It was first introduced during the "Invasion!" crossover in 1988. The alien Dominators discovered that most super-powered humans shared a common gene or set of genes, which when manipulated, could strengthen or weaken their powers. They used this information to create a "gene bomb" which nearly killed most of Earth's superheroes; however, the remaining heroes were able to reverse the effect.

The term metahuman is often used in DC to refer to everyone with superpowers, including aliens, wizards, and cyborgs, but technically only those with the metagene complex are metahuman. An artificial metagene has been invented by Lex Luthor under the Everyman project, but Luthor was able to "switch off" these genes, killing many new superheroes who were flying at the time. A metagene virus has also been used to create the latest Son of Vulcan.