HELICOBACTER PYLORI GENOME SEQUENCE EVOLUTION

描述(申请人提供)：这里提出的探索性R21计划研究的总体目标是更好地了解胃病原体幽门螺杆菌(HP)如何在人类群体中进化，特别是基因漂移和选择对细菌与宿主相互作用中重要基因的影响；以及最终，菌株的进化史对其感染活力、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。幽门螺杆菌在遗传上极其多样化：独立的分离株保守的家务基因的DNA序列通常相差约3%；不同地区(如西欧和东亚)的不同基因类型占主导地位。在初步研究中，我们发现来自偏远的秘鲁亚马逊部落社区的毒株在大多数座位上在序列上异常同质，但在两个粘附素基因上高度差异；此外，这些Shimaa毒株的代表性基因与亚洲相似，而来自秘鲁城市人(12,000年前也主要是亚洲血统&GT；)的毒株似乎在基因上大多是欧洲人。我们假设，Shimaa菌株的遗传一致性反映了在这个小型封闭社区中频繁的家族间传播，以及对适应最好的菌株的有效选择；粘附素基因多样性反映了对宿主受体亲和力频繁变化的选择。在这里，我们建议(I)对两个或更多具有代表性的Shimaa株的基因组进行测序；(Ii)搜索这些基因组中没有在其他已测序的HP基因组中代表的基因或等位基因类型[每个来自欧洲人]；以及(Iii)通过使用Shimaa株基因组序列设计的微阵列进行比较杂交来寻找其他快速进化的基因。对来自这样的特殊种群的菌株的比较研究可以产生巨大的生产力，导致特殊的进化见解，通常适用于不同的致病、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.