Extrinsic noise prevents the independent tuning of gene expression noise and protein mean abundance in bacteria.

It is generally accepted that prokaryotes can tune gene expression noise independently of protein mean abundance by varying the relative levels of transcription and translation. Here, we address this question quantitatively, using a custom-made library of 40 strains expressing a fluorescent protein under the control of different transcription and translation control elements. We quantify noise and mean protein abundance by fluorescence microscopy and show that for most of the natural transcription range of , expression noise is equally sensitive to variations in the transcription or translation rate because of the prevalence of extrinsic noise. In agreement, analysis of whole-genome transcriptomic and proteomic datasets suggests that noise optimization through transcription and translation tuning during evolution may only occur in a regime of weak transcription. Therefore, independent control of mean abundance and noise can rarely be achieved, which has strong implications for both genome evolution and biological engineering.