Analysis of the genetic diversity of Helicobacter pylori: the tale of two genomes

Abstract

Infection with Helicobacter pylori has been linked to numerous severe gastroduodenal diseases including peptic ulcer and gastric cancer. Several techniques have been used to measure the genetic heterogeneity of H. pylori at several different levels and to determine whether there is any correlation with severity of disease. The availability of two completed genome sequences from unrelated strains (J99 and 26,695) has allowed an analysis of the level of diversity from a large-scale yet detailed perspective. Although the two chromosomes are organized differently in a limited number of discrete regions, the genome size and gene order of these two "high-virulence" (cagA+ and vacA+) H. pylori isolates was found to be highly similar. The regions of organizational difference are associated with insertion sequences, DNA restriction/modification genes, repeat sequences, or a combination of the above. A significant level of variation at the nucleotide level is seen across the genome, providing an explanation for why the nucleotide-based typing techniques have such high discriminatory power among independent H. pylori isolates. This nucleotide variation together with the organizational rearrangements appears to have provided an over-estimation of the gene order diversity of H. pylori as assessed by pulse-field gel electrophoresis. Functional assignments are assigned to approximately only 60% of the gene products in each strain, with one-half of the remaining gene products of unknown function having homologues in other bacteria, while the remainder appear to be H. pylori-specific. Between 6% and 7% of the coding capacity of each strain are genes that are absent from the other strain, with almost one-half of these strain-specific genes located in a single hypervariable region called the plasticity zone. The majority of the strain-specific genes in each strain are also H. pylori-specific, with no homologues being identified in the public databases. Significantly, over one-half of the functionally assigned strain-specific genes in both H. pylori J99 and 26695 encode DNA restriction/modification enzymes. Analysis of the level of conservation between orthologues from the two strains indicates that the H. pylori specific genes have a lower level of conservation than those orthologues to which a putative function can be assigned. The plasticity zone represents one of several regions across each genome that is comprised of lower (G+C)% content DNA, some of which has been detected in self-replicating plasmids, suggesting that both horizontal transfer from other species and plasmid integration are responsible for the strain-specific diversity at this locus. These analyses have yielded results with important implications for understanding the genetic diversity of H. pylori and its associated diseases, and imply a need to reassess the respective roles of bacterial and host factors in H. pylori associated diseases.

Duodenal ulcer promoting gene of Helicobacter pylori

“…The other has been termed the "plasticity region," based on the variability in gene content among different isolates (approximately 3% to 4% of the chromosome). [17][18][19] Genome sequence comparisons indicated that nearly half of H pylori's strain-specific genes are located in the plasticity region. There has been considerable recent interest in this plasticity region.…”

A whole-genome microarray reveals genetic diversity among Helicobacter pylori strains

“…The PAI also induces IL-8 production by host cells independent of the CagA protein (9 -11). Efforts to classify H. pylori strains further by DNA fingerprinting uncovered extensive diversity (12,13). The sequencing of two H. pylori genomes from independent strains, both containing the PAI, revealed that much of this diversity is silent at the amino acid level and thus at the functional gene level (14,15).…”

Identification of strain-specific genes located outside the plasticity zone in nine clinical isolates of Helicobacter pylori b bThe GenBank accession numbers for the H. pylori sequences reported in this paper are AF326599–AF326607 for region A, AF326608–AF326616 for region B, AF326617–AF326625 for region C, AF326626–AF326634 for region D, AF327212–AF327220 for region E, AF328909–AF3289

“…Although these strain-specific genes were not clustered into one locus, their location did not seem to be random. Indeed, it was noted that in 17 corresponding loci both reference strains contained strainspecific genes, suggesting a limit in the flexibility of the genome to strain-specific content (Alm & Trust, 1999 ;. Hence, we proposed the hypothesis that other H. pylori strains contain their own set of specific genes located in similar loci.…”

“…The overall genome organization of the two sequenced strains of H. pylori differs by 10 inverted or transposed regions. Genes conserved in both strains and so-called strain-specific genes (Alm & Trust, 1999 ;Doig et al, 1999) have been identified by comparison of the gene content of the two strains. Strain-specific genes were originally defined as being present in only one of the two completely sequenced H. pylori genomes, although subsequent analysis has led to some of these genes being identified in other H. pylori isolates (Occhialini et al, 2000 ;Salama et al, 2000).…”