A one-gene system is the simplest form of subsystem, based entirely on the presence or absence of a single genetically encoded component.

An enzyme that uses no cofactors and performs a one-step detoxification, where neither the substrate nor the product has any other connection to normal cellular metabolism, represents a pure form of one-gene system. However, many additional cellular systems resemble the one-gene system in terms of the ability of comparative genomics techniques to detect the functional connections that exists. So many enzymes use NAD, for example, that the cofactor requirement of an NAD-dependent detoxification enzyme will be invisible to most comparative genomics analyses.

A one-gene system may be detected if it represents an alternative pathway, as the one-step direct aminoacylation of tRNA(Asn) does to the misacylation and GatABC amidotransferase system. More often, however, the one-gene system is intractable to study strictly by in silico techniques; high-throughput experimental techniques (e.g. metabolomics) will be more appropriate.