Variable gene expression within a clonal population of cells has been implicated in a number of important processes including mutation and evolution^{1, 2}, determination of cell fates^{3, 4} and the development of genetic disease^{5, 6}. Recent studies have demonstrated that a significant component of expression variability arises from extrinsic factors thought to influence multiple genes simultaneously^{7, 8, 9, 10}, yet the biological origins of this extrinsic variability have received little attention. Here we combine computational modelling^{11, 12, 13, 14, 15, 16, 17, 18} with fluorescence data generated from multiple promoter–gene inserts in Saccharomyces cerevisiae to identify two major sources of extrinsic variability. One unavoidable source arising from the coupling of gene expression with population dynamics leads to a ubiquitous lower limit for expression variability. A second source, which is modelled as originating from a common upstream transcription factor, exemplifies how regulatory networks can convert noise in upstream regulator expression into extrinsic noise at the output of a target gene⁹. Our results highlight the importance of the interplay of gene regulatory networks with population heterogeneity for understanding the origins of cellular diversity.

1. Department of Bioengineering, and
2. Institute for Nonlinear Science, University of California San Diego, La Jolla, California 92093, USA
3. Department of Biomedical Engineering, Boston University, 44 Cummington Street, Boston, Massachusetts 02215, USA
4. *These authors contributed equally to this work

Correspondence to: Jeff Hasty¹ Correspondence and requests for materials should be addressed to J.H. (Email: hasty@ucsd.edu).

Received 3 June 2005; Accepted 29 September 2005

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