HELICOBACTER PYLORI GENOME SEQUENCE EVOLUTION

描述（由申请人提供）：这里提出的探索性R21项目研究的总体目标是更好地了解胃病原体幽门螺杆菌（Hp）如何在人群中进化，特别是遗传漂变和选择对细菌-宿主相互作用中重要基因的影响；最终，一个菌株的进化历史对其感染能力、毒力和人类疾病风险的影响。作为背景，Hp与消化性溃疡和胃癌有关，尽管大多数感染是良性的，有些甚至可能是有益的。Hp在遗传上非常多样化：独立分离的保守持家基因的DNA序列通常相差约3%；不同的基因型组在不同地区占主导地位（例如，西欧与东亚）。在初步研究中，我们发现来自遥远的秘鲁亚马逊部落社区“Shima”的菌株在大多数位点的序列上异常均匀，但在两个粘附素基因上高度分化；此外，来自这些岛马菌株的代表性基因与亚洲人相似，而来自秘鲁城市人（他们的祖先也主要是亚洲人）的基因似乎主要是欧洲人。我们推测，Shimaa菌株的遗传一致性反映了在这个封闭的小群落中频繁的家族间传播，以及对最适应菌株的有效选择；黏附素基因的多样性反映了宿主受体亲和性频繁变化的选择。在此，我们建议(i)对两个或多个具有代表性的岛马菌株进行基因组测序；（ii）在这些基因组中搜索其他已测序的Hp基因组中未出现的基因或等位基因类型[均来自欧洲族裔]；（iii）利用Shimaa菌株基因组序列设计的微阵列进行比较杂交，寻找其他快速进化的基因。对来自这些特殊种群的菌株进行比较研究可能会非常有成效，从而产生特殊的进化见解，通常适用于各种致病、共生和有益的微生物物种。

DESCRIPTION (provided by applicant): 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.