The overall goal of the exploratory R21 program studies proposed here is to better understand how the gastric pathogen Helicobacter pylori (Hp) evolves in human populations especially the impact of genetic drift and selection on genes important in bacterial-host interactions;and ultimately, the impact of a strain's evolutionary history on its vigor of infection, virulence and the risk of human disease. As background, Hp is implicated in peptic ulcer and gastric cancer, although most infections are benign, and some may even be beneficial. Hp is extremely diverse genetically: independent isolates typically differ by ~3% in DNA sequence of conserved housekeeping genes;and different sets of genotypes predominate in different regions (e.g., West Europe vs. East Asia). In preliminary studies we found strains from a remote Peruvian Amazon tribal community, the `Shima', to be unusually homogeneous in sequence at most loci, but highly divergent in two adhesin genes;in addition, representative genes from these Shimaa strains were Asian-like, whereas those from urban Peruvians (who are also of primarily Asian ancestry >12,000 yrs ago) seemed mostly European genetically. We hypothesize that Shimaa strain genetic uniformity reflects frequent inter-family transmission in this small closed community, and effective selection for best-adapted strains;and that adhesin gene diversity reflects selection for frequent change in host receptor affinities. Here we propose (i) to sequence the genomes of two or more representative Shimaa strains;(ii) to search these genomes for genes or allele types not represented in other already sequenced Hp genomes [each from ethnic Europeans];and (iii) to find other rapidly evolving genes by comparative hybridization using microarrays designed from Shimaa strain genome sequences. Comparative studies of strains from special populations such as these can be immensely productive, leading to special evolutionary insights, generally applicable to diverse pathogenic, commensal and beneficial microbial species.
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