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Noise in Biological Systems: Pros, Cons, and Mechanisms of Control

  • Yitzhak PilpelEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 759)

Abstract

Genetic regulatory circuits are often regarded as precise machines that accurately determine the level of expression of each protein. Most experimental technologies used to measure gene expression levels are incapable of testing and challenging this notion, as they often measure levels averaged over entire populations of cells. Yet, when expression levels are measured at the single cell level of even genetically identical cells, substantial cell-to-cell variation (or “noise”) may be observed. Sometimes different genes in a given genome may display different levels of noise; even the same gene, expressed under different environmental conditions, may display greater cell-to-cell variability in specific conditions and more tight control in other situations. While at first glance noise may seem to be an undesired property of biological networks, it might be beneficial in some cases. For instance, noise will increase functional heterogeneity in a population of microorganisms facing variable, often unpredictable, environmental changes, increasing the probability that some cells may survive the stress. In that respect, we can speculate that the population is implementing a risk distribution strategy, long before genetic heterogeneity could be acquired. Organisms may have evolved to regulate not only the averaged gene expression levels but also the extent of allowed deviations from such an average, setting it at the desired level for every gene under each specific condition. Here we review the evolving understanding of noise, its molecular underpinnings, and its effect on phenotype and fitness – when it can be detrimental, beneficial, or neutral and which regulatory tools eukaryotic cells may use to optimally control it.

Key words

Noise in gene expression noise control mechanisms regulatory networks network biology 

Notes

Acknowledgments

The author thanks the European Research Council (REC) for grant support. The author also thanks Barbara Morgenstern for editorial help with the chapter.

