Changes in Acceptor Stem Identity Elements Correlate with Changes in the Code

The genetic code was first defined as a 'frozen accident by Francis Crick, who argued that its current structure was due to the fact that its evolution had reached an evolutionary dead-end [79]. Emerging from this cul-de-sac was not possible because the system was incapable of assimilating new changes. This notion of a 'frozen' code has been challenged by the discovery of variations in the code of certain organisms and, more notably, in eukaryotic organelles [80-82]. Nevertheless, the genetic code has remained mostly invariable across the phylogenetic tree. This supports the notion that, for the most part, the code has reached a degree of complexity that does not accept new variations with ease.

As stated above, the 'operational RNA code' for amino acids is the relationship between sequences and structures of acceptor stems and specific amino acids [20, 22, 83]. Through variations of the 'operational RNA code' the genetic code can change from organism to organism, because any change in the codon-amino acid equivalence has to be adopted by the 'operational RNA code'. Thus, it is conceivable that the frozen state of the genetic code is a consequence of the limitations of the 'operational RNA code'.

Misacylation errors are lethal to cells, and they are prevented through two different mechanisms. On the one hand, potential errors of amino acid recognition (caused by misrecognition of similar residues like isoleucine and valine) are corrected via editing domains contained in the error-prone synthetases [2, 58, 84-88]. On the other hand, potential errors in tRNA recognition are prevented by positive and negative identity elements in each tRNA [31, 32]. But the repertoire of identity elements might have limits. If the capacity of the 'operational RNA code' is limited then new variations in tRNA recognition mechanisms are not possible, because they would result in unacceptable levels of tRNA mischarging by the existing synthetases.

We propose that the fixed state of the genetic code is due to intrinsic limitations of the recognition of tRNAs by aminoacyl-tRNA synthetases. Expansion of the set of tRNAs is restricted because it runs the risk of causing acylation errors. However, incorporation of modifications to the genetic code requires changes in the cellular tRNA set. If the total set of tRNAs in a given organism is reduced, the discrimination problems faced by their cognate synthetases are decreased. This process would facilitate the evolution of tRNA sequences, because the available evolutionary space would increase. In turn, the divergence of tRNA sequences would open the possibility of changes in the genetic code.

Many of the genetic codes found to contain exceptions to the universal codon-amino acid assignments are in animal mitochondria. The first exception to the universal code was detected in the genomes of vertebrate mitochondria, where AUA codes for methionine instead of isoleucine, and UGA codes for tryptophan instead of being a stop triplet. Since that discovery, exceptions to the code have been detected in a large variety of organisms and organelles (reviewed in Ref. [82]). Most of the exceptions, however, are concentrated in metazoans (animals), involving changes of 11 different codons [82].

Additionally, animal mitochondria have experienced a dramatic reduction in their genome size and, in particular, in the number of tRNA genes [89]. If, as we propose, an initial requirement for changes in the code is the relaxation of the recognition constraints between ARS and tRNAs, then the large amount of variations in the genetic code of animal mitochondria should correlate with a large amount of changes in the 'operational RNA code' imbedded in their acceptor stem sequences.

As it can be seen in Table 4.2-2, the percentage of tRNA sequences in mitochondria that contain the recognition elements that are operational in bacteria or eukary-otes is significantly decreased for 16 amino acids. Remarkably, all tRNAs whose identity has been reported to change in mitochondria (tRNAIle, tRNAAr8, tRNAMet, tRNALys, and tRNASer) show important decreases in the conservation of identity elements (Table 4.2-2). Thus, in animal mitochondria, a reduction of tRNA genes is correlated with changes in the mechanisms of recognition between tRNAs and ARS and, simultaneously, with the largest concentration of changes in the genetic code.

Table 4.2-2 Drift of acceptor stem identity elements in animal mitochondrial tRNAs

Amino acid

Identity elements in acceptor stema

Conservation in non-animal mitochondria (%)b

Conservation in animal mitochondria (%)b


G3: U70

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