
Understandably, major effort has focused on the demonstration of nucleotide polymerization and, ultimately, RNA replication catalyzed by ribozymes, the key processes for the hypothetical, primordial RNA World. While these reactions are not directly involved in translation, they are highly relevant to the problem considered here inasmuch as replication with a fidelity above the Eigen threshold is a pre-requisite of biological evolution (see above). The outcome of the experiments aimed at the creation of ribozyme replicases so far has been somewhat mixed. Ribozymes have been obtained capable of extending a primer annealed to a template by 10–14 nucleotides; initially, the ribozymes with this activity could function only by specific base-pairing to the template but, subsequently, general ribozyme polymerases of this class have been evolved through additional selection [52-56]. However, these ribozyme polymerases are still a far cry from processive, sufficiently accurate (in terms of the Eigen threshold) replicases, capable of catalyzing replication of exogenous templates and themselves, that appear to be a conditio sine qua non for the evolution of the hypothetical RNA World.
It is often noted that the RNA World is not just a concept supported by the catalytic prowess of ribozymes: while overshadowed by the multitude of proteins with catalytic and structural functions, the RNA World still lurks within modern life forms [57,58]. Reactions catalyzed by ribozymes, while by far less numerous than those catalyzed by protein enzymes, are of crucial importance in modern cells. The foremost case of a today's natural ribozyme is the ribosome itself, where the crucial peptidyltransferase reaction is catalyzed by large-subunit rRNA without direct participation of proteins [59-61]. In the nearly ubiquitous tRNA-processing enzyme RNAse P, the catalytic moiety is an RNA molecule whereas the protein subunits play the role of cofactors stabilizing the RNA catalyst and facilitating the reaction [62,63]. Furthermore, group I and group II self-splicing introns, which are widespread in bacteria and in plant, fungal, and protozoan organelles, are ribozymes that catalyze their own excision from RNA transcripts, often, facilitated by specific proteins, the maturases [64-69]. It is generally believed that the myriads of eukaryotic spliceosomal introns, as well as the snRNAs that comprise the active moieties of the eukaryotic spliceosomes, have evolved from Group II introns [68,69], leaving, perhaps, the most conspicuous imprint of the RNA World on modern genomes [70]. Similarly, in the smallest known infectious agents, viroids and virusoids, the ribozyme-catalyzed reactions are directly involved in replication: although the polymerization of nucleotides is catalyzed by a protein polymerase, processing of replication intermediates into genomic units depends on a built-in ribozyme [71]. The existence and importance of these (and, perhaps, other, still undiscovered) RNA-catalyzed reactions in modern cells imply a major role of RNA catalysts in the early evolution of life but in no way prove the reality of the primordial RNA world as it is defined above – a large community of RNAs possessing diverse catalytic activities and replicated by ribozyme polymerases. Nevertheless, these features of modern RNAs are fully compatible with such an evolutionary stage and greatly add to its plausibility. In particular, the fundamental fact that the peptidyltransferase reaction in the ribosome is catalyzed by a ribozyme strongly suggests that this was the functional mode of the primordial translation system.
To recapitulate, three independent lines of evidence converge in support of a major role of RNA, and in particular, RNA catalysis at the earliest stages of life's history, and are compatible with the reality of a complex, ancient RNA world that was first postulated by Woese, Crick, and Orgel on purely logical grounds. First, comparative analysis of the protein components of the translation machinery and their homologs involved in other functions strongly suggests that extensive diversification of the protein world took place at the time when the translation system was comprised, primarily, of RNA. Second, several classes of ribozymes operate within modern cells, and their properties are compatible with the notion that they are relicts of the ancient RNA world. Third, while limited in scope and, obviously, inferior in catalytic activity compared to protein enzymes [41], ribozymes have been shown or, more to the point, evolved to catalyze a remarkable variety of reactions including those that are central to the evolution of translation (Table ​(Table1).
