Influence of multiplicative stochastic variation on translational elongation rates

Abstract

Experimental data indicate that stochastic effects exerted at the level of translation contribute substantially to the variation in abundance of proteins expressed at moderate to high levels. This study analyzes the theoretical consequences of fluctuations in residue-specific elongation rates during translation. A simple analytical framework shows that rate variation during elongation gives rise to protein production rates that consist of sums of products of random variables. Simulations show that because the contribution to total variation of products of random variables greatly exceeds that of sums of random variables, the overall distribution exhibits approximately log-normal behavior. Empirical fits of the data can be satisfied by either sums of log-normal distributions, or sums of log-normal and log-logistic distributions. Elongation rate stochastic variation offers an accounting for a major component of biological variation. The analysis provided here highlights a probability distribution that is a natural extension of the Poisson and has broad applicability to many types of multiplicative noise processes.

Extrinsic noise acts to lower protein production at higher translation initiation rates

“…This system of cotranslational insertion has been theoretically studied using the Totally Asymmetric Exclusion Process (TASEP) framework [26]. This model is also one of the many that study ribosome dynamics on the mRNA, making use of the TASEP framework [22,25,27,29]. The framework, in general, models unidirectional stochastic motion of particles on a onedimensional lattice.…”

“…Several experimental studies are now looking at how the individual components of translation affect and aid protein synthesis [15][16][17][18][19][20][21]. These studies have also inspired several modeling frameworks that look at mRNA translation as a whole [22][23][24][25][26][27][28], effects of the assembly of the ribosomal machinery [25,29] or protein expression bursts as a result of stochastic transcription and translation [2,4,11,[30][31][32][33][34][35][36][37][38][39][40]. In this work, we focus on the kinetic aspects of mRNA translation.…”

Negative DNA supercoiling makes protein-mediated looping deterministic and ergodic within the bacterial doubling time

“…Yet, in the thermal bath of the eukaryotic nucleus, or prokaryotic nucleoid, molecular motion is random and the behavior of a molecule can only be described in probabilistic terms ( 8 , 9 ). Single-molecule experimentation allows fluctuation analysis ( 10–12 ) and has revealed very heterogeneous behavior of molecules ( 13–18 ). Measurements have shown that protein-mediated loops form and rupture stochastically, and the lifetimes of such loops span several orders of magnitude ( 19–22 ).…”

Negative DNA supercoiling makes protein-mediated looping deterministic and ergodic within the bacterial doubling time

“…Yet, in the thermal bath of the eukaryotic nucleus, or prokaryotic nucleoid, molecular motion is random and the behavior of a molecule can only be described in probabilistic terms (Nelson, 2003;Phillips R. et al, 2013). Single-molecule experimentation allows fluctuation analysis (Bido et al;Kundu et al, 2020;Milenkovic et al, 2020) and has revealed the robustly heterogeneous looping behavior of molecules (Datta and Seed, 2018;Finzi and Gelles, 1995;Graham et al, 2017;Kumar et al, 2016;Manzo et al, 2011;Manzo et al, 2012;Miyashita et al, 2015;Neuman et al, 2003;Wang et al, 1998;Zurla, 2009). Indeed, protein-mediated loops form and rupture stochastically in purified systems, and the lifetimes of such loops span several orders of magnitude.…”

“…Yet, in the thermal bath of the eukaryotic nucleus, or prokaryotic nucleoid, molecular motion is random and the behavior of a molecule can only be described in probabilistic terms (6,7). Single-molecule experimentation allows fluctuation analysis (8)(9)(10) and has revealed very heterogeneous looping behavior of molecules (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Measurements have shown that protein-mediated loops form and rupture stochastically, and the lifetimes of such loops span several orders of magnitude.…”