The prevailing hypothesis on the evolution of codon usage suggests that the pattern of synonymous codon bias is a consequence of adaptation of codon usage to relative availability of tRNA's in the cellular matrix (reviewed by Ikemura 1992). A more relaxed hypothesis invokes the mutual adaptation of codon usage and tRNA availability (Bulmer 1988). According to this second hypothesis, there are three elements in the system determining the evolution of codon usage: mutation bias, tRNA availability, and random genetic drift (Bulmer 1991). Random genetic drift could lead to biased codon usage and unequal availability of different tRNA's in the absence of natural selection. If a synonymous codon that drifts to high frequency happens to be the one recognized by the most abundant tRNA, or if a tRNA that drifts to high abundance happens to be the one that recognizes the most frequently used codon, then these genetic drifts would result in increased translational efficiency and accuracy, and would therefore be favoured by natural selection. This would ultimately result in the most frequently used synonymous codon being recognized by the most abundant tRNA's (Gouy and Gautier 1982; Ikemura 1981; Ikemura 1982; Ikemura 1985; Ikemura 1992; Ikemura and Ozeki 1983). In short, the second hypothesis suggests that mutation bias, tRNA availability and random genetic drift form a self-contained system such that the interaction among the three elements is sufficient to explain the pattern of codon usage.
The results in this chapter indicate that this second hypothesis is too restrictive because some features of codon usage, such as the usage of A-ending codons, depend on factors that are not contained in the system of the three elements specified in that hypothesis. Specifically, our optimality model of the transcriptional process predicts that the pattern of synonymous codon usage should depend on the relative concentration of nucleotides in the cellular medium. This is consistent with the findings that the mitochondrial genome has a greater proportion of A-ending codons than the nuclear genome and that the nuclear genome in organisms with a high metabolic rate has a greater proportion of A-ending codons than the nuclear genome in organisms with a low metabolic rate. Thus, a more complete theory of the evolution of codon usage should consider the relative availability of ribonucleotides in the cellular matrix.
One potential misunderstanding concerning THCU and its predictions on biased usage of ATP in transcription is that, because ATP and GTP were used as energy sources in cellular processes, the use of ATP would tend to deplete available energy sources. The benefit of using ATP to enhance the transcription would consequently be offset by the cost of depleting the available energy sources. This argument arises from a misunderstanding that CTP and UTP can come free without spending ATP to synthesize them. It is in fact energetically more efficient to use ATP directly to fill a nucleotide site than to use ATP to synthesize an alternative NTP and then use that alternative NTP to fill in the nucleotide site. In other word, using ATP directly in transcription not only speeds up transcription, it also conserves available energy sources.
I should admit here that, although predictions from the model appears consistent with empirical data, the construction of the model itself is not vigorous because of simplifying assumptions. Protein synthesis is a multistep process including initiation of transcription, elongation of the mRNA chain, initiation of translation, and elongation of the peptide chain. By assuming that the rate of transcription rate is limiting, we have reduced the multi-step process to a one-step process, which obviously is a distortion of the reality. However, the recognition that even a very simple model could account for a substantial amount of variation in codon (nucleotide) usage would help to reduce the mystique surrounding the operation of natural selection on the biochemical systems in the living cell.
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