Accounting for experimental noise reveals that transcription dominates control of steady-state protein levels in yeast

Abstract

Cells respond to their environment by modulating protein levels through mRNA transcription and post-transcriptional control. Modest correlations between global steady-state mRNA and protein measurements have been interpreted as evidence that transcript levels determine roughly 40% of the variation in protein levels, indicating dominant post-transcriptional effects. However, the techniques underlying these conclusions, such as correlation and regression, yield biased results when data are noisy, missing systematically, and collinear—properties of mRNA and protein measurements—which motivated us to revisit this subject. Noise-robust analyses of 25 studies of budding yeast reveal that mRNA levels explain roughly 80% of the variation in steady-state protein levels. Post-transcriptional regulation amplifies rather than competes with the transcriptional signal. Measurements are highly reproducible within but not between studies, and are distorted in part by between-study differences in gene expression. These results substantially revise current models of protein-level regulation and introduce multiple noise-aware approaches essential for proper analysis of many biological phenomena.