Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Noise in protein expression scales with natural protein abundance


Noise in gene expression is generated at multiple levels, such as transcription and translation, chromatin remodeling and pathway-specific regulation. Studies of individual promoters have suggested different dominating noise sources, raising the question of whether a general trend exists across a large number of genes and conditions. We examined the variation in the expression levels of 43 Saccharomyces cerevisiae proteins, in cells grown under 11 experimental conditions. For all classes of genes and under all conditions, the expression variance was approximately proportional to the mean; the same scaling was observed at steady state and during the transient responses to the perturbations. Theoretical analysis suggests that this scaling behavior reflects variability in mRNA copy number, resulting from random 'birth and death' of mRNA molecules or from promoter fluctuations. Deviation of coexpressed genes from this general trend, including high noise in stress-related genes and low noise in proteasomal genes, may indicate fluctuations in pathway-specific regulators or a differential activation pattern of the underlying gene promoters.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Single-cell distributions of fluorescence levels.
Figure 2: Scaling of noise with mean protein abundance.
Figure 3: Theoretical analysis of noise propagation.
Figure 4: Noise pattern of PRE9.
Figure 5: Transient response to perturbations.
Figure 6: Noise residuals.

Similar content being viewed by others


  1. McAdams, H.H. & Arkin, A. It's a noisy business! Genetic regulation at the nanomolar scale. Trends Genet. 15, 65–69 (1999).

    Article  CAS  Google Scholar 

  2. McAdams, H.H. & Arkin, A. Stochastic mechanisms in gene expression. Proc. Natl. Acad. Sci. USA 94, 814–819 (1997).

    Article  CAS  Google Scholar 

  3. Elowitz, M.B. & Leibler, S. A synthetic oscillatory network of transcriptional regulators. Nature 403, 335–338 (2000).

    Article  CAS  Google Scholar 

  4. Barkai, N. & Leibler, S. Circadian clocks limited by noise. Nature 403, 267–268 (2000).

    Article  CAS  Google Scholar 

  5. Berg, O.G., Paulsson, J. & Ehrenberg, M. Fluctuations and quality of control in biological cells: zero-order ultrasensitivity reinvestigated. Biophys. J. 79, 1228–1236 (2000).

    Article  CAS  Google Scholar 

  6. Rao, C.V., Wolf, D.M. & Arkin, A.P. Control, exploitation and tolerance of intracellular noise. Nature 420, 231–237 (2002).

    Article  CAS  Google Scholar 

  7. Paulsson, J. Summing up the noise in gene networks. Nature 427, 415–418 (2004).

    Article  CAS  Google Scholar 

  8. Spudich, J.L. & Koshland, D.E. Jr. Non-genetic individuality: chance in the single cell. Nature 262, 467–471 (1976).

    Article  CAS  Google Scholar 

  9. Maloney, P.C. & Rotman, B. Distribution of suboptimally induces -D-galactosidase in Escherichia coli. The enzyme content of individual cells. J. Mol. Biol. 73, 77–91 (1973).

    Article  CAS  Google Scholar 

  10. Lobner-Olesen, A. Distribution of minichromosomes in individual Escherichia coli cells: implications for replication control. EMBO J. 18, 1712–1721 (1999).

    Article  CAS  Google Scholar 

  11. Becskei, A. & Serrano, L. Engineering stability in gene networks by autoregulation. Nature 405, 590–593 (2000).

    Article  CAS  Google Scholar 

  12. Gardner, T.S., Cantor, C.R. & Collins, J.J. Construction of a genetic toggle switch in Escherichia coli. Nature 403, 339–342 (2000).

    Article  CAS  Google Scholar 

  13. Raser, J.M. & O'Shea, E.K. Noise in gene expression: origins, consequences, and control. Science 309, 2010–2013 (2005).

    Article  CAS  Google Scholar 

  14. Kaern, M., Elston, T.C., Blake, W.J. & Collins, J.J. Stochasticity in gene expression: from theories to phenotypes. Nat. Rev. Genet. 6, 451–464 (2005).

    Article  CAS  Google Scholar 

  15. Thattai, M. & van Oudenaarden, A. Intrinsic noise in gene regulatory networks. Proc. Natl. Acad. Sci. USA 98, 8614–8619 (2001).

    Article  CAS  Google Scholar 

  16. Ozbudak, E.M., Thattai, M., Kurtser, I., Grossman, A.D. & van Oudenaarden, A. Regulation of noise in the expression of a single gene. Nat. Genet. 31, 69–73 (2002).

    Article  CAS  Google Scholar 

  17. Rosenfeld, N., Young, J.W., Alon, U., Swain, P.S. & Elowitz, M.B. Gene regulation at the single-cell level. Science 307, 1962–1965 (2005).

    Article  CAS  Google Scholar 

  18. Colman-Lerner, A. et al. Regulated cell-to-cell variation in a cell-fate decision system. Nature 437, 699–706 (2005).

    Article  CAS  Google Scholar 

  19. Becskei, A., Kaufmann, B.B. & van Oudenaarden, A. Contributions of low molecule number and chromosomal positioning to stochastic gene expression. Nat. Genet. 37, 937–944 (2005).

    Article  CAS  Google Scholar 

  20. Blake, W.J., Kaern, M., Cantor, C.R. & Collins, J.J. Noise in eukaryotic gene expression. Nature 422, 633–637 (2003).

