Computational Analysis of the Oscillatory Behavior at the Translation Level Induced by mRNA Levels Oscillations due to Finite Intracellular Resources

Each cell contains a limited number of macromolecules that participate in the gene expression process. These expression`s resources are shared between the different molecules that encode the genetic code, resulting in couplings and competitions between the different gene expression steps. We study the effect of the couplings and competitions for ribosomes by performing a whole-cell simulation of translation of S. cerevisiae, with parameters estimated from experimental data. We demonstrate that by periodically changing the mRNA levels of a endogenous or heterologous set of genes, the translation of all S. cerevisiae genes are affected in a periodic manner. We numerically estimate the exact impact of the mRNA levels periodicity on the translation process dynamics, and on the dynamics of the free ribosomal pool and the way it is affected by parameters such as the codon composition of the oscillating gene, its initiation rate and mRNA levels. Furthermore, we show that the codon compositions of synthetically highly expressed heterologous genes that are expected to oscillate must be carefully considered. For example, synonymous mutations resulting in "traffic jams" of ribosomes along the fluctuated mRNAs may cause significant fluctuations of up to 50% in the steady-state translation rates of all genes.