  The control of gene expression involves complex mechanisms that show large
variation in design. For example, genes can be turned on either by the binding
of an activator (positive control) or the unbinding of a repressor (negative
control). What determines the choice of mode of control for each gene? This
study proposes rules for gene regulation based on the assumption that free
regulatory sites are exposed to nonspecific binding errors, whereas sites bound
to their cognate regulators are protected from errors. Hence, the selected
mechanisms keep the sites bound to their designated regulators for most of the
time, thus minimizing fitness-reducing errors. This offers an explanation of
the empirically demonstrated Savageau demand rule: Genes that are needed often
in the natural environment tend to be regulated by activators, and rarely
needed genes tend to be regulated by repressors; in both cases, sites are bound
for most of the time, and errors are minimized. The fitness advantage of error
minimization appears to be readily selectable. The present approach can also
generate rules for multi-regulator systems. The error-minimization framework
raises several experimentally testable hypotheses. It may also apply to other
biological regulation systems, such as those involving protein-protein
interactions.
