Structural polymorphism and diversifying selection on the pregnancy malaria vaccine candidate VAR2CSA
Structural polymorphism and diversifying selection on the pregnancy malaria vaccine candidate VAR2CSA
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DOI：
10.1016/j.molbiopara.2007.06.007
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发表时间：
2007-10-01
影响因子：
1.5
通讯作者：
Smith, Joseph D.
中科院分区：
文献类型：
--
作者：
Bockhorst, Joseph;Lu, Fangli;Smith, Joseph D.
VAR2CSA是妊娠疟疾疫苗的主要候选者，但疫苗的开发可能会因序列多态而变得复杂。在这里，我们从106个寄生虫中获得了部分或全长的var2CSA序列，并应用新的计算方法和三维建模来研究VAR2CSA的地理变异和选择压力。我们的分析揭示了VAR2CSA序列变异的结构模式，其中多态位点聚集成有限多样性的片段。在这些片段中，两种或三种基本类型表征了绝大多数寄生虫样本。与灵长类疟疾相比，雷氏疟原虫表明这些基本类型都有古老的起源。在全球范围内，var2CSA基因由这些祖先的多态片段组成，这些片段在var2CSA等位基因之间广泛重组。三维建模显示，多态片段集中在6个VAR2CSA Duffy结合样(DBL)粘附域的特征位置的柔性环中。单个DBL结构域表面具有不同的多样化选择模式，这表明每个DBL结构域的有限和不同部分是宿主抗体的靶标。由于标准的系统发育树分析不适用于像var2CSA这样高度重组的基因，我们开发了一种新的系统发育方法，包括重组并跟踪片段类型中的新突变。在结果树中，赖氏疟原虫被确认为异常值，非洲和亚洲恶性疟原虫分离株略有分化。这些发现验证了一种在存在频繁重组的情况下模拟蛋白质进化的新方法，并提供了对var基因产物如何作为免疫逃避结合配体的更清晰的理解。(C)2007 Elsevier B.V.保留所有权利。
VAR2CSA is the main candidate for a pregnancy malaria vaccine, but vaccine development may be complicated by sequence polymorphism. Here, we obtained partial or full-length var2CSA sequences from 106 parasites and applied novel computational methods and three-dimensional modeling to investigate VAR2CSA geographic variation and selection pressure. Our analysis reveals structural patterns of VAR2CSA sequence variation in which polymorphic sites group into segments of limited diversity. Within these segments, two or three basic types characterize a substantial majority of the parasite samples. Comparison to the primate malaria Plasmodium reichenowi shows that these basic types have ancient origins. Globally, var2CSA genes are comprised of a mosaic of these ancestral polymorphic segments that have recombined extensively between var2CSA alleles. Three-dimensional modeling reveals that polymorphic segments concentrate in flexible loops at characteristic locations in the six VAR2CSA Duffy binding-like (DBL) adhesion domains. Individual DBL domain surfaces have distinct patterns of diversifying selection, suggesting that limited and differing portions of each DBL domain are targeted by host antibody. Since standard phylogenetic tree analysis is inadequate for highly recombining genes like var2CSA, we developed a novel phylogenetic approach that incorporates recombination and tracks new mutations in segment types. In the resulting tree, P. reichenowi is confirmed as an outlier and African and Asian P. falciparum isolates have slightly diverged. These findings validate a new approach to modeling protein evolution in the presence of frequent recombination and provide a clearer understanding of how var gene products function as immunoevasive binding ligands. (c) 2007 Elsevier B.V. All rights reserved.