Comparative Genomic Analysis of East Asian and Non-Asian Helicobacter pylori Strains Identifies Rapidly Evolving Genes

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.

Genomic evolution and transmission of Helicobacter pylori in two South African families

“…These three genes encoded unknown hypothetical proteins (24). These results are consistent with previously reported variations in the selective pressures acting between as well as within the genes of H. pylori (17,25,26). To guard against these variations, as well as against the relative strength of selection across time frames (16,27) and the interaction between recombination and selection (28), we only used the synonymous substitutions in the remainder of the analysis.…”

Worldwide Population Structure, Long-Term Demography, and Local Adaptation of Helicobacter pylori

“…The opposite is true in non-African strains, where we show that H. pylori had a very low ancestral effective population size, coupled with the high population growth rates in our global sample. It may, therefore, be reasonable to hypothesize that the long-term African association of this bacterium with human populations may have led to selection for reduced pathogenicity, whereas a founder effect and rapid growth during the colonization of populations in other areas of the world could have freed this population from these long-term selective constraints, possibly resulting in a more virulent and pathogenic bacterial population (Argent et al 2008;Duncan et al 2013). Concerning the divergence of the American population, we did not detect a clear signature of a founder event.…”

Comparative Analysis of the Full Genome of Helicobacter pylori Isolate Sahul64 Identifies Genes of High Divergence

“…Purifying and diversifying selection can be predicted by analyzing the ratio of synonymous to nonsynonymous (d N /d S ) single nucleotide polymorphisms (SNPs) (10), and such analysis has been successfully applied to H. pylori (11). The d N /d S ratio is highly informative for orthologous genes; however, as diversity increases, noise also increases (12). In addition, intragenomic changes, including rearrangements and horizontal gene transfer (HGT), also generate diversity in genomes of H. pylori (13).…”