Stable SNPs in malaria antigen genes in isolated populations
Stable SNPs in malaria antigen genes in isolated populations
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DOI：
10.1126/science.1092077
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发表时间：
2004-01-23
期刊：
影响因子：
56.9
通讯作者：
Kaneko, A
中科院分区：
文献类型：
--
作者：
Tanabe, K;Sakihama, N;Kaneko, A
人类疟原虫恶性疟原虫的表面抗原承受着巨大的免疫压力，其位点受到正向选择 (1, 2)。恶性疟原虫显示出显着的遗传变异性，如耐药性的迅速出现[例如，20 年来氯喹 (CQ) 耐药性转运基因 pfcrt 出现 10 次突变 (3)]。因此，对自然获得性免疫或疫苗诱导免疫具有抗性的寄生虫种群的选择是一个潜在的问题。在这里，我们提供了西南太平洋瓦努阿图恶性疟原虫抗原位点稳定的单核苷酸多态性（SNP）但重复长度快速变化的证据。瓦努阿图的疟疾流行病学环境适合测试抗原多态性是否快速演变，因为岛屿之间有限的人类活动和低传播水平限制了寄生虫种群的多样性 (4)。我们分析了 1996 年至 1998 年来自四个岛屿（Malakula、Gaua、Santo 和 Pentecost）的恶性疟原虫种群的三个疫苗候选抗原位点 msp1、msp2 和 csp (4)。我们获得了 90 个完整的 msp1 序列（六个等位基因）。比对区域包含 48 个 SNP，其中包括 7 个同义替换（图 1）。等位基因对之间的核苷酸取代数量从 4 到 37 不等。值得注意的是，等位基因之间的 SNP 没有逐步进展。在 136 个完整的 csp 序列中，我们鉴定了 6 个等位基因，其中 5 个等位基因的中央 12 碱基对重复的数量和模式不同（图 1）。在非重复区域，两个 SNP 出现在 Th3R（T 细胞表位区域）中，导致取代 N 3 D 和 E 3 Q (5)。没有中间等位基因；即，既不是 NQ，也不是 DE。部分 msp2 序列 (n 142) 属于 FC27 或 3D7 等位基因类型 (图 S1)。在重复区域之外，独特序列在FC27型和3D7型中分别包含6个和3个非同义SNP。在这两种类型中，替换都不是逐步进行的。因此，SNP 在三个位点的等位基因之间没有显示出任何逐步变化。重要的是，一些等位基因在多个岛屿上被发现。这些发现表明，观察到的 SNP 起源于瓦努阿图境外，而新的 SNP 并未在瓦努阿图境内进化，这表明岛屿上存在稳定的 SNP。与 SNP 相比，串联重复的数量逐步变化。 Malakula (1996) 中 csp 等位基因的 NANP 重复次数为 39 至 43 个，Gaua 中 NANP 重复次数为 39 至 41 个（图 1）。在 msp2 等位基因中，Malakula (1996) 中 96 碱基对重复的数量为 2 个和 3 个，Gaua 中 3D7 等位基因类型中 GGSA 重复的数量为 10 到 13 个（图 S1）。观察到的重复长度在相同的单倍型背景中变化。 1996 年在 Malakula 的两个基因座中发现的重复变异已在 1998 年消失。此外，将 1997 年在 Santo 获得的样本中 msp1 和 msp2 的当前结果与 1992 年至 1994 年在 Santo 中这些等位基因的先前结果进行比较 (6)，表明重复长度变异减少。这些发现表明重复长度多态性在相对较短的时间内快速进化。为了推断三个位点中观察到的 SNP 的年龄，我们监测了 pfcrt 中的多态性。所有研究的分离株均在残基 72 至 76 处具有巴布亚新几内亚 CQ 抗性单倍型 SVMNT (7)。尽管瓦努阿图第一份 CQ 耐药性报告于 1980 年发表，但早在 1967 年就注意到瓦努阿图 CQ 耐药性的高流行率 (8)。因此，我们推测观察到的 SNP 在瓦努阿图已有至少 30 年的历史。巴布亚新几内亚和瓦努阿图之间的人员流动有限。人类运动介导的……
Surface antigens of the human malaria parasite Plasmodium falciparum are under intense immune pressure, and their loci are subject to positive selection (1, 2). P. falciparum shows substantial genetic variability, as seen in rapid emergence of drug resistance [eg, 10 mutations in pfcrt, the chloroquine (CQ) resistance transporter gene over 20 years (3)]. Hence, selection of parasite populations resistant to naturally acquired immunity or vaccine-induced immunity is of potential concern. Here we present evidence of stable single-nucleotide polymorphisms (SNPs) but rapid repeat length changes in P. falciparum antigen loci in Vanuatu, in the southwestern Pacific. The epidemiological settings for malaria in Vanuatu are suitable to test whether antigen polymorphisms evolve rapidly because limited human movement among the islands and low transmission levels limit the diversity of parasite populations (4). We analyzed three vaccine candidate antigen loci, msp1, msp2, and csp of P. falciparum populations from four islands (Malakula, Gaua, Santo, and Pentecost) from 1996 to 1998 (4). We obtained 90 complete msp1 sequences (six alleles). The aligned region contained 48 SNPs, including seven synonymous substitutions (Fig. 1). The number of nucleotide substitutions between pairs of alleles varied from 4 to 37. Notably, there was no stepwise progression of SNPs between alleles. In 136 complete csp sequences, we identified six alleles, five of which differed in the number and pattern of central 12–base pair repeats (Fig. 1). In the nonrepeat region, two SNPs occurred in Th3R, the T cell epitope region, resulting in substitutions N 3 D and E 3 Q (5). There was no intermediate allele; ie, neither NQ nor DE. Partial msp2 sequences (n 142) were either of the FC27 or 3D7 allelic type (fig. S1). Outside the repeat regions, unique sequences contained six and three nonsynonymous SNPs in FC27 type and 3D7 type, respectively. In both types, substitutions were not stepwise progressions. Thus, SNPs did not show any stepwise changes among alleles at the three loci. Importantly, some alleles were found on more than one island. These findings suggest that the observed SNPs originated outside Vanuatu, and that novel SNPs have not evolved within Vanuatu, indicating stable SNPs on islands. In contrast to SNPs, the number of tandem repeats varied stepwise. The number of NANP repeats in csp alleles was 39 to 43 in Malakula (1996) and 39 to 41 in Gaua (Fig. 1). In msp2 alleles the number of 96–base pair repeats was two and three in Malakula (1996), and the number of GGSA repeats in 3D7 allelic type was 10 to 13 in Gaua (fig. S1). The observed repeat length varied in an identical haplotype background. The repeat variations found in the two loci in Malakula in 1996 had disappeared by 1998. Also, comparison of the present results for msp1 and msp2 from samples obtained in 1997 in Santo with previous results for these alleles in 1992 to 1994 in Santo (6) indicates reduction in repeat length variation. These findings suggest rapid evolution of repeat length polymorphism within a relatively short time span. To infer the age of the observed SNPs in the three loci, we monitored polymorphism in pfcrt. All of the isolates studied had the Papua New Guinean CQ-resistant haplotype, SVMNT, at residues 72 to 76 (7). Although the first report of CQ resistance in Vanuatu was published in 1980, a high prevalence of CQ resistance in Vanuatu had been noticed as early as 1967 (8). Therefore, we presume that the observed SNPs are at least 30 years old in Vanuatu. There is limited human movement between Papua New Guinea and Vanuatu. Human movement–mediated …