All these arguments in favor of the reality of the RNA World notwithstanding, there are two major sources of doubts. First, despite all invested effort, the in vitro evolved ribozymes remain (relatively) poor catalysts; the lack of efficient ribozyme polymerases seems particularly troubling. Admittedly, it might be unrealistic to expect that experiments on in vitro evolution of ribozymes could easily mimic the actual complexity of the primordial RNA world. Indeed, although these experiments harness the power of selection, they are, obviously, performed on a totally different time scale and conditions that cannot possibly reproduce those of life's origin. The latter, of course, are not known but it seems reasonable to surmise that, if there was a complex RNA World at the brink of the Translation Breakthrough, it was brought about by millions of years of evolution of ensembles of replicating RNAs in a compartmentalized environment similar, at least, in principle, to the networks of iron sulfide compartments existing at hydrothermal vents [72-74]. The environment of this type can be reproduced in the laboratory but condensing eons of evolution into a manageable timescale is a grand challenge. Interestingly, a recent simulation study indicates that, if there was some RNA synthesis in such compartments[75,76], the resulting polyribonucleotides would accumulate to very high concentrations, an observation that increases the plausibility of this model. Of course, this scenario remains a model; other forms of compartmentalization are conceivable.
A recent study of Szathmary and coworkers puts some important numbers on the complexity that, potentially, might be attainable in the RNA World and the replication fidelity required to reach this level of complexity [77]. An estimate based on the functional tolerance of well-characterized ribozymes to mutations suggests that, at a fidelity of 10-3 errors per nucleotide per replicase cycle, an RNA "organism" with ~100 "genes" the size of a tRNA (~80 nucleotides) would be sustainable. This level of fidelity would require only an order of magnitude improvement over the most accurate ribozyme polymerases obtained by in vitroselection [52,78]. Conceivably, this is, roughly, the intrinsic complexity limit on ensembles of co-evolving "selfish cooperators" that might have been the "organisms" of the RNA world [74]. As aptly commented by Poole, "Getting from an RNA world to modern cells just got a little easier" [79]. Of course, "a little" is a crucial qualification here as all this evidence falls far short from proving the reality of a fully fledged RNA world; nevertheless, in the rest of this article, we proceed with the RNA world as a premise.
Even under the best case scenario, the RNA world does not appear to have potential to evolve beyond very simple "organisms". To attain greater complexity, invention of translation and the Protein Breakthrough were required. However, the selective forces underlying the emergence of the translation system in the RNA World remain obscure, and tracing the path to translation is extremely hard. This lack of clarity with regard to the continuity of evolution from the RNA World to an RNA-protein world can be construed as a second major objection against the RNA World as a crucial stage of life's evolution, an objection, perhaps, even more prohibitive than the first one, dealing with the imperfection of ribozymes. A radical alternative, "no RNA World" hypothesis, is considered elsewhere [17]. In the rest of this article, we discuss possible ways to derive the translation from the RNA World through a path of evolution adhering to the Continuity Principle.

