Repeat-associated phase variable genes in the complete genome sequence of Neisseria meningitidis strain MC58

Phase variation, mediated through variation in the length of simple sequenc e repeats, is recognized as an important mechanism for controlling the expr ession of factors involved in bacterial virulence. Phase variation is assoc iated with most of the currently recognized virulence determinants of Neiss eria meningitidis. Based upon the complete genome sequence of the N. mening itidis serogroup B strain MC58, we have identified tracts of potentially un stable simple sequence repeats and their potential functional significance determined on the basis of sequence context. Of the 65 potentially phase va riable genes identified, only 13 were previously recognized. Comparison wit h the sequences from the other two pathogenic Neisseria sequencing projects shows differences in the length of the repeats in 36 of the 65 genes ident ified, including 25 of those not previously known to be phase variable. Six genes that did not have differences in the length of the repeat instead ha d polymorphisms such that the gene would not be expected to be phase variab le in at least one of the other strains. A further 12 candidates did not ha ve homologues in either of the other two genome sequences. The large propor tion of these genes that are associated with frameshifts and with differenc es in repeat length between the neisserial genome sequences is further corr oborative evidence that they are phase variable. The number of potentially phase variable genes is substantially greater than for any other species st udied to date, and would allow N. meningitidis to generate a very large rep ertoire of phenotypes through expression of these genes in different combin ations. Novel phase variable candidates identified in the strain MC58 genom e sequence include a spectrum of genes encoding glycosyltransferases, toxin related products, and metabolic activities as well as several restriction/ modification and bacteriocin-related genes and a number of open reading fra mes (ORFs) for which the function is currently unknown. This suggests that the potential role of phase variation in mediating bacterium-host interacti ons is much greater than has been appreciated to date. Analysis of the dist ribution of homopolymeric tract lengths indicates that this species has seq uence-specific mutational biases that favour the instability of sequences a ssociated with phase variation.