Schematic representation of the evolutionary relationships between the AID/APOBECs and the rest of the zinc-dependent deaminases. The only other zinc-dependent deaminase families widely expressed in metazoans and from which the AID/APOBECs (shaded in red) could have originated are the cytidine deaminases (CDA), the dCMP deaminases (DCDT) or the tRNA adenosine deaminases (Tad/ADAT2) (all shown in orange). CDAs and DCDTs act on free pyrimidines in the salvage pathway, the Tad/ADAT2s edit adenosine 34 at the anticodon of various tRNAs to inosine and are essential in bacteria, yeast and metazoans . AID/APOBECs are unlikely to have originated from CDAs because of the differences in gene organization and catalytic domain [7,10]; DCDTs, despite the similar secondary structure, differ substantially from the AID/APOBECs in their substrate (free nucleotides), dependency on Mg and dCTP, and aggregation into homohexamers . Phylogenetic data , species representation, and structural/functional features favor the tRNA-editing enzymes as the origin of the AID/APOBECs [7,8], a model supported by the observation that ADAT2 from trypanosomes can deaminate DNA . The tRNAAla adenosine 37 deaminases type 1 (ADAT1) and the mRNA adenosine deaminases 1, 2, and 3 (ADARs) (shaded in green) are thought to have originated from the Tad/ADAT2 family independently of the AID/APOBECs. CoDA, cytosine deaminases; RibD, riboflavin deaminases; GuanineD, guanine deaminases.