The relationship between third-codon position nucleotide content, codon bias, mRNA secondary structure and gene expression in the drosophilid alcoholdehydrogenase genes Adh and Adhr

To gain insights into the relationship between codon bias, mRNA secondary s tructure, third-codon position nucleotide distribution, and gene expression , we predicted secondary structures in two related drosophilid genes, Adh a nd Adhr, which differ in degree of codon bias and level of gene expression. Individual structural elements (helices) were inferred using the comparati ve method. For each gene, four types of randomization simulations were perf ormed to maintain/remove codon bias and/or to maintain or alter third-codon position nucleotide composition (M). In the weakly expressed, weakly biase d gene Adhr; the potential for secondary structure formation was found to b e much stronger than in the highly expressed, highly biased gene Adh. This is consistent with the observation of approximately equal G and C percentag es in Adhr (similar to 31% across species), whereas in Adh the N3 distribut ion is shifted toward C (42% across species). Perturbing the N3 distributio n to approximately equal amounts of A, G, C, and T increases the potential for secondary structure formation in Adh, but decreases it in Adhr. On the other hand, simulations that reduce codon bias without changing N3 content indicate that codon bias per se has only a weak effect on the formation of secondary structures. These results suggest that, for these two drosophilid genes, secondary Structure is a relatively independent, negative regulator of gene expression. Whereas the degree of codon bias is positively correla ted with level of gene expression, strong individual secondary Structural e lements may be selected for to retard mRNA translation and to decrease gene expression.