Evolution of the Multi-Domain Structures of Virulence Genes in the Human Malaria Parasite, Plasmodium falciparum

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.

恶性疟原虫（Plasmodium falciparum）的var基因家族编码免疫显性的变异表面抗原PfEMP1。这些高度多态性的蛋白是重要的毒力因子，可介导与多种宿主组织的细胞黏附，使受感染的红细胞滞留在包括大脑、胎盘在内的重要器官中。获得变异特异性抗体与抵御重症疟疾感染相关；然而，var基因的模块化遗传结构编码了数量不等、结合特异性各异的抗原结构域，这使得解析基因表达与感染结局之间的关联变得复杂。通过分析已完成全序列测定的var基因库的结构域组成，我们发现var基因所含结构域的数量与其序列保守性之间存在显著且非随机的关联。据此，var基因可分为短小且多态的类型与长且保守的类型，提示基因长度是var基因分类的一项重要特征。随后我们借助进化分析框架，阐明了作用于单个基因层面的相同进化力量如何同时塑造了该寄生虫的基因库结构。序列保守性、基因结构与基因库结构之间的上述关联，可通过宿主内适合度优化与宿主间免疫选择压力最小化之间的权衡得到解释。本研究结果阐明了简单的进化机制如何在多个层面解释var基因的结构形成，并为解析恶性疟原虫疟疾复杂的流行病学特征提供了重要参考。