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)是一种强有力的疟疾疫苗候选基因。然而，编码MSP-1(MSPL)基因的高度多态特性为有效疫苗的开发提供了潜在的障碍。此外，人们越来越担心疫苗可能出现耐药性，因为抗原多态被认为是快速进化的，就像抗疟疾药物的耐药性一样。为了评估寄生虫能够以多快的速度产生新的MSPL多样性，研究现代寄生虫种群中MSPL多态的进化历史是至关重要的。我们以前对西南太平洋瓦努阿图恶性疟原虫种群的分析表明，包括MSPL在内的主要表面抗原基因的单核苷酸多态(SNPs)进化不快，而重复长度多态进化很快。为了推断MSPL基因SNPs在世界寄生虫种群中的年龄，我们从坦桑尼亚、泰国、所罗门群岛和巴西等不同地区获得了300多个完整序列并进行了比较。坦桑尼亚的一个寄生虫种群显示出比其他种群更高的核苷酸多样性，坦桑尼亚和其他地区共享了大量相同的SNP，包括同义SNPs。与MSPL相反，编码P型钙转运ATPase(PfATP6)的选择性中性基因SERCA如预期的那样具有有限的SNPs数量，并且在所有地理区域SERCA的核苷酸多样性都低于MSPL。重要的是，坦桑尼亚和其他地区在SERCA共享完全相同的SNPs的情况非常有限。结合地理区域寄生虫种群最近共同祖先(TMRCA)的时间数据，我们的结果表明，MSPL中的许多SNPs在相当长的一段时间内是稳定的，其年龄早于现代人走出非洲的最近扩张。

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.