    Article  CAS  Google Scholar 

  21. Elowitz, M.B., Levine, A.J., Siggia, E.D. & Swain, P.S. Stochastic gene expression in a single cell. Science 297, 1183–1186 (2002).

    Article  CAS  Google Scholar 

  22. Raser, J.M. & O'Shea, E.K. Control of stochasticity in eukaryotic gene expression. Science 304, 1811–1814 (2004).

    Article  CAS  Google Scholar 

  23. Pedraza, J.M. & van Oudenaarden, A. Noise propagation in gene networks. Science 307, 1965–1969 (2005).

    Article  CAS  Google Scholar 

  24. Swain, P.S., Elowitz, M.B. & Siggia, E.D. Intrinsic and extrinsic contributions to stochasticity in gene expression. Proc. Natl. Acad. Sci. USA 99, 12795–12800 (2002).

    Article  CAS  Google Scholar 

  25. Huh, W.K. et al. Global analysis of protein localization in budding yeast. Nature 425, 686–691 (2003).

    Article  CAS  Google Scholar 

  26. Ghaemmaghami, S. et al. Global analysis of protein expression in yeast. Nature 425, 737–741 (2003).

    Article  CAS  Google Scholar 

  27. Volfson, D. et al. Origins of extrinsic variability in eukaryotic gene expression. Nature (2005).

  28. Rigney, D.R. & Schieve, W.C. Stochastic model of linear, continuous protein synthesis in bacterial populations. J. Theor. Biol. 69, 761–766 (1977).

    Article  CAS  Google Scholar 

  29. Berg, O.G. A model for the statistical fluctuations of protein numbers in a microbial population. J. Theor. Biol. 71, 587–603 (1978).

    Article  CAS  Google Scholar 

  30. Peccoud, J. & Ycart, B. Markovian modelling of gene-product synthesis. Theor. Popul. Biol. 48, 222–234 (1995).

    Article  Google Scholar 

  31. Argollo de Menezes, M. & Barabasi, A.L. Separating internal and external dynamics of complex systems. Phys. Rev. Lett. 93, 068701 (2004).

    Article  CAS  Google Scholar 

  32. de Menezes, M.A. & Barabasi, A.L. Fluctuations in network dynamics. Phys. Rev. Lett. 92, 028701 (2004).

    Article  Google Scholar 

  33. Fraser, H.B., Hirsh, A.E., Giaever, G., Kumm, J. & Eisen, M.B. Noise minimization in eukaryotic gene expression. PLoS Biol. 2, e137 (2004).

    Article  Google Scholar 

  34. Kussell, E. & Leibler, S. Phenotypic diversity, population growth, and information in fluctuating environments. Science 309, 2075–2078 (2005).

    Article  CAS  Google Scholar 

  35. Paulsson, J. Models of stochastic gene expression. Phys. Life Rev. 2, 157–175 (2005).

    Article  Google Scholar 

  36. Holstege, F.C. et al. Dissecting the regulatory circuitry of a eukaryotic genome. Cell 95, 717–728 (1998).

    Article  CAS  Google Scholar 

  37. Velculescu, V.E. et al. Characterization of the yeast transcriptome. Cell 88, 243–251 (1997).

    Article  CAS  Google Scholar 

  38. Wang, Y. et al. Precision and functional specificity in mRNA decay. Proc. Natl. Acad. Sci. USA 99, 5860–5865 (2002).

    Article  CAS  Google Scholar 

  39. Garcia-Martinez, J., Aranda, A. & Perez-Ortin, J.E. Genomic run-on evaluates transcription rates for all yeast genes and identifies gene regulatory mechanisms. Mol. Cell 15, 303–313 (2004).

    Article  CAS  Google Scholar 

  40. Newman, J.R.S. et al. Single-cell proteomics of the budding yeast Saccharomyces cerevisiae. Nature (in the press).

Download references


We thank the members of the Barkai and Pilpel labs for discussions and help in the experiments. This work was supported by the Tauber fund through the Foundations of Cognition Initiative. N.B. acknowledges the hospitality of the Bauer Center at Harvard, where part of this research was performed. Y.P. is an incumbent of the Aser Rothstein Career Development chair in Genetic Diseases. Y.P. acknowledges financial support from EMBRACE (a European Model for Bioinformatics Research and Community Education), funded by the European Commission within its FP6 Program.

Author information

Authors and Affiliations


Corresponding authors

Correspondence to Yitzhak Pilpel or Naama Barkai.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Dual reporter assay. (PDF 414 kb)

Supplementary Fig. 2

Doubling time effect. (PDF 16 kb)

Supplementary Fig. 3

Correlation between protein abundance and fluorescence. (PDF 4 kb)

Supplementary Fig. 4

mRNA data set comparison. (PDF 6 kb)

Supplementary Figure 5

GFP-fused versus promoter-GFP. (PDF 6 kb)

Supplementary Fig. 6

Normal and log-normal patterns. (PDF 9 kb)

Supplementary Methods (PDF 73 kb)

Supplementary Note (PDF 81 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bar-Even, A., Paulsson, J., Maheshri, N. et al. Noise in protein expression scales with natural protein abundance. Nat Genet 38, 636–643 (2006).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing