The First Messengers RNAs Codified Successions of Interactions Between Different PeptideRNAs

If, as seems to be the case, a stage was reached in which all protocell catalysis was performed by covalent complexes of peptides and RNAs (peptide-RNA) (Wong, 1991; Di Giulio, 1997; Wong and Xue, 2002; Di Giulio, 2003), then any improvement in peptide-RNA synthesis must have had a highly positive effect on protocell activity. More specifically, the improvement of peptide-RNA synthesis must have passed through certain stages. The most elementary must have been a direct interaction between two different peptide-RNAs (Orgel, 1989; Wong, 1991; Di Giulio, 1994, 1997, 2003), obviously mediated by hydrogen bonds between bases which could lead, for instance, to a lengthening of the peptide attached to one of the RNA or to a simple and different peptidation of an RNA (Fig. 1, stage 1) and therefore to an improvement in catalysis.

However, by direct interaction between peptide-RNAs (two or more than two), these syntheses would undergo a veritable improvement only when some peptide-RNAs started to be used as coordinators (templates) of the successions (sequences) of interactions between different peptide-RNAs (Fig. 1, stage 2). The RNA component of some peptide-RNAs probably began to favour (codify) the successions of interactions between peptide-RNAs (Fig. 1, stage 2). It seems to me, that this is the oldest form of messenger RNA (mRNA) that can be identified. In other words, the ancestor of mRNA could be an RNA codifying the successions of interactions between different peptide-RNAs. Clearly, in the early evolutionary stages, these interactions took place using regions that were not necessarily short and contiguous on the template RNA (Fig. 1, stage 2). In order to optimise these interactions between peptide-RNAs on the template of an RNA, evolution must have favoured the template RNAs that clearly used short and contiguous regions of the template RNA (Fig. 1, stages 3 and 4). Therefore, the first form of 'genetic code' can be seen in these early 'mRNAs' which codified these sequences of interactions between peptide-RNAs in the form of a message which, at its beginning, might have been highly heterogeneous in the sense that it could use a number of different bases (2, 3, 4, 5, or more) to codify one of these interactions (Fig. 1, stage 4). Therefore, at the dawn of the genetic code, codification was not performed only by three nucleotides.

Werkbladen Groep

Fig. 1 This shows various evolutionary stages of the origin of protein synthesis and the first mRNA. Circles indicate single amino acids, and hence peptides, while the RNAs are symbolised by curved or straight lines. In the last two stages each short segment indicates a single pairing of nucleotides or single nucleotides, while the tRNA-like molecules are indicated using L-shaped structures. The protoribosome is not represented. Every single stage shows the most characteristic molecules for that stage, sometimes in a number higher than that which were simultaneously interacting, and this is particularly true for stages 7 and 8

Fig. 1 This shows various evolutionary stages of the origin of protein synthesis and the first mRNA. Circles indicate single amino acids, and hence peptides, while the RNAs are symbolised by curved or straight lines. In the last two stages each short segment indicates a single pairing of nucleotides or single nucleotides, while the tRNA-like molecules are indicated using L-shaped structures. The protoribosome is not represented. Every single stage shows the most characteristic molecules for that stage, sometimes in a number higher than that which were simultaneously interacting, and this is particularly true for stages 7 and 8

4 Why the Genetic Code Originated Stage 5

4 Why the Genetic Code Originated Stage 5

Fig. 1 (continued)

4 The Birth of the First mRNA

We must now show how an evolutionary stage in which the RNA templates codified for the interactions between peptide-RNAs (Fig. 1, stages 3 and 4) lead on to mRNAs proper (Fig. 1, stage 8).

It is clear that for RNAs (pre-mRNAs) which codified the successions of interactions between peptide-RNAs it would have been more convenient to have these codifications concentrated on rigorously contiguous regions as this would have made the interactions between peptide-RNAs more efficient. Therefore, we expect an evolutionary stage in which the pre-mRNA molecules evolved (probably through intensive use of genetic recombination between pre-mRNA molecules) the codification of the successions of interactions between peptide-RNAs so that each of these codifications was strictly contiguous to the next one on the pre-mRNAs (Fig. 1, stage 5). In other words, at this evolutionary stage the pre-mRNAs had evolved a message primarily made up of 'words' of code that were contiguous to one another (Fig. 1, stage 5) but of different lengths.

It is equally clear that the evolutionary stages envisaging interaction between pre-mRNAs and peptide-RNAs (Fig. 1, stage 2 on, but perhaps also in stage 1) triggered a selective pressure to favour the origin of protoribosome, that is to say a structure, which was somehow able to favour all these interactions between pre-mRNAs and peptide-RNAs. Here I will not address the evolution of ribosome except in using the word protoribosome when necessary, given that the model I analyse here justifies its evolution.

