Evolutionary comparison of the mechanism of DNA cleavage with respect to immune diversity and genomic instability.

It is generally assumed that the genetic mechanism for immune diversity is unique and distinct from that for general genome diversity, in part because of the high efficiency and strict regulation of immune diversity. This expectation was partially met by the discovery of RAG1 and -2, which catalyze V(D)J recombination to generate the immune repertoire of B and T lymphocyte receptors. RAG1 and -2 were later shown to be derived from a transposon. On the other hand, activation-induced cytidine deaminase (AID), which mediates both somatic hypermutation (SHM) and the class-switch recombination (CSR) of the immunoglobulin genes, evolved earlier than RAG1 and -2 in jawless vertebrates. This review compares immune diversity and general genome diversity from an evolutionary perspective, shedding light on the roles of DNA-cleaving enzymes and target recognition markers. This comparison revealed that AID-mediated SHM and CSR share the cleaving enzyme topoisomerase 1 with transcription-associated mutation (TAM) and triplet contraction, which is involved in many genetic diseases. These genome-altering events appear to target DNA with non-B structure, which is induced by the inefficient correction of the excessive supercoiling that is caused by active transcription. Furthermore, an epigenetic modification on chromatin (histone H3K4 trimethylation) is used as a mark for DNA cleavage sites in meiotic recombination, V(D)J recombination, CSR, and SHM. We conclude that acquired immune diversity evolved via the appearance of an AID orthologue that utilized a preexisting mechanism for genomic instability, such as TAM.