DNA methyltransferases (MTases), unlike MTases acting on other substrates, exhibit sequence permutation. Based on the sequential order of the cofactor-binding subdomain, the catalytic subdomain, and the target recognition domain (TRD), several classes of permutants have been proposed. The majority of known DNA MTases fall into the α, β, and γ classes. There is only one member of the ζ class known and no members of the δ and ε classes have been identified to date. Two mechanisms of permutation have been proposed: one involving gene duplication and in-frame fusion, and the other involving inter- and intragenic shuffling of gene segments.
Two novel cases of sequence permutation in DNA MTases implicated in restriction-modification systems have been identified, which suggest that members of the δ and ζ classes (M.MwoI and M.TvoORF1413P, respectively) evolved from β-class MTases. This is the first identification of the δ-class MTase and the second known ζ-class MTase (the first ζ-class member among DNA:m4C and m6A-MTases).
Fragmentation of a DNA MTase gene may result from attack of nucleases, for instance when the RM system invades a new cell. Its reassembly into a functional form, the order of motifs notwithstanding, may be strongly selected for, if the cognate ENase gene remains active and poses a threat to the host's chromosome. The "cut-and-paste" mechanism is proposed for β-δ permutation, which is non-circular and involves relocation of one segment of a gene. The circular β-ζ permutation may be explained both by gene duplication or shuffling of gene fragments. These two mechanisms are not mutually exclusive and probably both played a role in the evolution of permuted DNA MTases.