Antibody class switching emerged in evolutionary history when bony fish grew legs and became amphibians. On page 733, Barreto and colleagues show that the switch-inducing enzyme AID (activation-induced cytidine deaminase) is in working order in bony fish, suggesting that the evolution of the switch reaction had to wait for the acquisition of some other component.

Bony fish produce antibodies but lack class switch recombination, a process by which the constant region of the antibody heavy chain is swapped for that of a different isotype. This process is missing in fish despite the expression of AID and the presence of antibody somatic hypermutation, a process also initiated by AID.

This group recently showed that COOH-terminal mutations in AID robbed the enzyme of its class-switching function without affecting hypermutation. The zebrafish AID gene contains COOH-terminal mutations, suggesting that fish AID might be unable to recruit essential cofactors or to bind appropriately to the heavy chain locus. But Barreto et al. now show that AID from zebrafish restored normal class switching in AID-deficient mouse B cells, indicating that the functional domains of AID that are required for class switching were all intact.

Thus it appears that the rate-limiting step for class switching was not the evolution of a switch-capable AID protein, but rather the evolution of appropriate DNA switch regions, which are indeed missing from fish heavy chain locus.