Porphyromonas gingivalis is implicated in the etiology of chronic periodontitis. Genotyping studies suggest that genetic variability exists among P. gingivalis strains; however, the extent of variability remains unclear and regions of variability remain largely unidentified. To assess P. gingivalis strain diversity, we previously used heteroduplex analysis of the ribosomal operon intergenic spacer region (ISR) to type strains in clinical samples and identified 22 heteroduplex types. Additionally, we used ISR sequence analysis to determine the relatedness of P. gingivalis strains to one another and demonstrated a link between ISR sequence phylogeny and the disease-associated phenotype of the strains. In the current study, heteroduplex analysis of the ISR was used to determine the worldwide genetic variability and distribution of P. gingivalis, and microarray-based comparative genomic hybridization (CGH) analysis was used to more comprehensively examine the variability of major heteroduplex type strains by using the entire genome. Heteroduplex analysis of clinical samples from geographically diverse populations identified 6 predominant geographically widespread heteroduplex types (prevalence, >5%) and 14 rare heterodpulex types (prevalence, <2%) which are found in one or a few locations. CGH analysis of the genomes of seven clinically prevalent heteroduplex type strains identified 133 genes from strain W83 that were divergent in at least one of the other strains. The relatedness of the strains to one another determined on the basis of genome content (microarray) analysis was highly similar to their relatedness determined on the basis of ISR sequence analysis, and a striking correlation between the genome contents and disease-associated phenotypes of the strains was observed.Porphyromonas gingivalis is a gram-negative anaerobe that has been strongly implicated as a pathogen in adult (chronic) periodontitis (3,15,20,32,39,40), a destructive disease that affects the gingiva and supporting structures of the teeth. The bacterium is found under conditions of both health and disease, with prevalences that range from 10% to 25% in healthy individuals and 79% to 90% in individuals with periodontitis being found (20,23,24). Previous epidemiologic studies have demonstrated that P. gingivalis strains vary with respect to their levels of human disease association (4,5,21). Studies have also demonstrated that P. gingivalis strains vary in their virulence (soft tissue destruction and death) in animal models, with some strains being classified as virulent, e.g., strains W83, W50, ATCC 49417, and A7A1, and others being classified as avirulent, e.g., strains 381, 33277, and 23A4 (19, 25, 37).Many studies have assessed the genetic diversity that exists among P. gingivalis strains, resulting in the finding of a high degree of diversity in some cases (17, 29, 31, 34) and a considerably lower degree of diversity in others (2, 28). The amount of variability found may be due to the different techniques used in the studies. In a previous ...