Molecular population genetic study on the evolution of antigen polymorphism of malaria parasites

恶性疟原虫裂殖子表面蛋白1（MSP-1）是一种很强的疟疾疫苗候选者。然而，编码MSP-1（mspl）的基因的高度多态性性质对有效疫苗的开发提出了潜在的障碍。此外，人们越来越关注疫苗耐药性的潜在出现，因为抗原多态性被认为会迅速演变，如对抗疟疾药物的耐药性所见。为了评估寄生虫如何快速地产生新的mspl多样性，调查现代寄生虫种群中mspl多态性的进化历史是至关重要的。我们以前的分析表明，在太平洋西南部瓦努阿图的恶性疟原虫种群的主要表面抗原基因，包括mspl的单核苷酸多态性（SNP）不会迅速演变，而重复长度多态性迅速演变。为了推断世界寄生虫种群中mspl SNP的年龄，我们获得并比较了来自不同地理区域的300多个完整序列;坦桑尼亚、泰国、所罗门群岛和巴西。坦桑尼亚寄生虫种群显示出比其他种群更高的核苷酸多样性，并且坦桑尼亚和其他地区之间共享大量相同的SNP，包括同义SNP。与mspl相反，编码P型钙转运ATP酶（PfATP 6）的选择性中性基因serca具有有限数量的SNP，正如预期的那样，并且在所有地理区域中serca的核苷酸多样性低于mspl。重要的是，在坦桑尼亚和其他地区之间的serca，相同的SNP的共享基本上是有限的。再加上数据的时间最近的共同祖先（TMRCA）的寄生虫种群的地理区域，我们的研究结果表明，许多SNP在mspl是稳定的相当长的一段时间与年龄早于最近的扩张现代人类出非洲。

The merozoite surface protein 1 (MSP-1) of Plasmodium falciparum is a strong malaria vaccine candidate. However, the highly polymorphic nature of the gene encoding MSP-1 (mspl) presents a potential obstacle to the development of effective vaccines. Also, there is a growing concern of the potential emergence of vaccine resistance because antigen polymorphism is believed to evolve rapidly as seen in resistance to anti-malarial drugs. To assess how rapidly parasites are able to generate novel mspl diversity, investigations of the evolutionary history of mspl polymorphism in modern parasite populations are crucial. Our previous analyses of P falciparum populations from Vanuatu in the southwestern Pacific have shown that single nucleotide polymorphisms (SNPs) in major surface antigen genes, including mspl do not evolve rapidly, whereas repeat length polymorphisms do evolve rapidly. To infer the age of SNPs of mspl in the world parasite populations, we obtained and compared more than 300 complete sequences from geographically diverse areas ; Tanzania, Thailand, Solomon Islands and Brazil. A Tanzanian parasite population showed higher nucleotide diversity than other populations, and a large number of identical SNPs, including synonymous SNPs, were shared between Tanzania and other areas. In contrast to mspl, serca, a selectively neutral gene encoding a P-type calcium-transporting ATPase (PfATP6), had limited numbers of SNPs, as expected, and nucleotide diversity was lower in serca than in mspl in all the geographic areas. Importantly, sharing of identical SNPs was substantially limited in serca between Tanzania and other areas. Together with data of the time to the most recent common ancestor (TMRCA) of parasite populations in geographic areas, our results indicate that much of SNPs in mspl are stable for a considerably long term with the age predating the recent expansion of modern humans out-of-Africa.