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INTRODUCTION ============ *Helicobacter pylori*, a Gram-negative human pathogen, colonizes the stomach and is associated with several gastrointestinal disorders including peptic ulcers and gastric cancers ([@B1]). Over half of the world\'s population is estimated to harbor *H. pylori*, but only 15--20% of those infected develop severe disease. *Helicobacter pylori* is known for its remarkably high level of genetic diversity. A comparison of the fully sequenced genomes of three clinical isolates revealed substantial differences in chromosomal structure and a large number of genes that are variably present or absent among strains (up to 25% of the total coding regions) ([@B2],[@B3]). These observations have raised many questions, including how genetic diversity is generated in *H. pylori* and how variable genes contribute to disease outcome. One class of highly variable genes are restriction--modification (R--M) systems ([@B2]), which are typically composed of both a restriction endonuclease (REase) and a cognate DNA methyltransferase (MTase). Generally, the REase cleaves a specific DNA sequence unless it is methylated by the cognate MTase. R--M systems have been divided in type I, II or III, according to their cofactor requirement, molecular structure, mode of action and structure of the recognition sequence site ([@B4]). Typical type II R--M systems consist of two independent enzymes that act on the same sequence, usually a 4- to 8-bp palindrome. The recent sequencing of more than 400 bacterial and archaeal genomes has revealed that ∼90% of the genomes contain at least one R--M system and over 80% contain multiple R--M systems ([@B5]), but only a small fraction have been comprehensively studied. The *H. pylori* chromosome encodes a large number of active and inactive R--M systems. Analysis of the sequenced genomes of *H. pylori* strain 26695 and J99 predicted 26 putative R--M systems including 14 and 16 type II R--M systems, respectively. Comparative genomics of these systems suggests they have a high degree of sequence heterogeneity and that only a small fraction retained full activity ([@B6],[@B7]). Interestingly, for some R--M systems, MTase activity may be preserved despite inactivation of the respective REase. Although still under debate, R--M systems may carry out several biological roles. They have traditionally been implicated in bacterial defense from bacteriophage infection, which have in turn evolved a variety of anti-restriction defense mechanisms ([@B8]). R--M systems also regulate genetic exchange among bacteria, particularly relevant for bacteria like *H. pylori* that are naturally competent for DNA uptake ([@B9]). By constituting an effective barrier against DNA transformation in a bacterial population, R--M systems may provide the genetic isolation required for adaptation of the organisms to a special ecological niche ([@B10]). Paradoxically, R--M systems were also suggested to promote homologous recombination from the small DNA fragments produced by the incomplete digestion of incoming DNA by REases ([@B11]). Kobayashi and colleagues have suggested that R--M systems have attributes of selfish genes, and may act as invasive elements independent of any selective advantage to their host ([@B12],[@B13]). This hypothesis emerged from the findings that several R--M systems are horizontally transferred and that a fully active type II R--M