Genetic Analysis of Host Specificity in Schistosoma mansoni

曼氏血吸虫宿主特异性的遗传分析

• 批准号: 8586839
• 负责人: Tim J Anderson
• 金额: $ 58.09万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8586839
• 关键词: Alleles; American; Behavior; Behavioral; Binding; Biomphalaria; Chemicals; Chromosome Mapping; Development; Epidemiology; Evolution; Funding; Gene Expression; Gene Frequency; Genes; Genetic; Genetic Crosses; Genetic Variation; Genome; Genome Mappings; Genotype; Helminths; Human; Hybrids; Immune response; Individual; Infection; Inheritance Patterns; Laboratories; Larva; Location; Malaria; Maps; Measures; Methods; Molecular; Molecular Genetics; Parasites; Parents; Penetration; Phase; Physiological; Proliferating; Publishing; Quantitative Trait Loci; RNA Interference; Relative (related person); Resistance; Resources; Schistosoma; Schistosoma mansoni; Schistosome Parasite; Snails; Species Specificity; Specificity; Staging; System; Transfection; Work; Yeasts; base; gene function; genetic analysis; genetic linkage analysis; genome sequencing; genome-wide; novel; positional cloning; research study; response; segregation; tool; trait; transmission process; vector

DESCRIPTION (provided by applicant): Parasites characteristically show strong specificity to particular hosts, but the genetic basis for this host specificity is poorly understood. In Schistosoma mansoni, one of three medically important schistosome species infecting humans, elegant experimental work demonstrates that both chemical recognition of the intermediate snail host and survival of parasites within snails follow a simple Mendelian pattern of inheritance. While Egyptian parasites show strong chemical recognition of the sympatric snail Biomphalaria alexandrina, Brazilian parasites show no specificity and are attracted to even non-vector snail hosts. Similarly, while both Egyptian and Brazilian parasites infect and proliferate in their sympatric snail hosts, F1 hybrids develop only in S. American B. glabrata snails. New molecular tools allow us to determine the parasite genes that determine host specificity in this host-parasite system, providing a means to understand key molecular interactions between parasites and snail vector. Using R21 funding we have (a) developed a 5 cM linkage map for S. mansoni, and (b) demonstrated the utility of linkage mapping by identifying a strong QTL (LOD = 21) for oxamniquine resistance to a short region of chr 6. We now propose to exploit the genetic map, together with the recently published genome sequence of S. mansoni identify the genome region(s) that underlie host specificity in the S. mansoni - Biomphalaria system. Host specificity involves two components (a) chemical location of snails by miracidia and (b) penetration and clonal proliferation of schistosome larvae within snails. For both traits, we will conduct genetic crosses between Brazilian and Egyptian S. mansoni, using snail infections with single miracidia to generate single genotype infections in snails. We will quantify chemical recognition behavior of single F2 miracidia to both B. glabrata and B. alexandrina, and then genotype individual miracidia using SNPs spaced at ~4 cM (2Mb) intervals across the S. mansoni genome to identify QTLs for this trait. Genetic mapping of survival and clonal proliferation within the snail host is not possible using classical linkage mapping methods, because parasites that do not grow within snails cannot be genotyped. We will therefore use extreme QTL (X-QTL) methods, developed by malaria and yeast geneticists, to examine allele frequencies of F2 cercariae emerging from either B. glabrata or B. alexandrina snails. At the causative loci, we expect alleles from the Egyptian S. mansoni parent to be overrepresented in F2 cercariae emerging from B. alexandrina relative to those emerging from B. glabrata. Hence locus specific deviation from normal Mendelian segregation allows QTL location. Having fine mapped QTL regions for both traits, we will use RNAi disruption of gene function or retroviral based transfection to aid identification of causative loci. Understanding the genetic and molecular basis of host specificity in the S. mansoni - Biomphalaria system is critical for control efforts that aim to disrupt this step in the parasite lifecycle and provides a key to understanding evolution of host specificity in the most important of the human helminth parasites.

描述（由申请人提供）：寄生虫对特定宿主的特异性表现出很强的特异性，但是该宿主特异性的遗传基础知之甚少。在曼氏血吸虫中，曼森是感染人类的​​三个具有医学重要的棘构物种之一，优雅的实验性工作表明，蜗牛内的中间蜗牛宿主的化学识别和寄生虫的存活都遵循了一种简单的孟德尔遗传模式。尽管埃及寄生虫对同胞蜗牛生物掌callaria Alexandrina表现出强烈的化学识别，但巴西寄生虫没有特殊性，甚至被非载体蜗牛宿主吸引。同样，尽管埃及和巴西寄生虫都在其同胞蜗牛宿主中感染和增殖，但F1杂种仅在S. American B. Glabrata蜗牛中发展。新的分子工具使我们能够确定确定该宿主 - 寄生虫系统中宿主特异性的寄生虫基因，从而提供了一种理解寄生虫与蜗牛载体之间关键分子相互作用的方法。使用R21资金，我们（a）为曼森（S. Mansoni）开发了5厘米的链接图，（b）通过识别出强大的QTL（lod = 21）来证明链接映射的实用性，以抗oxamniquine的抗性chr 6的较短区域。 - 生物掌系统。宿主特异性涉及两个组成部分（a）奇迹的蜗牛化学位置，以及（b）蜗牛内棘小幼虫的穿透和克隆增殖。对于这两个特征，我们都将使用带有单个奇迹的蜗牛感染在巴西和埃及链球菌之间进行遗传杂交，从而在蜗牛中产生单个基因型感染。我们将使用跨跨链球菌基因组的〜4 cm（2Mb）间隔的SNP量化单个F2奇迹的化学识别行为，然后使用SNP识别该性状的QTLS。使用经典的连锁图方法，无法使用蜗牛宿主内生存和克隆增殖的遗传学映射，因为不能在蜗牛内生长的寄生虫不能进行基因分型。因此，我们将使用由疟疾和酵母遗传学家开发的极端QTL（X-QTL）方法来检查从B. glabrata或Alexandrina蜗牛中出现的F2 cercariae等位基因频率。在病原基因座，我们期望来自埃及曼氏链球菌的等位基因在F2 cercariae中的代表过多，而来自Alexandrina B. Alexandrina则相对于来自Glabrata的那些。因此，基因座特异性偏离正常的孟德尔隔离允许QTL位置。我们将使用两个特征的QTL区域进行绘制的QTL区域，我们将使用基因功能或基于逆转录病毒的转染的RNAi破坏来帮助鉴定病因基因座。了解植物链球菌-Biomphalaria系统中宿主特异性的遗传和分子基础对于旨在破坏寄生虫生命周期中这一步骤的控制工作至关重要，并为理解人类最重要的人类蠕虫寄生虫中宿主特异性的演变提供了关键。