Helicobacter pylori genetic diversity and risk of human disease
Genetic diversity of the human gastric pathogen Helicobacter pylori in an individual host .. There was no statistical difference in the extents of genetic variation. We investigated the association between genetic variation in the O-glycan transferase encoding gene (A4GNT) and H. pylori infection and gastric cancer risk. The association between Helicobacter pylori gene diversity and gastric cancer has . Statistically significant differences were evaluated by the Chi-square test.
A4GNT and gastric cancer, haplotype analysis Similarly as for single locus analysis, haplotypes at the seven loci were not associated with gastric cancer risk overall data not shown.
In stratified analyses, the haplotypes constructed from rsrsrs loci were borderline associated with the intestinal type of gastric cancer global P value 0. Compared with the most frequent haplotype C-A-A However, the global P value was non-significant in the permutation test empirical P value 0.
For the diffuse type of gastric cancer, none of the haplotypes was associated with risk data not shown. Stratifying the analysis by tumour location did not reveal material differences. Evidence from in vitro studies demonstrates that O-glycans capped with the residue A4GN alpha-1, 4Gal beta is capable of exerting an inhibitory effect on H. One explanation for this discrepancy may be that there exist functionally impotent subclasses of the A4GNT-encoded enzyme. Hosts with up-regulated expression of non-functional A4GNT subclasses would be less capable of preventing H.
Since the effect of A4GNT only has been demonstrated in one sequence that came from the same research group, functional studies on subclasses of A4GNT encoded by other sequences are warranted. Such a relatively low prevalence requires a larger sample-size study to examine for moderate or modest effects of A4GNT on gastric cancer risk. In summary, this preliminary study, suggests that the A-A haplotype at rsrs may be related with an increased risk for H.
A4GNT gene is polymorphic in population. Whether the polymorphism of A4GNT is related to Helicobacter pylori infection in the population and how this further relates with gastric cancer development is unknown. However, this relation does not affect the development of gastric cancer. Chuen Seng Tan for statistical consultancy. Footnotes No conflict of interests declared.
Weimin Ye Specific author contributions: Zongli Zheng, Weimin Ye Potential competing interests: Global cancer statistics, CA Cancer J Clin. Is it time to screen and treat H pylori to prevent gastric cancer? Gastric cancer and human leukocyte antigen: As depicted in Figure 1HR is a three-step process involving presynapsis, synapsis and postsynapsis. The presynapsis pathway is dictated by the nature of the DNA substrate.
The result is a nucleoprotein filament that is ready for the search of homologous sequence in the DNA duplex and RecA-mediated strand exchange once that homologous sequence is found. This synapsis step leads to the formation of a structure termed the D-loop. RecG has also been shown to be involved in recombination and to catalyse branch migration, in addition to its role in replication fork reversal. Proteins involved at the different steps are indicated in black for the model organism E.
The presence of most HR genes in H. Intragenomic recombination in families of genes encoding outer membrane proteins leads to H. Mutants in recA, addA or recG had lower rates of sabA adhesin gene conversion suggesting that RecA-independent gene conversion exists and that this recombination may be initiated by a double-strand break [ 79 ]. The RecA deficient mutants are sensitive to DNA damaging agents such as UV light, methyl methanesulfonate, ciprofloxacin, and metronidazole [ 8081 ].
RecA was the first HR protein to be characterized in H. Lack of cross-species complementation was first attributed to the putative post-translational modification of RecA [ 80 ], however, studies showed that the lack of complementation was due to species specific interaction of RecA with proteins involved in presynapsis such as RecA loading on the single stranded DNA by AddAB [ 82 ].
The interconnection of natural competence and DNA damage through RecA highlights the role of HR in persistence and in generating genetic diversity. Alternatively, and not exclusive to a role in generation of genetic diversity, RecA-mediated genetic exchange might represent a mechanism for genome integrity maintenance in an extreme DNA-damaging environment.
Several gene deletion studies have shown that H. The single addA mutant and double mutant addA recO exhibit similar sensitivity to double strand break inducing agents, suggesting that AddAB is involved in the double strand break repair pathway, and RecOR in gap repair. Both pathways are required in vivo for robust colonization and persistence based on the lower colonization loads of single addA, recO, and recR mutants in the mouse model of H.
As expected for recombinational repair proteins, RecN mediated DNA double strand break recognition and initiation of DNA recombination is also required in vivo for robust colonization [ 85 ]. Colonization of the recombinational repair mutant, ruvC, was affected and 35 days post-infection the ruvC mutant was cleared by mice.
Persistence of Helicobacter pylori Infection: Genetic and Epigenetic Diversity
Furthermore, the ruvC deletion mutant elicited a Th1 biased immune response compared to a Th2 biased response observed for wild-type, highlighting the role of homologous recombination in H. Unexpectedly, the RecG homolog in H. Mutation of RecG increased recombination frequencies in line with a role of RecG in generating genetic diversity.
Further regulation of homologous recombination is mediated by the MutS2 protein that displays high affinity for DNA structures such as recombination intermediates thus inhibiting DNA strand exchange and consequent recombination [ 89 ].
MutS2 deficient cells have a 5-fold increase in recombination rate [ 90 ]. Deletion of xerH in H. The inability of the xerH mutant to survive in the gastric niche contrasts with ruvC mutant colonization and further supports the idea that XerH is not involved in DNA repair but in chromosome maintenance such as chromosome dimer resolution, regulation of replication and possibly in chromosome unlinking.
This, in turn, suggests that slow growing H.
Genetic variation in a4GnT in relation to Helicobacter pylori serology and gastric cancer risk.
Rearrangement of the middle region of the cagY gene, independent of RecA [ 92 ], leads to in frame insertion or deletion of CagY and gain or loss of function of the CagA type IV secretion system.
Recombination of cagY was proposed to be a mechanism to regulate the inflammatory response to adapt and persist in the gastric niche [ 93 ].
To date the exact recombination mechanism involving direct repeats in the middle region of cagY remains unknown.
Phase variation Host adapted human pathogens, such as H. Phenotypic variation of the bacterial external composition will alter the appearance of the bacterium as sensed by the host immune system. One common regulatory mechanism to achieve antigen diversity within a bacterial population is known as phase variation [ 9495 ].
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In pathogens, simple sequence repeats SSRs are tandem iterations of a single nucleotide or short oligonucleotides that, with respect to their length, are hypermutable Figure 2. Additionally, SSRs may occur in the promoter region of genes where variation in their length may affect promoter strength by mechanisms such as alteration of the distance between and elements.
Phase variation and generation of epigenetic diversity by phasevarions. Slipped strand mispairing of short sequence repeats during DNA replication results in alteration of repeat length in descendants.