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The nature and origins of the genetic code: a stereochemical correspondence between amino acids and codons or anticodons, a frozen accident, selection, or all of the above?


To understand how translation might have emerged, the nature and origin of the codon assignments in the universal genetic code are crucial. The problem of code evolution fascinated researchers even before the code was fully deciphered, and the earliest treatises on the subject already clearly recognized three, not necessarily mutually exclusive models: i) steric complementarity resulting in specific interactions between amino acids and the cognate codon (codon recognition model, or CRM) or anticodon triplets (anticodon recognition model, or ARM), ii) "frozen accident" – fixation of a random code that would have been virtually impossible to significantly change afterwards (frozen accident model, or FAM), and iii) adaptive evolution of the code starting from an initially random codon assignment [35,36,80-86]. The internal structure of the code is such that codons for related amino acids are adjacent in the code table resulting in a high (although not maximum) robustness of the code to mutations and translation errors as first noticed by Woese at a qualitative level [35,82] and subsequently demonstrated quantitatively [87-93]. The robustness of the code seems to falsify the frozen-accident scenario in its pure form; however, the stereochemical model, the selection model, a combination thereof, or frozen accident followed by adaptation all could explain the observed properties of the code.
The principal dilemma is whether or not a stereochemical correspondence between amino acids and cognate triplets (in the form of either CRM or ARM) exists or not. The answer to this straightforward question proved to be surprisingly elusive. The early attempts to establish specificity in interactions of (poly)amino acids and polynucleotides have been inconclusive, indicating that, if a correspondence exists, it must be much less than precise, and the interactions involved would be weak and dependent on extraneous factors [94-96]. Although some tantalizing cases of non-randomness in amino-acid-nucleotide interactions have been claimed (e.g., [97-102]), one is forced to conclude that, in general, the attempts to demonstrate such interactions directly have failed.
A recent resurgence of the stereochemical hypothesis was brought about by the application of the selection amplification (SELEX) methodology for isolation of oligonucleotides (aptamers) that specifically bind amino acids [103,104]. The latest survey by Yarus and coworkers reports detailed aptamer data for 8 amino acids: phenylalanine, isoleucine, leucine, histidine, glutamine, arginine, tyrosine, and tryptophan [104]. With the sole exception of glutamine, the aptamers for each amino acids were enriched for codon and/or anticodon triplets at a statistically highly significant level [104-106]. On the whole, associations with anticodons were more pronounced than those with codons. However, the results are complementary in that arginine (the amino acid characterized in greatest detail in aptamer experiments) showed a significant enrichment only for codons in binding sites, whereas for phenylalanine, leucine, and tryptophan, the binding sites were significantly enriched for anticodons; rather surprisingly, isoleucine and tyrosine were associated with both types of cognate triplets [104]. Taken together, the experimental results on aptamer binding that, in the case of arginine, have been analyzed in great detail for possible effects of statistical and chemical artifacts [107] are construed as a strong argument for the stereochemical hypothesis of code origin [104]. Moreover, for histidine, isoleucine, and tryptophan, it has been shown directly that the simplest binding aptamers contained the cognate codon or anticodon [108-112], lending credence to the idea that similar molecules might be relevant for modeling evolution in the RNA world [104].
Nevertheless, serious questions remain as to the ultimate validity and relevance of these results. The presence of both codons and antidocons in aptamers binding several amino acids is hard to interpret in terms of stereochemical complementarity. Furthermore, the amino acids for which detailed aptamer data is available are those that have complex side chains (which, presumably, mediate interactions with the aptamers) and are thought to be late recruitments to the genetic code [113]. At least, until similar results are obtained for simpler, supposedly, ancient amino acids, it is hard to view the aptamer selection results as a definitive case for the stereochemical hypothesis of code origin.
A different, and elegant version of the stereochemical correspondence hypothesis has been proposed by Copley and coworkers[114]. This scenario links the origin of the code to the synthesis of amino acids by postulating that, under prebiotic conditions, dinucleotides covalently bound α-keto acids and specifically enhanced amino acid synthesis from these precursors. Unfortunately, there is no empirical evidence in support of this interesting model.
Thus, the jury is still out with regard to any role direct interactions between amino acids and cognate triplets might have played in the origin of the code. Accordingly, in what follows, we strive to be objective and consider the origin of the code in three distinct contexts: i) specific interaction between amino acids and the cognate codons (CRM), ii) specific interactions between amino acids and the cognate anticodons (ARM), and iii) frozen accident (FAM) as the starting point for the evolution of the code.



