Replication catastrophes

The idea that life started with RNA replicators implies that the primitive Earth became populated by RNAs that could either replicate themselves or could catalyse the replication of other RNAs. Up until now it has not yet been proved that RNAs can self-replicate, but it has been shown that some of them do have a weak replicase activity, and can therefore replicate other RNAs, thus forming a system that is, collectively, capable of replication. This allows us to conclude that some primitive RNAs could behave, to a certain extent, as the replicases used by Spiegelman and Eigen in their experiments, and that similar experiments were performed by nature, on a far larger scale, some 4 billion years ago. 

The environmental conditions of the primitive Earth were surely different from those of Spiegelman s and Eigen s test-tubes, but this can be regarded as a secondary complication, and in a first approximation it can be ignored. What we cannot ignore, however, is the fact that any replication process is inevitably affected by errors, and it is therefore imperative to understand the consequences that such errors have for the very survival of a replicating system. This is a crucial problem for all replication-first theories, because it has been proved that any self-replicating system can tolerate replication errors only below a critical threshold. Above such a threshold, the system is overwhelmed by a runaway error catastrophe, and is inexorably condemned to collapse. This is a fundamental problem, and in order to address it we need first to quantify the critical threshold. 

If a replicating system is described by N bits of information, and every bit is copied with an error probability e, the total number of errors made in every generation is Ne. The systems that make many 

Condition 5.1 is a very severe constraint because it means that a replicating system can increase N (i.e. can become more complex) only if its replication becomes more efficient. In practice, condition 5.1 requires that the average replication error e be inversely proportional to N, and a system can therefore increase its complexity by an order of magnitude only if the replication errors decrease by an order of magnitude. 

This conclusion allows us to explain the experimental results obtained by Spiegelman and Eigen the RNA molecules of an in vitro replicating system can reach a length of 100-200 monomers, and no more, because longer molecules are overrun by the error catastrophe. The threat of this catastrophe of course also existed for primitive RNAs, whatever the environmental conditions, and we must therefore find out whether it was possible to avoid it. Eigen himself (1977) raised the problem and proposed a possible solution. 

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For the time being, therefore, the only reasonable conclusion is that a true replication mechanism appeared only at the end of precellular evolution, when the first cells came into being. Both chemical evolution and postchemical evolution, in other words, had to take place with metabolic systems that were able to tolerate errors, because only in this way could they be immune to the replication catastrophes. 

A hypercycle is a more complex organisation form. Its precondition is the presence of several RNA quasi-species which are able to amalgamate chemically with certain proteins (enzymes or their precursors). If such a protein is linked to a quasi-species, the resulting duo favours the replication of a second quasispecies. According to Dyson, the linked populations get stuck in a stable equilibrium. Problems occur at this level Any theory on the origin of replication has the central problem that the replication process must occur perfectly in order to ensure survival . If there are replication errors, these will increase from generation to generation, until the system collapses the error catastrophe has then occurred ... 

The egoistic RNA this catastrophe occurs when, after a mutation, one RNA molecule learns to replicate faster than the others, forgetting to act as a catalyst. 

Of course there is more to being alive than pure chemical self-replication. At the very least there must be an ability to evolve in response to non-catastrophic local environmental changes. As long as those changes occurred on a timescale that allowed several generations to pass then a viable population would be expected to have evolved to exist under the new conditions. 

Primitive RNAs, in conclusion, could certainly behave both as genes and enzymes, but this does not save the replication paradigm, because it cannot avoid the various catastrophes that necessarily affect all replicators. 

Biological replication, despite its theoretical simplicity, was extremely difficult to achieve in practice, and became possible only with the evolution of a system that was sufficiently complex to withstand the error catastrophes. And the first system that did achieve that complexity level can rightly be regarded as the first living cell. 

Let us now come to the second part of postchemical evolution, the stage that was destined to lead to the origin of the first cells. It is in this stage that we must look for an answer to the problem that the replication paradigm has been unable to solve how did primitive systems manage to increase their complexity without being destroyed by error catastrophes The ribotype answer is based on three points. 

This then is the solution of the ribotype theory in order to avoid the error catastrophes in the journey toward exact replication, it was necessary to have high molecular weight protoribosomes, and the production of these ribosomes for an indefinite number of generations was possible, before exact replication, because ribosoids could achieve it with processes of self-assembly and quasi-replication. The development of high-molecular-weight protoribosomes took place during postchemical evolution, simply because all necessary conditions existed in that period, and the development could be realised with processes that were both natural and primitive. 

