Completely uncoupled and perfectly coupled gene expression in repressible systems

Two forms of extreme coupling have been documented for the regulation of gene expression in repressible systems governed by a regulator protein. The first form, complete uncoupling, is distinguished by a constant level of regulator protein. The second form, perfect coupling, is distinguished by a level of regulator protein that varies coordinately with the level of the regular-ed enzyme. To determine how these two forms of coupling influence the performance of a system, so that we might predict the conditions under which each evolves through natural selection, we have used a mathematical approach to compare systems with complete uncoupling and perfect coupling. Our comparisons, which are controlled so that alternative systems are free from irrelevant differences, are based on a priori criteria that are related to various aspects of a system's performance, such as temporal responsiveness. By examining the influence of physical constraints that are related to the subunit structure of regulatory proteins and that limit the cooperativity of regulatory interactions, we have extended an early theory of gene circuitry for repressible systems. We obtain new results and testable predictions that can be summarized as follows. For typical systems with a low gain, performance is better with perfect coupling than with complete uncoupling if the mode of regulation is negative and better with complete uncoupling than with perfect coupling if the mode of regulation is positive. For systems with a high gain, these preferred forms of coupling are prevented by the physical constraints on cooperativity, and other forms of coupling can be expected. Tests of our predictions are illustrated by using data available in the literature. (C) 1997 Academic Press Limited.