Previous hypotheses on the origin of translation


During the 40 years since the discovery of the translation mechanism and deciphering of the genetic code, numerous theoretical (inevitably, speculative, sometimes, far fetched, often, extremely ingenious) models of the origin and evolution of various components of the translation apparatus and aspects of the process itself have been proposed. A comprehensive, critical review of this literature would be a truly daunting task and will not be attempted here. We outline only a few of the more straightforward and, in our opinion, more plausible, evolutionary schemes and then discuss in somewhat greater detail the only published coherent scenario for the evolution of the translation system we are aware of.
One popular and potentially important idea on the origin of the genetic code is the hypothesis of Szathmary on the role of so-called coding coenzyme handles (CCH), i.e., oligonucleotides with various ribozyme activities using amino acids as cofactors, as evolutionary progenitors of tRNAs [115-117]. This hypothesis ties in with the idea that tRNAs evolved by two successive duplications of amino-acid-binding hairpins [118]. The CCH are thought to have assembled via their proto-anticodons on emerging mRNAs. A modification of the CCH hypothesis proposed by Knight and Landweber involves evolution of aminoacylating ribozymes (which is compatible with the available experimental data – see Table ​Table1)) and emergence of non-templated, ribozyme-mediate peptide synthesis as an intermediate stage in the evolution of translation [107]. An alternative to the CCH scheme is the direct-RNA-templating (DRT) hypothesis of translation origin proposed by Yarus [119]. Under the DRT model, the original form of amino-acid-proto-tRNA interaction was direct binding, presumably, via anticodon triplets; subsequently, direct binding has been supplanted by the adaptor mechanism, probably, with the participation of aminoacylating ribozymes, as under the modified CCH hypothesis.
These and other hypotheses tackle important aspects of the origin and evolution of the translation system. However, they all stop short of proposing a complete, coherent scenario for the transition from the RNA world to the modern mode of translation. We believe that the reason for the near lack of such scenarios in the current literature is the formidable difficulty of breaking this transition into incremental steps associated with a biologically plausible selective advantage, thus making the entire transition compatible with the Continuity Principle.
We are aware of two proposals that come closest to such a complete scenario, and it seems to be more than a remarkable coincidence that the two present essentially the same model, differences in detail notwithstanding. The essence of this model, originally sketched by Altstein [120-122], and later, independently and more completely developed by Poole, Jeffares, and Penny [8,123], is that the ribosome and the translation mechanism are derived from an ancient ribozyme replicase.
Let us examine in some detail the model of Poole and coworkers, which is better reconciled with various facets of the RNA World than the original proposal of Altstein (not surprisingly, given that the first version of Altstein's hypothesis [120] has been proposed prior to the discovery of ribozymes). Crucially, in this model, the protoribosome is postulated to have functioned as a "triplicase", i.e., a complex ribozyme combining the activities of a RNA polymerase and a RNA ligase by building a nascent RNA molecule complementary to the template in three-nucleotide steps. The "triplicase"-protoribosome would facilitate the assembly of tRNA-like molecules (perhaps, analogous to the CCH) on the template RNA through base-pairing of (proto)anticodons with complementary triplets (codons) on the template, cleaving off the rest of the pre-tRNA, and joining (ligating) adjacent triplets (Fig. ​(Fig.2 in [8,123]). A RNA-based replication mechanism involving complementary interaction of trinucleotides with the template, as opposed to mononucleotides, was deemed plausible by Poole et al., given the low efficiency (long characteristic turnover times) of ribozymes. A complex of template RNA with a complementary trinucleotide would persist orders of magnitude longer than a complex with a mononucleotide, giving the triplicase a chance to ligate the adjacent triplets. The hypothetical triplicase mechanism was considered particularly plausible [8] in view of the demonstration, by Fredrick and Noller, that the ribosome, without the involvement of translation factors, threads mRNA through the ribosome in three-nucleotides steps, with concordant movements of tRNAs [124]. Thus, the modern ribosome, of which the primary functional part is rRNA, is a versatile machine that catalyzes the stepwise joining of amino acids to form polypeptide chains and also mediates the associated movements of RNA molecules. It seems tempting to view this mechanism, which is crucial for modern translation, as a relic of the primordial "triplicase" system of RNA replication [8].
Of course, the transition from a triplicase to a modern-type translation-replication system requires the emergence of the genetic code, in this case, at the level of amino acid recognition by the proto-tRNAs, and the feedback between translation and RNA replication. Furthermore, a subfunctionalization stage would be required where the triplicase would give rise to separate proto-ribosome and replicase, the latter having to switch from triplet joining to the conventional, one nucleotide at a time, replication mechanism. Perhaps, most damningly, the triplicase/protoribosome would have to be a tremendously advanced, complex RNA machine. Poole et al. [123] are not particularly specific about the organization of this machine and the likely mechanisms of and selective forces behind each of the necessary evolutionary steps, which renders the triplicase model incomplete and leaves one with the suspicion that, all its attraction notwithstanding, the triplicase might not be the most likely solution to the origin of translation problem. Nevertheless, regardless of the validity of its details, the triplicase model drives home a crucial point: evolution having no foresight, protein synthesis could not be the selective advantage that fuelled the initial evolution of the translation system; inevitably, it must have evolved via the exaptation route.
An overview of the existing models for the origins of translation and coding shows that none of them, not even the attractive triplicase model, offer a complete, compatible with the Continuity Principle outline of the path to the Protein Breakthrough. In the rest of this article, we explore three versions of such scenarios, two building upon specific interactions between amino acids and codons or anticodons, respectively, and the third one centered around frozen accident. We draw on aspects of the previously published models, in particular, the DRT, CCH, and triplicase hypotheses, and the experimental data on ribozymes, and also propose several original steps.