For the first time we study the effects of thermal denaturation at the single molecule level. Partial denaturation of a population of molecules results in the total loss of activity of a portion of the molecules with the surviving molecules unaffected. There is no evidence for the conversion of active molecules to a conformation of lower activity. Thermal denaturation is a catastrophic phenomenon. Our data provides no evidence for the universality of catastrophic denaturation it would be interesting to replicate these experiments with other enzymes. 

Here, ln(ot) is typically 0( 1), while the error rate in the replication of monomer is estimated to be around 0.01-0.1, in the usual polymer replication process. Then the above condition gives N < 100 or so. In other words, information using a polymer with a sequence longer than this threshold N is hardly sustained. This problem was first posed by Eigen and is called error catastrophe [7]. On the other hand, information for the replication for a minimal life system must require much more information. Of course, the error rate could be reduced once some machinery for faithful replication as in the present life emerges. However, such machinery requires much more information to be transmitted by the polymer. 

One might say that the maintenance of replication is not surprising at all, since a gene for the DNA polymerase is included in the beginning. However, enzyme with such catalytic activity is rare. Indeed, with mutations some proteins that lost such catalytic activity but are synthesized in the present system could appear, which might take over the system. Then the self-replication activity would be lost. In fact, this is nothing but the error catastrophe by Eigen, discussed in Section n.A. Then, why is the self-replication activity maintained in the present experiment ... 

Catastrophic genetic damage can occur If cells progress to the next phase of the cell cycle before the previous phase is properly completed. For example, when S-phase cells are induced to enter mitosis by fusion to a cell In mitosis, the MPF present In the mitotic cell forces the chromosomes of the S-phase cell to condense. However, since the replicating chromosomes are fragmented by the condensation process, such premature entry into mitosis is disastrous for a cell. 

We have recently developed a quasi-species approach for analyzing mutation and selection in catalytic reactions of varying order. We discussed how the error catastrophe that reflects the transition from localized to delocalized quasi-species population is affected by catalytic replication of different reaction orders. Specifically, the second-order mechanisms lead to a discontinuity in the mean fimess of the popnlation at the error threshold. This is in contrast to the behavior of the first-order, antocatalytic replication mechanism, considered in the standard quasi-species model. This suggested that quasi-species models with higher order of replication mechanisms produce discontinuities in the mean fitness and, hence, in the viable population fraction, at the error threshold, while lower-order replication mechanisms yield a continuous mean fitness fnnction. 

Low copying fidelities can lead to an error catastrophe where a replicative process cannot maintain the sequence information [41—45]. The error threshold marks the onset of this catastrophe it refers to a critical value in the ratio n s of the mutation rate to the selection strength s. Beyond the threshold, the mutants with compromised function dominate over the original master sequence, because the... 

It is important to note, however, that the concept of an error threshold can acquire a somewhat different meaning in the prebiotic context. In particular, if we consider the molecules that form the core of a primitive replication process, then the most fundamental maintenance requirement is that the process generates at least one functional copy per core replication molecule before the template is destroyed. This situation differs from the standard error threshold scenario In the latter case, both master and mutants replicate and an error catastrophe results from their competition, whereas in the former case the catastrophe is no replication at all. However, this replication breakdown can also be induced by a low copying fidelity. 

Protein synthesis is a series of reactions, each with a high degree of fidelity. Yet mistakes can occur as a result of mistranslation, incorporation of unusual amino acids that are substrates of tRNA acylation reactions, premature termination of nascent peptides, and point mutations where amino acids are substituted (Ballard, 1977). Errors in protein synthesis are especially important if they are introduced into an enzyme, since the catalytic properties of the enzyme may be modified. If such errors occurred in ribosomal proteins or in other enzymes associated with protein synthesis, RNA synthesis, or DNA replication, a cell could be faced with a cataclysmic series of mistakes. Indeed, this concept forms the basis of a theory of aging, the "error catastrophe" theory of Orgel (1963, 1973). It is hardly surprising, therefore, that cells... 

On the RTV-SM assembly, component location and position had a strong effect on time-to-first-failure for PLCC-84 and LCCC-44 devices. While there was a wide range of performance exhibited across the eight solder alloys, a similarly wide variation in performance was observed among the various component sites on the same board. Furthermore, a wide variation in performance was also observed at all locations across the three replicate boards used to test each solder. It was concluded that this position effect, coupled with general data variability, overshadowed the effect attributable to the solder alloy alone, and masked the ability to distinguish one solder alloy from any other. None of the Pb-free alloys exhibited catastrophic failure or distinguishably poorer performance than the other Pb-free alloys or the eutectic Sn-Pb control. Component type determined the failure time and mode. There were no clear differences between solder alloys or PWB surface finishes under the vibration conditions studied. 

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