References

  1. 1.
    Nagalakshmi, U., Wang, Z., Waern, K., et al. (2008) The transcriptional landscape of the yeast genome defined by RNA sequencing. Science 320, 1344–1349.PubMedCrossRefGoogle Scholar
  2. 2.
    Shalem, O., Dahan, O., Levo, M., et al. (2008) Transient transcriptional responses to stress are generated by opposing effects of mRNA production and degradation. Mol. Syst. Biol. 4, 223.PubMedCrossRefGoogle Scholar
  3. 3.
    Ingolia, N. T., Ghaemmaghami, S., Newman, J. R., and Weissman, J. S. (2009) Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science 324, 218–223.PubMedCrossRefGoogle Scholar
  4. 4.
    Li, J. B., Levanon, E. Y., Yoon, J. K., et al. (2009) Genome-wide identification of human RNA editing sites by parallel DNA capturing and sequencing. Science 324, 1210–1213.PubMedCrossRefGoogle Scholar
  5. 5.
    Balaban, N. Q., Merrin, J., Chait, R., Kowalik, L., and Leibler, S. (2004) Bacterial persistence as a phenotypic switch. Science 305, 1622–1625.PubMedCrossRefGoogle Scholar
  6. 6.
    Nachman, I., Regev, A., and Ramanathan, S. (2007) Dissecting timing variability in yeast meiosis. Cell 131, 544–556.PubMedCrossRefGoogle Scholar
  7. 7.
    Feinerman, O., Veiga, J., Dorfman, J. R., Germain, R. N., and Altan-Bonnet, G. (2008) Variability and robustness in T cell activation from regulated heterogeneity in protein levels. Science 321, 1081–1084.PubMedCrossRefGoogle Scholar
  8. 8.
    Cohen, A. A., Geva-Zatorsky, N., Eden, E., et al. (2008) Dynamic proteomics of individual cancer cells in response to a drug. Science 322, 1511–1516.PubMedCrossRefGoogle Scholar
  9. 9.
    Raser, J. M., and O’Shea, E. K. (2005) Noise in gene expression: origins, consequences, and control. Science 309, 2010–2013.PubMedCrossRefGoogle Scholar
  10. 10.
    Thattai, M., and van Oudenaarden, A. (2001) Intrinsic noise in gene regulatory networks. Proc. Natl. Acad. Sci. USA 98, 8614–8619.PubMedCrossRefGoogle Scholar
  11. 11.
    Ozbudak, E. M., Thattai, M., Kurtser, I., Grossman, A. D., and van Oudenaarden A. (2002) Regulation of noise in the expression of a single gene. Nat. Genet. 31, 69–73.PubMedCrossRefGoogle Scholar
  12. 12.
    Blake, W. J., Kaern, M., Cantor, C. R., and Collins, J. J. (2003) Noise in eukaryotic gene expression. Nature 422, 633–637.PubMedCrossRefGoogle Scholar
  13. 13.
    Sigal, A., Milo, R., Cohen, A., et al. (2006) Dynamic proteomics in individual human cells uncovers widespread cell-cycle dependence of nuclear proteins. Nat. Methods 3, 525–531.PubMedCrossRefGoogle Scholar
  14. 14.
    Paulsson, J. (2004) Summing up the noise in gene networks. Nature 427, 415–418.PubMedCrossRefGoogle Scholar
  15. 15.
    Cai, L., Friedman, N., and Xie, X. S. (2006) Stochastic protein expression in individual cells at the single molecule level. Nature 440, 358–362.PubMedCrossRefGoogle Scholar
  16. 16.
    Rosenberger, R. F., and Hilton, J. (1983) The frequency of transcriptional and translational errors at nonsense codons in the lacZ gene of Escherichia coli. Mol. Gen. Genet. 191, 207–212.PubMedCrossRefGoogle Scholar
  17. 17.
    Gordon, A. J, Halliday, J. A., Blankschien, M. D., Burns, P. A, Yatagai, F., and Herman, C. (2009) Transcriptional infidelity promotes heritable phenotypic change in a bistable gene network. PLoS Biol. 24, e44.CrossRefGoogle Scholar
  18. 18.
    Elowitz, M. B., Levine, A. J., Siggia, E. D., and Swain, P. S. (2002) Stochastic gene expression in a single cell. Science 297, 1183–1186.PubMedCrossRefGoogle Scholar
  19. 19.
    Raser, J. M., and O'Shea, E. K. (2004) Control of stochasticity in eukaryotic gene expression. Science 304, 1811–1814.PubMedCrossRefGoogle Scholar
  20. 20.
    Bar-Even, A., Paulsson, J., Maheshri, N., et al. (2006) Noise in protein expression scales with natural protein abundance. Nat. Genet. 38, 636–643.PubMedCrossRefGoogle Scholar
  21. 21.
    Newman, J. R., Ghaemmaghami, S., Ihmels, J., et al. (2006) Single-cell proteomic analysis of S. cerevisiae reveals the architecture of biological noise. Nature 441, 840–846.PubMedCrossRefGoogle Scholar
  22. 22.
    Huh, W. K., Falvo, J. V., Gerke, L. C., et al. (2003) Global analysis of protein localization in budding yeast. Nature 425, 686–691.PubMedCrossRefGoogle Scholar
  23. 23.
    Kussell, E., and Leibler, S. (2005) Phenotypic diversity, population growth, and information in fluctuating environments. Science 309, 2075–2078.PubMedCrossRefGoogle Scholar