http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1894784/?tool=pubmed

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Origins of Life: New Model May Explain Emergence of Self-Replication on Early Earth

Template-assisted replication, which helps polymers grow longer while passing on sequences from generation to generation, could have enabled jump from monomers to self-replicating polymers

Released: 23-Jul-2015 2:05 PM EDT
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Journal of Chemical Physics
Newswise — WASHINGTON, D.C., July 28, 2015 -- When life on Earth began nearly 4 billion years ago, long before humans, dinosaurs or even the earliest single-celled forms of life roamed, it may have started as a hiccup rather than a roar: small, simple molecular building blocks known as "monomers" coming together into longer "polymer" chains and falling apart in the warm pools of primordial ooze over and over again.

Then, somewhere along the line, these growing polymer chains developed the ability to make copies of themselves. Competition between these molecules would allow the ones most efficient at making copies of themselves to do so faster or with greater abundance, a trait that would be shared by the copies they made. These rapid replicators would fill the soup faster than the other polymers, allowing the information they encoded to be passed on from one generation to another and, eventually, giving rise to what we think of today as life.

Or so the story goes. But with no fossil record to check from those early days, it's a narrative that still has some chapters missing. One question in particular remains problematic: what enabled the leap from a primordial soup of individual monomers to self-replicating polymer chains?

A new model published this week in The Journal of Chemical Physics, from AIP Publishing, proposes a potential mechanism by which self-replication could have emerged. It posits that template-assisted ligation, the joining of two polymers by using a third, longer one as a template, could have enabled polymers to become self-replicating.

"We tried to fill this gap in understanding between simple physical systems to something that can behave in a life-like manner and transmit information," said Alexei Tkachenko, a researcher at Brookhaven National Laboratory. Tkachenko carried out the research alongside Sergei Maslov, a professor at the University of Illinois at Urbana-Champaign with joint appointment at Brookhaven.

Origins of Self-Replication

Self-replication is a complicated process -- DNA, the basis for life on earth today, requires a coordinated cohort of enzymes and other molecules in order to duplicate itself. Early self-replicating systems were surely more rudimentary, but their existence in the first place is still somewhat baffling.

Tkachenko and Maslov have proposed a new model that shows how the earliest self-replicating molecules could have worked. Their model switches between "day" phases, where individual polymers float freely, and "night" phases, where they join together to form longer chains via template-assisted ligation. The phases are driven by cyclic changes in environmental conditions, such as temperature, pH, or salinity, which throw the system out of equilibrium and induce the polymers to either come together or drift apart.

