Although the mechanism of codon bias selection remains controversial, possible explanations for this bias fall into two general categories. One explanation revolves around the selectionist theory, in which codon bias contributes to the efficiency and/or accuracy of protein expression and therefore undergoes positive selection. The selectionist model also explains why more frequent codons are recognized by more abundant tRNA molecules, as well as the correlation between preferred codons, tRNA levels, and gene copy numbers. Although it has been shown that the rate of amino acid incorporation at more frequent codons occurs at a much higher rate than that of rare codons, the speed of translation has not been shown to be directly affected and therefore the bias towards more frequent codons may not be directly advantageous. However, the increase in translation elongation speed may still be indirectly advantageous by increasing the cellular concentration of free ribosomes and potentially the rate of initiation for messenger RNAs (mRNAs).
The second explanation for codon usage can be explained by mutational bias, a theory which posits that codon bias exists because of nonrandomness in the mutational patterns. In other words, some codons can undergo more changes and therefore result in lower equilibrium frequencies, also known as “rare” codons. Different organisms also exhibit different mutational biases, and there is growing evidence that the level of genome-wide GC content is the most significant parameter in explaining codon bias differences between organisms. Additional studies have demonstrated that codon biases can be statistically predicted in prokaryotes using only intergenic sequences, arguing against the idea of selective forces on coding regions and further supporting the mutation bias model. However, this model alone cannot fully explain why preferred codons are recognized by more abundant tRNAs.