Origins of extrinsic variability in eukaryotic gene expression

Variable gene expression within a clonal population of cells has been implicated in a number of important processes including mutation and evolution1,2, determination of cell fates3,4 and the development of genetic disease5,6. Recent studies have demonstrated that a significant component of expression variability arises from extrinsic factors thought to influence multiple genes simultaneously7,8,9,10, yet the biological origins of this extrinsic variability have received little attention. Here we combine computational modelling11,12,13,14,15,16,17,18 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.