We have thus reached an evolutionary stage in which pre-mRNAs used contiguous 'words' of different-length nucleotides to codify the individual interactions between peptide-RNAs (Fig. 1, stage 5). We must now show the crucial phase in the appearance of the first mRNA, that is to say, from pre-mRNA (Fig. 1, stage 5) to mRNA proper (Fig. 1, stage 8).

It seems clear to me that if the synthesis of peptide-RNAs had to be improved and, in particular, make the sequences of peptides in these complexes more reproducible, then at this evolutionary stage (Fig. 1, stage 5) it would have been necessary to trigger a selective pressure that would evolve tRNA-like molecules carrying a single amino acid because it is only the addition of a single amino acid that can faithfully reproduce a precise sequence of a peptide or a polypeptide. Indeed, the addition of more than one amino acid at a time to a peptide in order to reproduce a given sequence may create certain difficulties that are not encountered by adding a single amino acid residue at a time to the growing peptide: in this way the reproduction of the peptide, residue by residue, started to evolve (Fig. 1, stage 6). Moreover, it can be hypothesised that tRNA-like molecules carrying a single amino acid were no longer directly involved in catalysis as this role was performed by their 'products'. Finally, and paradoxically, it is also possible that the selection to reproduce a specific sequence of a peptide might never have actually been operative; nevertheless, the evolution of tRNA-like molecules carrying a single amino acid might have evolved by means of specific peptidation of the catalytic RNA. In other words, the RNAs might have behaved as a scaffold on which to attach the amino acids and, therefore, transform them into more active catalysts.

This might have had repercussions on the sequences of the pre-mRNAs and on protoribosome in the sense that particular classes of pre-mRNAs as well as a particular type of protoribosome, more suitable for acting with these new pre-mRNAs and with the tRNA-like molecules carrying a single amino acid, might have evolved. These particular classes of pre-mRNAs might, for instance, have been made up of words of code that were similar in length but not necessarily equal, for example with a prevalence of three-letter words of code (codons) but also many long words comprising four, five, six, or more nucleotides. In any case, all these words of code were mostly recognised by specific tRNA-like molecules carrying a single amino acid residue but not only by these molecules in the sense that there still existed at this stage tRNA-like molecules carrying more than one amino acid (dipeptides, tripeptides, etc.) (Fig. 1, stage 7).

Finally, it seems to me that the evolution from stage 7 in Fig. 1 to the translation of mRNA proper (Fig. 1, stage 8) can be conjectured by simply postulating the evolution of a particular subclass of pre-mRNA, that is to say mRNAs (with triplets, i.e. codons) codifying only for precursor amino acids (Ala, Gly, Ser, Asp, and Glu) as predicted by the co-evolution theory of the origin of the genetic code (Wong, 1975; Di Giulio and Medugno, 1999). The only specification to be made is that, initially, these mRNAs had to represent only a tiny fraction of all the translatable RNAs and that these took an incredibly long time to replace all the pre-mRNAs. Even if it is a question of transforming a pre-mRNA codifying for a message with a heterogeneous reading, i.e. mostly made up of triplets but with interspersed words of four, five, six, or more bases, into an mRNA with words solely of triplets, I think that this is not the cause of strong evolutionary discontinuity if these mRNAs were, as already said, very few in number at the beginning of their evolution and codified only for the five precursor amino acids because: (i) in the pre-mRNA population there might have existed some with marked mRNA characters because protoribosome might also favoured the evolution of just one particular type of pre-mRNA; (ii) many pre-mRNAs, rather than evolving, i.e. transforming into new mRNAs, might have been replaced by new mRNAs which were only partially in relation with the original pre-mRNAs; (iii) a pre-mRNA editing mechanism, such as the addition or removal of bases (Landweber and Gilbert, 1994), might have favoured the evolution of the first mRNAs. Furthermore, the codification limited only to the five precursor amino acids must have taken place very slowly and might initially have been favoured by their use only for very few and not necessarily fundamental functions. However, it seems to me that the evolution of enzymatic catalysis, that is to say, the reproducibility of some polypeptide-RNAs can still be considered the main adaptive theme characterising this evolutionary stage and leading to the codification of only the precursor amino acids. The replacement of the entire population of pre-mRNAs by mRNAs (Fig. 1, stages 7 and 8) must have been favoured by the hypothesis that catalysis, at this evolutionary stage, was still fairly rudimental and this clearly favoured the predominance of mRNAs which were able to better reproduce polypeptides because they used only the addition of a single amino acid residue at a time to the growing polypeptide (Fig. 1, stage 8).

In conclusion, the replacement of pre-mRNAs by the emerging mRNAs could not have been the cause of an insurmountable evolutionary discontinuity if the time available was enormous (perhaps billions of years) and if the substitution mechanism was above all based on an evolution ex novo of mRNAs which replaced the pre-mRNAs and only partially evolved from the latter: the duplication of messages and their recombination must have played a determining role in the origin of the first mRNA.

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