Efficient manipulations of synonymous mutations for controlling translation rate: an analytical approach

Gene translation is a central process in all living organism with important ramifications to almost every biomedical field. Previous systems evolutionary studies in the field have demonstrated that in many organisms coding sequence features undergo selection to optimize this process. In the current study, we report for the first time analytical proofs related to the various aspects of this process and its optimality. Among our results we show that coding sequences with mono- tonic increasing profiles of translation efficiency (i.e., with slower codons near the 5'UTR), mathematically optimize ribosomal allocation by minimizing the number of ribosomes needed for translating a codon per time unit. Thus, the genomic translation efficiency profile reported in previous studies for many organisms is optimal in this sense. In addition, we show that improving translation efficiency of a codon in a gene may result in a decrease in the translation rate of other genes, demonstrating that the relation between codon bias and protein translation rate is less trivial than was assumed before. Based on these observations we describe an efficient heuristic for designing coding sequences with specific translation efficiency and minimal ribosomal allocation for heterologous gene expression. We demonstrate how this heuristic can be used in biotechnology for engineering a heterologous gene before expressing it in a new host.     

Strong association between mRNA folding strength and protein abundance in S. cerevisiae

One of the open questions in regulatory genomics is how the efficiency of gene translation is encoded in the coding sequence. Here we analyse recently generated measurements of folding energy in Saccharomyces cerevisiae, showing that genes with high protein abundance tend to have strong mRNA folding (mF; R=0.68). mF strength also strongly correlates with ribosomal density and mRNA levels, suggesting that this relation at least partially pertains to the efficiency of translation elongation, presumably by preventing aggregation of mRNA molecules.     

The effect of tRNA levels on decoding times of mRNA codons

The possible effect of transfer ribonucleic acid (tRNA) concentrations on codons decoding time is a fundamental biomedical research question; however, due to a large number of variables affecting this process and the non-direct relation between them, a conclusive answer to this question has eluded so far researchers in the field. In this study, we perform a novel analysis of the ribosome profiling data of four organisms which enables ranking the decoding times of different codons while filtering translational phenomena such as experimental biases, extreme ribosomal pauses and ribosome traffic jams. Based on this filtering, we show for the first time that there is a significant correlation between tRNA concentrations and the codons estimated decoding time both in prokaryotes and in eukaryotes in natural conditions (−0.38 to −0.66, all P values <0.006); in addition, we show that when considering tRNA concentrations, codons decoding times are not correlated with aminoacyl-tRNA levels. The reported results support the conjecture that translation efficiency is directly influenced by the tRNA levels in the cell. Thus, they should help to understand the evolution of synonymous aspects of coding sequences via the adaptation of their codons to the tRNA pool.     

Entrainment to Periodic Initiation and Transition Rates in a Computational Model for Gene Translation

Periodic oscillations play an important role in many biomedical systems. Proper functioning of biological systems that respond to periodic signals requires the ability to synchronize with the periodic excitation. For example, the sleep/wake cycle is a manifestation of an internal timing system that synchronizes to the solar day. In the terminology of systems theory, the biological system must entrain or phase-lock to the periodic excitation. Entrainment is also important in synthetic biology. For example, connecting several artificial biological systems that entrain to a common clock may lead to a well-functioning modular system. The cell-cycle is a periodic program that regulates DNA synthesis and cell division. Recent biological studies suggest that cell-cycle related genes entrain to this periodic program at the gene translation level, leading to periodically-varying protein levels of these genes. The ribosome flow model (RFM) is a deterministic model obtained via a mean-field approximation of a stochastic model from statistical physics that has been used to model numerous processes including ribosome flow along the mRNA. Here we analyze the RFM under the assumption that the initiation and/or transition rates vary periodically with a common period . We show that the ribosome distribution profile in the RFM entrains to this periodic excitation. In particular, the protein synthesis pattern converges to a unique periodic solution with period . To the best of our knowledge, this is the first proof of entrainment in a mathematical model for translation that encapsulates aspects such as initiation and termination rates, ribosomal movement and interactions, and non-homogeneous elongation speeds along the mRNA. Our results support the conjecture that periodic oscillations in tRNA levels and other factors related to the translation process can induce periodic oscillations in protein levels, and may suggest a new approach for re-engineering genetic systems to obtain a desired, periodic, protein synthesis rate.     

Analysis of Global and Site-Specific Radiation Damage in Cryo-EM

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