Deciphering mRNA Sequence Determinants of Protein Production Rate

Abstract

One of the greatest challenges in biophysical models of translation is to identify coding sequence features that affect the rate of translation and therefore the overall protein production in the cell. We propose an analytic method to solve a translation model based on the inhomogeneous totally asymmetric simple exclusion process, which allows us to unveil simple design principles of nucleotide sequences determining protein production rates. Our solution shows an excellent agreement when compared to numerical genome-wide simulations of S. cerevisiae transcript sequences and predicts that the first 10 codons, which is the ribosome footprint length on the mRNA, together with the value of the initiation rate, are the main determinants of protein production rate under physiological conditions. Finally, we interpret the obtained analytic results based on the evolutionary role of the codons' choice for regulating translation rates and ribosome densities.

Inferring efficiency of translation initiation and elongation from ribosome profiling

“…This result is consistent with a recent study in which replacing the first 8 codons with their slower synonymous variants significantly reduced protein expression without affecting mRNA levels 45 . Furthermore, the first codons have been recognised as critical in determining protein synthesis both theoretically 12,13,47 and experimentally 46,[48][49][50] . Beyond the first 10 codons, the metagene profile of TEE further reveals a small but noticeable drop between codons 10 and 20, followed by a slow increase between codons 20 and 100.…”

“…This is possible since we have recently found a mathematical expression for the ribosome density profile in terms of translation initiation, elongation and termination rates. This expression was obtained under the assumption of a limiting initiation rate α 12,27 , which is supposed to hold for most of the mRNAs under physiological conditions (see Appendix A). However, we emphasise that the initiation-limited approximation does not assume that ribosome collisions are absent.…”

“…Our previous theoretical work on the exclusion process showed that if translation is rate-limited by initiation, then TIE predominately depends on the κ i of the first ≈ 10 codons, which is the ribosome footprint on the mRNA 12 . Based on that prediction, TIE > 0.5 is a strong signature that the codon sequences, and in particular the first codons of Saccharomyces cerevisiae genes might have been selected to optimise translation initiation.…”

“…The RPKM is proportional to the ribosome density, which in turn is assumed to be proportional to the rate of translation -the more ribosomes on a transcript, the more efficient is protein synthesis. However, a large body of work based on mathematical modelling of ribosome dynamics suggests that the protein synthesis rate is negatively affected by increased ribosome density due to ribosome collisions [11][12][13] . To which extent ribosome collisions can be found using ribosome profiling has been an active topic of research [14][15][16][17][18] One of the goals of ribosome profiling is to understand how the elongation rate along the transcript depends on the choice of codons.…”

“…This step is necessary because our solution of the model is approximate, see Refs. 12,27 and also the Appendix A.…”