  Even under constant external conditions, the expression levels of genes
fluctuate. Much emphasis has been placed on the components of this noise that
are due to randomness in transcription and translation; here we analyze the
role of noise associated with the inputs to transcriptional regulation, the
random arrival and binding of transcription factors to their target sites along
the genome. This noise sets a fundamental physical limit to the reliability of
genetic control, and has clear signatures, but we show that these are easily
obscured by experimental limitations and even by conventional methods for
plotting the variance vs. mean expression level. We argue that simple, global
models of noise dominated by transcription and translation are inconsistent
with the embedding of gene expression in a network of regulatory interactions.
Analysis of recent experiments on transcriptional control in the early
Drosophila embryo shows that these results are quantitatively consistent with
the predicted signatures of input noise, and we discuss the experiments needed
to test the importance of input noise more generally.
