Abstract
Geographic partitioning is postulated to foster divergence of Helicobacter pylori populations as an adaptive response to local differences in predominant host physiology. H. pylori's ability to establish persistent infection despite host inflammatory responses likely involves active management of host defenses using bacterial proteins that may themselves be targets for adaptive evolution. Sequenced H. pylori genomes encode a family of eight or nine secreted proteins containing repeat motifs that are characteristic of the eukaryotic Sel1 regulatory protein, whereas the related Campylobacter and Wolinella genomes each contain only one or two such “Sel1-like repeat” (SLR) genes (“slr genes”). Signatures of positive selection (ratio of nonsynonymous to synonymous mutations, dN/dS = ω > 1) were evident in the evolutionary history of H. pylori slr gene family expansion. Sequence analysis of six of these slr genes (hp0160, hp0211, hp0235, hp0519, hp0628, and hp1117) from representative East Asian, European, and African H. pylori strains revealed that all but hp0628 had undergone positive selection, with different amino acids often selected in different regions. Most striking was a divergence of Japanese and Korean alleles of hp0519, with Japanese alleles having undergone particularly strong positive selection (ωJ > 25), whereas alleles of other genes from these populations were intermingled. Homology-based structural modeling localized most residues under positive selection to SLR protein surfaces. Rapid evolution of certain slr genes in specific H. pylori lineages suggests a model of adaptive change driven by selection for fine-tuning of host responses, and facilitated by geographic isolation. Characterization of such local adaptations should help elucidate how H. pylori manages persistent infection, and potentially lead to interventions tailored to diverse human populations.
Highlights
Helicobacter pylori chronically infects billions of people worldwide, typically for decades
The many decades during which H. pylori can persist in the gastric mucosa despite inflammation and other host defenses, the differences among individuals and geographic regions in the intensity and specificity of host responses, and the changes in responses with age and as infection progresses, all coupled with the possibility of H. pylori exploiting these responses while avoiding clearance by them [23], suggests a need for active response management by the bacterium
It is especially in this framework that we studied the evolutionary dynamics of the H. pylori slr gene family
Summary
Helicobacter pylori chronically infects billions of people worldwide, typically for decades. Phylogenetic analyses of H. pylori housekeeping gene sequences revealed differences in predominant genotypes between East Asian, European, and African populations that are far greater than those seen with most other pathogens Such patterns reflect a combination of mutation, recombination, selection to retain gene function, and random genetic drift, which itself likely stems from H. pylori’s highly localized (preferentially intrafamilial; nonepidemic) mode of transmission, and a resulting relative lack of H. pylori gene flow between well-separated human populations [6,7,10,11,12]. Correlated with this geographic partitioning of H. pylori populations are striking differences in predominant clinical consequences of infection.
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