According to their model, during the night cycles, multiple short polymers bond to longer polymer strands, which act as templates. These longer template strands hold the shorter polymers in close enough proximity to each other that they can ligate to form a longer strand -- a complementary copy of at least part of the template. Over time, the newly synthesized polymers come to dominate, giving rise to an autocatalytic and self-sustaining system of molecules large enough to potentially encode blueprints for life, the model predicts

Polymers can also link together without the aid of a template, but the process is somewhat more random -- a chain that forms in one generation will not necessarily be carried over into the next. Template-assisted ligation, on the other hand, is a more faithful means of preserving information, as the polymer chains of one generation are used to build the next. Thus, a model based on template-assisted ligation combines the lengthening of polymer chains with their replication, providing a potential mechanism for heritability.

While some previous studies have argued that a mix of the two is necessary for moving a system from monomers to self-replicating polymers, Maslov and Tkachenko's model demonstrates that it is physically possible for self-replication to emerge with only template-assisted ligation.

"What we have demonstrated for the first time is that even if all you have is template-assisted ligation, you can still bootstrap the system out of primordial soup," said Maslov.

The idea of template-assisted ligation driving self-replication was originally proposed in the 1980s, but in a qualitative manner. "Now it's a real model that you can run through a computer," said Tkachenko. "It's a solid piece of science to which you can add other features and study memory effects and inheritance."

Under Tkachenko and Maslov's model, the move from monomers to polymers is a very sudden one. It's also hysteretic -- that is, it takes a very certain set of conditions to make the initial leap from monomers to self-replicating polymers, but those stringent requirements are not necessary to maintain a system of self-replicating polymers once one has leapt over the first hurdle.

One limitation of the model that the researchers plan to address in future studies is its assumption that all polymer sequences are equally likely to occur. Transmission of information requires heritable variation in sequence frequencies -- certain combinations of bases code for particular proteins, which have different functions. The next step, then, is to consider a scenario in which some sequences become more common than others, allowing the system to transmit meaningful information.

Maslov and Tkachenko's model fits into the currently favored RNA world hypothesis -- the belief that life on earth started with autocatalytic RNA molecules that then lead to the more stable but more complex DNA as a mode of inheritance. But because it is so general, it could be used to test any origins of life hypothesis that relies on the emergence of a simple autocatalytic system.

"The model, by design, is very general," said Maslov. "We're not trying to address the question of what this primordial soup of monomers is coming from" or the specific molecules involved. Rather, their model shows a physically plausible path from monomer to self-replicating polymer, inching a step closer to understanding the origins of life.

The article, "Spontaneous emergence of autocatalytic information-coding polymers," is authored by Alexei Tkachenko and Sergei Maslov. It will appear in The Journal of Chemical Physics on July 28, 2015. After that date, it can be accessed at: http://scitation.aip.org/content/aip/journal/jcp/143/4/10.1063/1.4922545

ABOUT THE JOURNAL

The Journal of Chemical Physics publishes concise and definitive reports of significant research in the methods and applications of chemical physics. See: http://jcp.aip.org

BACKGROUNDER: Waiter, there's an RNA in my Primordial Soup -- Tracing the Origins of Life, from Darwin to Today

Nearly every culture on earth has an origins story, a legend explaining its existence. We humans seem to have a deep need for an explanation of how we ended up here, on this small planet spinning through a vast universe. Scientists, too, have long searched for our origins story, trying to discern how, on a molecular scale, the earth shifted from a mess of inorganic molecules to an ordered system of life. The question is impossible to answer for certain -- there's no fossil record, and no eyewitnesses. But that hasn't stopped scientists from trying.

Over the past 150 years, our shifting understanding of the origins of life has mirrored the emergence and development of the fields of organic chemistry and molecular biology. That is, increased understanding of the role that nucleotides, proteins and genes play in shaping our living world today has also gradually improved our ability to peer into their mysterious past.

