Ribosome demand links transcriptional bursts to protein expression noise.

Stochastic variation in protein expression generates phenotypic heterogeneity in a cell population and has an important role in antibiotic persistence, mutation penetrance, tumor growth, and therapy resistance. Studies investigating molecular origins of noise have predominantly focused on the transcription process. However, the noise generated in the transcription process is further modulated by translation. This influences the expression noise at the protein level which eventually determines the extent of phenotypic heterogeneity in a cell population. Studies across different organisms have revealed a positive association between translational efficiency and protein noise. However, the molecular basis of this association has remained unknown. In this work, through stochastic modeling of translation in single mRNA molecules and empirical measurements of protein noise, we show that ribosome demand associated with high translational efficiency in a gene drives the correlation between translational efficiency and protein noise. We also show that this correlation is present only in genes with bursty transcription. Thus, our work reveals the molecular basis of how coding sequence of genes, along with their promoters, can regulate noise. These findings have important implications for investigating protein noise and phenotypic heterogeneity across biological systems.