Genome-wide diversity and differentiation in New World populations of the human malaria parasite <i>Plasmodium vivax</i>

Background The Americas were the last continent colonized by humans carrying malaria parasites. Plasmodium falciparum from the New World shows very little genetic diversity and greater linkage disequilibrium, compared with its African counterparts, and is clearly subdivided into local, highly divergent populations. However, limited available data have revealed extensive genetic diversity in American populations of another major human malaria parasite, P. vivax. Methods We used an improved sample preparation strategy and next-generation sequencing to characterize 9 high-quality P. vivax genome sequences from northwestern Brazil. These new data were compared with publicly available sequences from recently sampled clinical P. vivax isolates from Brazil (BRA, total n = 11 sequences), Peru (PER, n = 23), Colombia (COL, n = 31), and Mexico (MEX, n = 19). Principal findings/Conclusions We found that New World populations of P. vivax are as diverse (nucleotide diversity π between 5.2 × 10−4 and 6.2 × 10−4) as P. vivax populations from Southeast Asia, where malaria transmission is substantially more intense. They display several non-synonymous nucleotide substitutions (some of them previously undescribed) in genes known or suspected to be involved in antimalarial drug resistance, such as dhfr, dhps, mdr1, mrp1, and mrp-2, but not in the chloroquine resistance transporter ortholog (crt-o) gene. Moreover, P. vivax in the Americas is much less geographically substructured than local P. falciparum populations, with relatively little between-population genome-wide differentiation (pairwise FST values ranging between 0.025 and 0.092). Finally, P. vivax populations show a rapid decline in linkage disequilibrium with increasing distance between pairs of polymorphic sites, consistent with very frequent outcrossing. We hypothesize that the high diversity of present-day P. vivax lineages in the Americas originated from successive migratory waves and subsequent admixture between parasite lineages from geographically diverse sites. Further genome-wide analyses are required to test the demographic scenario suggested by our data.背景 美洲是最后一个被携带疟原虫的人类殖民的大陆。与非洲同类种群相比，新大陆恶性疟原虫（Plasmodium falciparum）的遗传多样性极低，连锁不平衡程度更高，且可明确划分为多个高度分化的本地种群。然而现有有限数据显示，另一种主要人类疟原虫——间日疟原虫（Plasmodium vivax）的美洲种群却拥有极为丰富的遗传多样性。 方法 本研究采用优化后的样本制备策略结合二代测序（next-generation sequencing）技术，对来自巴西西北部的9株高质量间日疟原虫基因组序列进行了解析。将这批新获得的序列与公开可用的近期采样序列进行比对，这些公开序列分别来自巴西（BRA，共11株）、秘鲁（PER，共23株）、哥伦比亚（COL，共31株）和墨西哥（MEX，共19株）的临床间日疟原虫分离株。 主要发现与结论 本研究发现，新大陆间日疟原虫种群的遗传多样性（核苷酸多样性π值介于5.2×10⁻⁴至6.2×10⁻⁴之间）与疟疾传播强度显著更高的东南亚间日疟原虫种群相当。这些种群在已知或疑似与抗疟药物耐药相关的基因（如dhfr、dhps、mdr1、mrp1及mrp-2）中存在多个非同义核苷酸替换（其中部分为此前未被报道的新变异），但未在氯喹耐药转运蛋白同源基因（crt-o）中发现此类变异。此外，美洲间日疟原虫的地理种群结构分化程度远低于恶性疟原虫的本地种群，全基因组水平的种群间遗传分化程度较低，两两种群间的FST值介于0.025至0.092之间。最后，间日疟原虫种群的连锁不平衡程度随多态位点间距增加而快速下降，这与频繁发生的异交（outcrossing）现象相符。我们推测，当前美洲地区间日疟原虫谱系的高多样性源于多次迁移事件以及来自不同地理区域的寄生虫谱系后续发生的遗传混合。仍需开展进一步的全基因组分析，以验证本研究数据所提示的种群演化历史假说。