When Charles Darwin published his seminal On the Origin of the Species in 1859, he said little about the emergence of life itself, possibly because, at the time, there was no way to test such ideas. His only real remarks on the subject come from a later letter to a friend, in which he suggested a that life emerged out of a "warm little pond" with a rich chemical broth of ions. Nevertheless, Darwin's influence was far-reaching, and his offhand remark formed the basis of many origins of life scenarios in the following years.

In the early 20th century, the idea was popularized and expanded upon by a Russian biochemist named Alexander Oparin. He proposed that the atmosphere on the early earth was reducing, meaning it had an excess of negative charge. This charge imbalance could catalyze existing a prebiotic soup of organic molecules into the earliest forms of life.

Oparin's writing eventually inspired Harold Urey, who began to champion Oparin's proposal. Urey then caught the attention of Stanley Miller, who decided to formally test the idea. Miller took a mixture of what he believed the early earth's oceans may have contained -- a reducing mixture of methane, ammonia, hydrogen, and water -- and activated it with an electric spark. The jolt of electricity, acting like a strike of lightening, transformed nearly half of the carbon in the methane into organic compounds. One of the compounds he produced was glycine, the simplest amino acid.

The groundbreaking Miller-Urey experiment showed that inorganic matter could give rise to organic structures. And while the idea of a reducing atmosphere gradually fell out of favor, replaced by an environment rich in carbon dioxide, Oparin's basic framework of a primordial soup rich with organic molecules stuck around.

The identification of DNA as the hereditary material common to all life, and the discovery that DNA coded for RNA, which coded for proteins, provided fresh insight into the molecular basis for life. But it also forced origins of life researchers to answer a challenging question: how could this complicated molecular machinery have started? DNA is a complex molecule, requiring a coordinated team of enzymes and proteins to replicate itself. Its spontaneous emergence seemed improbable.

In the 1960s, three scientists -- Leslie Orgel, Francis Crick and Carl Woese -- independently suggested that RNA might be the missing link. Because RNA can self-replicate, it could have acted as both the genetic material and the catalyst for early life on earth. DNA, more stable but more complex, would have emerged later.

Today, it is widely believed (though by no means universally accepted) that at some point in history, an RNA-based world dominated the earth. But how it got there -- and whether there was a simpler system before it -- is still up for debate. Many argue that RNA is too complicated to have been the first self-replicating system on earth, and that something simpler preceded it.

Graham Cairns-Smith, for instance, has argued since the 1960s that the earliest gene-like structures were not based on nucleic acids, but on imperfect crystals that emerged from clay. The defects in the crystals, he believed, stored information that could be replicated and passed from one crystal to another. His idea, while intriguing, is not widely accepted today.

Others, taken more seriously, suspect that RNA may have emerged in concert with peptides -- an RNA-peptide world, in which the two worked together to build up complexity. Biochemical studies are also providing insight into simpler nucleic acid analogs that could have preceded the familiar bases that make up RNA today. It's also possible that the earliest self-replicating systems on earth have left no trace of themselves in our current biochemical systems. We may never know, and yet, the challenge of the search seems to be part of its appeal.

Recent research by Tkachenko and Maslov, published July 28, 2015 in The Journal of Chemical Physics, suggests that self-replicating molecules such as RNA may have arisen through a process called template-assisted ligation. That is, under certain environmental conditions, small polymers could be driven to bond to longer complementary polymer template strands, holding the short strands in close enough proximity to each other that they could fuse into longer strands. Through cyclic changes in environmental conditions that induce complementary strands to come together and then fall apart repeatedly, a self-sustaining collection of hybridized, self-replicating polymers able to encode the blueprints for life could emerge.




http://www.newswise.com/articles/origins-of-life-new-model-may-explain-emergence-of-self-replication-on-early-earth

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