(A) Model of alternative host interactions according to status of mutable loci, modeled on the cag PaI. The H. pylori genome contains multiple hypermutable loci, creating many contingency genes. The status of each gene confers a particular phenotype to the H. pylori cell, affecting its host interactions. The strain on the left has an operating genetic element, which induces a greater host response; on the right is the same strain with a deleted element, inducing a lower response. The host responses create environmental constraints that select within the H. pylori population, creating a dynamic equilibrium (56). (B) Microevolution of cagA within a family. All four subjects in family F12 are colonized with strain 25, and subject D is also colonized with strain 26. Subjects C and D both have two clones of strain 25 with cagA with four and five type C (active) TPMs – these have evolved by simple duplication of the TPM-containing region. They are identical between these subjects, and so likely have been passed between them. Strain 25 in subject A possesses cagA with a variable region (VR) that is nearly identical to strain 26, implying these strains have recombined in subject D: strain 25 has acquired cagA from strain 26 and then been passed to subject A. Duplication of the TPM-C motif may have occurred within subject D or subject A. Strain 25 from subject B lacks the entire cag PaI and may have evolved by deletion from strain 25 from any family member. Solid lines indicate identical strains between hosts, whereas dashed lines represent proposed transmission. Adapted with permission from Clinical cancer research (43) (B).