Abstract
Helicobacter pylori infection is a risk factor for the development of gastric adenocarcinoma, a disease that has a high incidence in East Asia. Genes that are highly divergent in East Asian H. pylori strains compared to non-Asian strains are predicted to encode proteins that differ in functional activity and could represent novel determinants of virulence. To identify such proteins, we undertook a comparative analysis of sixteen H. pylori genomes, selected equally from strains classified as East Asian or non-Asian. As expected, the deduced sequences of two known virulence determinants (CagA and VacA) are highly divergent, with 77% and 87% mean amino acid sequence identities between East Asian and non-Asian groups, respectively. In total, we identified 57 protein sequences that are highly divergent between East Asian and non-Asian strains, but relatively conserved within East Asian strains. The most highly represented functional groups are hypothetical proteins, cell envelope proteins and proteins involved in DNA metabolism. Among the divergent genes with known or predicted functions, population genetic analyses indicate that 86% exhibit evidence of positive selection. McDonald-Kreitman tests further indicate that about one third of these highly divergent genes, including cagA and vacA, are under diversifying selection. We conclude that, similar to cagA and vacA, most of the divergent genes identified in this study evolved under positive selection, and represent candidate factors that may account for the disproportionately high incidence of gastric cancer associated with East Asian H. pylori strains. Moreover, these divergent genes represent robust biomarkers that can be used to differentiate East Asian and non-Asian H. pylori strains.
Highlights
Over half of the world’s human population is persistently colonized with Helicobacter pylori, a Gram-negative bacterium that inhabits the human stomach
Similar to CagA and vacuolating cytotoxin (VacA), these proteins represent a panel of candidates that may contribute to H. pylori virulence and may account for the high incidence of gastric cancer associated with East Asian H. pylori strains
multilocus sequence typing (MLST) Analysis of H. pylori Strains In an analysis of H. pylori strains for which complete or nearlycomplete genome sequences were available in Genbank when this study was initiated, we identified eight strains that were classified as East Asian, based on MLST analysis (Fig. 1)
Summary
Over half of the world’s human population is persistently colonized with Helicobacter pylori, a Gram-negative bacterium that inhabits the human stomach. Gastric adenocarcinoma is the second leading cause of cancerrelated death worldwide [5,6,7,8,9]. The incidence of this malignancy varies globally, and is high in several parts of East Asia [5,7,8]. Multiple populations and subpopulations of H. pylori with distinct geographic distributions have been recognized, based on multilocus sequence typing (MLST) analysis of conserved housekeeping genes [13,14,15]. Genetic diversity in H. pylori decreases with geographic distance from eastern Africa, a finding that is consistent with an African origin of H. pylori [16,17,18]
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