Genetics & Population Structure of Plasmodium falciparum

描述（由申请人提供）：目前全球最致命的人类疟疾寄生虫恶性疟原虫的种群被认为在过去几千年的某个时候经历了瓶颈。 尽管最近的共同起源，恶性疟原虫种群的特点是高度的蛋白质多态性，特别是在某些免疫显性表面蛋白。 这种广泛的遗传变异提供了寄生虫逃避宿主免疫反应的巨大适应潜力。本建议的主要目的是不仅要确定恶性疟原虫种群中抗原多样性的程度，而且要确定产生和维持这种变异的主要机制。 我们将研究遗传多态性之间的自然分离的恶性疟原虫从几个地方性的非洲网站。 从这些分离株，我们将量化的多态性之间的几个分子标记，这是分散在三个完全测序的染色体（chr 2，chr 3，和chr 10）。所检测的基因位点是3个编码的表面蛋白基因--环孢子蛋白（Csp，在Chr 2上）和裂殖子表面蛋白-2（Msp-2，在Chr 3上），以及25 kd的恶性疟原虫性期抗原（pfs-25，在Chr 10上）。 这些基因座中的每一个在其表达中具有生命周期阶段特异性，并且是目前正在开发的一种或多种疫苗的靶标。除了这些蛋白质编码基因，我们将类型排列在相同的三条染色体上的几个高度多态性的微卫星位点。每个分离株的多基因座基因型将用于直接检测：（1）天然恶性疟原虫分离株基因组之间的减数分裂重组水平，（2）关键蛋白质编码基因之间多样化选择的程度，（3）滑动链（有丝分裂）突变在维持免疫原性核苷酸重复基因座（Csp和Msp-2）变异性中的作用。 这项工作将增加我们对这种寄生虫基因组进化的理解，为评估干预疾病传播的适当策略提供有价值的信息。

DESCRIPTION (provided by applicant): The current global population of the most deadly human malaria parasite, P. falciparum, is thought to have undergone a bottleneck sometime within the past several thousand years. Despite a recent common origin, P. falciparum populations are characterized by a high degree of protein polymorphism, particularly among certain immunodominant surface proteins. This extensive genetic variation provides the great adaptive potential by which the parasite evades the host immune response. The major objective of this proposal is to determine not only the degree of antigenic diversity in P. falciparum populations, but also to determine the principle mechanisms by which this variation is generated and maintained. We will examine the genetic polymorphism among natural isolates of P. falciparum from several endemic African sites. From these isolates, we will quantify the polymorphism among several molecular markers, which are dispersed on three completely sequenced chromosomes (chr2, chr3, and chr10). The genetic loci to be examined are three encoded surface protein genes--circumsporozoite protein (Csp, on Chr2) and merozoite surface protein-2 (Msp-2, on Chr3), and the 25kd P. falciparum sexual-stage antigen (pfs25, on Chr10). Each of these loci is life cycle-stage-specific in its expression and is the target of one or more vaccines currently in development. In addition to these protein-encoding genes, we will type several highly polymorphic microsatellite loci arrayed on the same three chromosomes. The resulting multi-locus genotype of each isolate will be used to test directly; (1) the level of meiotic recombination among genomes of natural P. falciparum isolates, (2) the extent of diversifying selection among the crucial protein-encoding genes, (3) the role of slipped-strand (mitotic) mutation in maintaining variability in immunogenic, nucleotide-repeat loci (Csp and Msp-2). This work will increase our understanding of the genomic evolution of this parasite will yield valuable information for evaluating appropriate strategies for intervening in disease transmission.