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.

性状（由申请方提供）：寄生虫的特征是对特定宿主表现出很强的特异性，但对这种宿主特异性的遗传基础知之甚少。曼氏血吸虫（Schistosoma mansoni）是感染人类的三种医学上重要的寄生虫之一，优雅的实验工作表明，中间蜗牛宿主的化学识别和蜗牛内寄生虫的存活都遵循简单的孟德尔遗传模式。虽然埃及的寄生虫表现出强烈的化学识别的同域蜗牛Biomphalaria alexandrina，巴西的寄生虫没有表现出特异性，甚至被吸引到非载体蜗牛主机。同样，埃及和巴西的寄生虫都能在同域蜗牛宿主中感染和增殖，而F1杂种只在S.美国B。光滑蜗牛新的分子工具使我们能够确定寄生虫的基因，决定在这个主机寄生虫系统的主机特异性，提供了一种手段来了解寄生虫和蜗牛载体之间的关键分子相互作用。利用R21基金，我们（a）开发了一个5 cM的连锁图谱。mansoni，和（B）通过鉴定对chr 6的短区域的奥曲喹抗性的强QTL（LOD = 21）证明了连锁作图的实用性。我们现在建议利用的遗传图谱，连同最近公布的基因组序列的S。mansoni鉴定了S. mansoni-Biomphalaria系统宿主特异性包括两个组成部分：（a）毛蚴对蜗牛的化学定位和（B）蜗牛内寄生虫幼虫的侵入和克隆增殖。对于这两个性状，我们将进行巴西和埃及S。mansoni，使用具有单一毛蚴的蜗牛感染在蜗牛中产生单一基因型感染。我们将量化单个F2毛蚴对两种B的化学识别行为。glabrata和B. alexandrina，然后使用在S. mansoni基因组，以确定该性状的QTL。使用经典的连锁作图方法不可能对蜗牛宿主内的存活和克隆增殖进行遗传作图，因为不能对不在蜗牛内生长的寄生虫进行基因分型。因此，我们将使用极端QTL（X-QTL）的方法，疟疾和酵母遗传学家开发的，检查等位基因频率的F2尾蚴出现从B。glabrata或B.亚历山大蜗牛。在致病基因座上，我们预计等位基因来自埃及S。从B出现的F2尾蚴中，曼氏亲本的比例过高。alexandrina相对于从B出现的那些。光滑的因此，基因座特异性偏离正常孟德尔分离允许QTL定位。在对这两个性状的QTL区域进行精细定位后，我们将使用RNAi破坏基因功能或基于逆转录病毒的转染来帮助鉴定致病基因座。了解宿主特异性的遗传和分子基础，在S。mansoni-Biomphalaria系统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，并为理解最重要的人类蠕虫寄生虫中宿主特异性的进化提供了关键。