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PLoS Genet. 2015 May 7;11(5):e1005206. doi: 10.1371/journal.pgen.1005206. eCollection 2015 May.

Accounting for experimental noise reveals that mRNA levels, amplified by post-transcriptional processes, largely determine steady-state protein levels in yeast.

Author information

1
Dept. of Statistics, Harvard University, Cambridge, Massachusetts, United States of America.
2
Dept. of Statistics, Harvard University, Cambridge, Massachusetts, United States of America,; The Broad Institute of Harvard & MIT, Cambridge, Massachusetts, United States of America.
3
Dept. of Biochemistry & Molecular Biology, University of Chicago, Chicago, Illinois, United States of America,; Dept. of Human Genetics, University of Chicago, Chicago, Illinois, United States of America.

Abstract

Cells respond to their environment by modulating protein levels through mRNA transcription and post-transcriptional control. Modest observed correlations between global steady-state mRNA and protein measurements have been interpreted as evidence that mRNA 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 24 studies of budding yeast reveal that mRNA levels explain more than 85% of the variation in steady-state protein levels. Protein levels are not proportional to mRNA levels, but rise much more rapidly. Regulation of translation suffices to explain this nonlinear effect, revealing post-transcriptional amplification of, rather than competition with, transcriptional signals. These results substantially revise widely credited models of protein-level regulation, and introduce multiple noise-aware approaches essential for proper analysis of many biological phenomena.

PMID:
25950722
PMCID:
PMC4423881
DOI:
10.1371/journal.pgen.1005206
[Indexed for MEDLINE]
Free PMC Article

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