  24. 24.
    Pedraza, J. M., and van Oudenaarden, A. (2005) Noise propagation in gene networks. Science 307, 1965–1969.PubMedCrossRefGoogle Scholar
  25. 25.
    Wang, Y., Liu, C. L., Storey, J. D., Tibshirani, R. J., Herschlag, D., and Brown, P. O. (2002) Precision and functional specificity in mRNA decay. Proc. Natl. Acad. Sci. USA 99, 5860–5865.PubMedCrossRefGoogle Scholar
  26. 26.
    Belle, A., Tanay, A., Bitincka, L., Shamir, R., and O'Shea, E. K. (2006) Quantification of protein half-lives in the budding yeast proteome. Proc. Natl. Acad. Sci. USA 103, 13004–13009.PubMedCrossRefGoogle Scholar
  27. 27.
    Fraser, H. B., Hirsh, A. E., Giaever, G., Kumm, J., and Eisen, M. B. (2004) Noise minimization in eukaryotic gene expression. PLoS Biol. 2, e137.PubMedCrossRefGoogle Scholar
  28. 28.
    dos Reis, M., Savva, R., and Wernisch, L. (2004) Solving the riddle of codon usage preferences: a test for translational selection. Nucleic Acids Res. 32, 5036–5044.PubMedCrossRefGoogle Scholar
  29. 29.
    Gasch, A. P., Spellman, P. T., Kao, C. M., et al. (2000) Genomic expression programs in the response of yeast cells to environmental changes. Mol. Biol. Cell. 11, 4241–4257.PubMedGoogle Scholar
  30. 30.
    Rodríguez Martínez, M., Soriano, J., Tlusty, T., Pilpel, Y., and Furman, I. (2010) Messenger RNA fluctuations and regulatory RNAs shape the dynamics of a negative feedback loop. Phys. Rev. E. Stat. Nonlin. Soft Matter Phys. 81, 031924.PubMedCrossRefGoogle Scholar
  31. 31.
    Murphy, K. F., Balázsi, G., and Collins, J. J. (2007) Combinatorial promoter design for engineering noisy gene expression. Proc. Natl. Acad. Sci. USA 104, 12726–12731.PubMedCrossRefGoogle Scholar
  32. 32.
    Blake, W. J., Balázsi, G., Kohanski, M. A., et al. (2006). Phenotypic consequences of promoter-mediated transcriptional noise. Mol. Cell 24, 853–865.PubMedCrossRefGoogle Scholar
  33. 33.
    Segal, E., and Widom, J. (2009) What controls nucleosome positions? Trends Genet. 25, 335–343.PubMedCrossRefGoogle Scholar
  34. 34.
    Kim, H. D., and O'Shea, E. K. (2008) A quantitative model of transcription factor-activated gene expression. Nat. Struct. Mol. Biol. 15, 1192–1198.PubMedCrossRefGoogle Scholar
  35. 35.
    Hornung, G., and Barkai, N. (2008) Noise propagation and signaling sensitivity in biological networks: a role for positive feedback. PLoS Comput. Biol. 4, e8PubMedCrossRefGoogle Scholar
  36. 36.
    Cağatay, T., Turcotte, M., Elowitz, M. B., Garcia-Ojalvo, J., and Süel GM. (2009) Architecture-dependent noise discriminates functionally analogous differentiation circuits. Cell 139, 512–522.PubMedCrossRefGoogle Scholar
  37. 37.
    Kafri, R., Levy, M., and Pilpel, Y. (2006) The regulatory utilization of genetic redundancy through responsive backup circuits. Proc. Natl. Acad. Sci. USA 103, 11653–11658.PubMedCrossRefGoogle Scholar
  38. 38.
    Kafri, R., Springer, M., and Pilpel, Y. (2009) Genetic redundancy: new tricks for old genes. Cell 136, 389–392.PubMedCrossRefGoogle Scholar
  39. 39.
    Hendrickson, D. G., Hogan, D. J., McCullough, H. L., et al. (2009) Concordant regulation of translation and mRNA abundance for hundreds of targets of a human microRNA. PLoS Biol. 7, e1000238.PubMedCrossRefGoogle Scholar
  40. 40.
    Rinaudo, K., Bleris, L., Maddamsetti, R., Subramanian, S., Weiss, R., and Benenson, Y. (2007) A universal RNAi-based logic evaluator that operates in mammalian cells. Nat. Biotechnol. 25, 795–801.PubMedCrossRefGoogle Scholar
  41. 41.
    Sniegowski, P. D., Gerrish, P. J., and Lenski, R. E. (1997) Evolution of high mutation rates in experimental populations of E. coli. Nature 387, 703–705.PubMedCrossRefGoogle Scholar
  42. 42.
    Koonin, E. V., and Wolf, Y. I. (2009) Is evolution Darwinian or/and Lamarckian? Biol. Direct. 4, 42.PubMedCrossRefGoogle Scholar
  43. 43.
    Acar, M., Mettetal, J. T., and van Oudenaarden, A. (2008) Stochastic switching as a survival strategy in fluctuating environments. Nat. Genet. 40, 471–475.PubMedCrossRefGoogle Scholar
  44. 44.
    Sigal, A., Milo, R., Cohen, A., et al. (2006) Variability and memory of protein levels in human cells. Nature 444, 643–646.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press 2011

Authors and Affiliations

  1. 1.Department of Molecular GeneticsWeizmann Institute of ScienceRehovotIsrael

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