Evolution of the Multi-Domain Structures of Virulence Genes in the Human Malaria Parasite, Plasmodium falciparum
Evolution of the Multi-Domain Structures of Virulence Genes in the Human Malaria Parasite, Plasmodium falciparum
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DOI：
10.1371/journal.pcbi.1002451
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发表时间：
2012-04-01
影响因子：
4.3
通讯作者：
Recker, Mario
中科院分区：
文献类型：
--
作者：
Buckee, Caroline O.;Recker, Mario
恶性疟原虫的 var 基因家族编码免疫显性变异表面抗原 PfEMP1。这些高度多态性的蛋白质是重要的毒力因子，可介导细胞粘附到多种宿主组织，导致重要器官（包括大脑或胎盘）中寄生红细胞的隔离。获得变体特异性抗体与预防严重疟疾感染相关；然而，由于var基因的模块化遗传结构，编码不同数量的具有不同结合特异性的抗原结构域，理解基因表达和感染结果之间的关系变得复杂。通过分析完全测序的 var 基因库的结构域结构，我们揭示了组成 var 基因的结构域数量与其序列保守性之间存在显着的非随机关联。因此，var 基因可以分为短且多样化的基因和长且保守的基因，这表明基因长度是 var 基因分类中的一个重要特征。然后，我们使用进化框架来证明作用于个体基因水平的相同进化力量如何也塑造了寄生虫的基因库。因此，观察到的序列保守性、基因结构和库结构之间的关联可以通过优化宿主内适应性和最小化宿主间免疫选择压力之间的权衡来解释。我们的结果证明了简单的进化机制如何在多个层面上解释 var 基因结构，并对理解恶性疟疾的多方面流行病学具有重要意义。
The var gene family of Plasmodium falciparum encodes the immunodominant variant surface antigens PfEMP1. These highly polymorphic proteins are important virulence factors that mediate cytoadhesion to a variety of host tissues, causing sequestration of parasitized red blood cells in vital organs, including the brain or placenta. Acquisition of variant-specific antibodies correlates with protection against severe malarial infections; however, understanding the relationship between gene expression and infection outcome is complicated by the modular genetic architectures of var genes that encode varying numbers of antigenic domains with differential binding specificities. By analyzing the domain architectures of fully sequenced var gene repertoires we reveal a significant, non-random association between the number of domains comprising a var gene and their sequence conservation. As such, var genes can be grouped into those that are short and diverse and genes that are long and conserved, suggesting gene length as an important characteristic in the classification of var genes. We then use an evolutionary framework to demonstrate how the same evolutionary forces acting on the level of an individual gene may have also shaped the parasite's gene repertoire. The observed associations between sequence conservation, gene architecture and repertoire structure can thus be explained by a trade-off between optimizing within-host fitness and minimizing between-host immune selection pressure. Our results demonstrate how simple evolutionary mechanisms can explain var gene structuring on multiple levels and have important implications for understanding the multifaceted epidemiology of P. falciparum malaria.