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 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(7-10), yet the biological origins of this extrinsic variability have received little attention. Here we combine computational modelling(11-18) 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 gene(9). Our results highlight the importance of the interplay of gene regulatory networks with population heterogeneity for understanding the origins of cellular diversity.