H.PYLORI POPULATION GENETICS AND GENOME EVOLUTION

描述(由申请人提供)：幽门螺杆菌(HP)是最具遗传多样性的细菌物种之一。我们基于DNA的初步系统发育分析表明，西班牙的Hp基因分型与东亚的不同，利马秘鲁人的Hp基因分型大多与西班牙相似。为这一批款期提出的研究有四个主要的具体目标。目的1.更好地了解幽门螺杆菌的遗传多样性和基因组进化。我们将把目前的系统发育研究扩展到来自拉丁美洲其他美洲人的HP菌株，以检验大多数这样的HP菌株在大多数位置也将是西班牙相似的预测。与西班牙不同的是，任何被发现具有丰富等位基因的惠普人群都将被进一步检查。还将研究来自欧洲、亚洲和非洲其他地区的幽门螺杆菌，(I)更好地了解世界各地的幽门螺杆菌种群遗传结构，(Ii)测试预测，即日本和西班牙的幽门螺杆菌基因库分别代表更具遗传多样性的东亚和欧洲基因库的子集。目的2.识别影响适合度的自然发生的等位基因差异，并了解其基础。我们将测试我们发现的comB9基因的东亚类型等位基因在利马美国人的HP中丰富的普遍性，并测试这是否反映了选择。更广泛地说，将调查其他特殊等位基因或基因异常丰富的情况，以确定在宿主相互作用的特异性中重要的细菌特征。对候选基因或等位基因适合度的影响将使用基因操纵的啮齿动物适应的HP菌株以及小鼠和沙鼠感染模型进行检验。目的3.为了检验家庭单位内幽门螺杆菌的进化动态，将对来自秘鲁个别家庭的父母和孩子的幽门螺杆菌菌株进行基因分型，以深入了解在总体感染风险较高的社会中幽门螺杆菌的亲缘关系、家庭内传播与社区传播，以及幽门螺杆菌的突变、重组和选择。目的4.检测社区间传播、混合感染和重组的可能性。来自日本秘鲁人的幽门螺杆菌将进行基因分型，以检测(I)祖先日本型基因的保留，与推定的秘鲁本土(西班牙型)菌株的社区获得；(Ii)混合感染，特别是涉及不同种族来源的菌株；(Iii)在短时间内重组的程度；以及(Iv)特定基因或等位基因的选择。

DESCRIPTION (provided by applicant): Helicobacter pylori (Hp) are one of the most genetically diverse of bacterial species. Our preliminary DNA-based phylogenetic analyses showed that genotypes of Hp in Spain differ from those in East Asia, and that genotypes of Hp from Peruvians in Lima are mostly Spanish-like. The studies proposed for this grant period have four main specific aims. AIM 1. To better understand Hp genetic diversity and genome evolution. We will extend current phylogenetic studies to Hp strains from other Amerind people in Latin America, to test predictions that most such Hp strains will also be Spanish-like at most loci. Any Hp population found to be rich in alleles unlike those of Spain will be examined further. Hp from elsewhere in Europe, Asia and Africa will also be studied (i) to better understand Hp population genetic structure worldwide, (ii) test predictions that Hp gene pools in Japan and Spain represent subsets of more genetically diverse East Asian and European gene pools, respectively. AIM 2. To identify naturally occurring allele differences that affect fitness and understand their basis. We will test the generality of our finding that East Asian-type alleles of the comB9 gene are abundant in Hp from Amerinds in Lima, and test if this reflects selection. More generally, additional cases of unusual abundance of particular alleles or genes will be investigated to identify bacterial traits important in specificity of host interaction. Effects on fitness of candidate genes or alleles will be examined using genetically manipulated rodent-adapted Hp strains and mouse and gerbil infection models. AIM 3. To examine Hp evolutionary dynamics within family units, Hp strains from parents and children in individual Peruvian families will be genotyped to gain insights into relatedness, intrafamilial vs. community transmission, and mutation, recombination, and selection on Hp in societies where overall risks of infection are high. AIM 4. To detect transmission between communities, mixed infection, and potential for recombination. Hp from Japanese Peruvians will be genotyped to detect (i) retention of ancestral Japanese-type genes, vs. community acquisition of putative Native Peruvian (Spanish-type) strains; (ii) mixed infections, especially involving strains of different ethnic origins, (iii) extent of recombination in a brief time frame, and (iv) selection for particular genes or alleles.