A Complex Control Circuit

Abstract

Temperate bacteriophages can stably display 2 essentially different behaviors. In the immune state a gene (cI) produces a repressor which prevents expression of all other viral genes; in the non-immune state the typical viral functions are expressed. The choice between the 2 pathways and the establishment of one of them have much in common with cell determination and differentiation. This choice depends on a complex control system, in fact one of the most intricate nets of regulation known in detail. A formal description and partial analysis of this regulatory net is provided. Even for relatively simple known models, this kind of analysis uncovers predictions which had previously remained hidden. Some of these predictions were checked experimentally. The experimental part chiefly deals with the efficiency of lysogenization [of Escherichia coli] by thermoinducible .lambda. phage carrying mutations in one or more of the regulatory genes, N, cro and cII. Although N- mutations prevent efficient integration, and N- and cII mutations prevent efficient establishment of immunity, N- and cII- phage efficiently lysogenize at low temperature if they are in addition cro-, as predicted by a simple model. In contrast .lambda. N- cro+, .lambda. N- cro- is not propagated as a plasmid at low temperature, precisely because it establishes immunity too efficiently. Genetic control circuits are described in terms of sets of logic equations, which relate the state of expression of genes or of chemical reactions (functions) to input (genetic and environmental) variables and to the presence of gene and reaction products (internal or memorization variables). From the set of equations, a matrix which shows the stable stationary states (if any) of the system is derived, from which the pathways (temporal sequences of states) consistent with the model are derived. This kind of analysis is complementary to the more widely used analysis based on differential equations; it allows analysis of more complex systems in less detail. The language might be used in fields very different from genetics. The role of positive feedback loops in establishment and maintenance of immunity in temperate bacteriophages and in dedevelopmental genetics in general is discussed. Cell determination (for a given character) probably depends on a set of genes whose interaction constitutes a positive feedback loop. Such a system has 2 stable stationary states: which one is chosen will usually depend on additional controls grafted on the loop.