Kenya Medical Research Institute, Centre for Geographic Medicine Research Coast, Kilifi, Kenya.
Mol Biol Evol. 2010 Oct;27(10):2344-51. doi: 10.1093/molbev/msq119. Epub 2010 May 9.
Signatures of balancing selection operating on specific gene loci in endemic pathogens can identify candidate targets of naturally acquired immunity. In malaria parasites, several leading vaccine candidates convincingly show such signatures when subjected to several tests of neutrality, but the discovery of new targets affected by selection to a similar extent has been slow. A small minority of all genes are under such selection, as indicated by a recent study of 26 Plasmodium falciparum merozoite-stage genes that were not previously prioritized as vaccine candidates, of which only one (locus PF10_0348) showed a strong signature. Therefore, to focus discovery efforts on genes that are polymorphic, we scanned all available shotgun genome sequence data from laboratory lines of P. falciparum and chose six loci with more than five single nucleotide polymorphisms per kilobase (including PF10_0348) for in-depth frequency-based analyses in a Kenyan population (allele sample sizes >50 for each locus) and comparison of Hudson-Kreitman-Aguade (HKA) ratios of population diversity (π) to interspecific divergence (K) from the chimpanzee parasite Plasmodium reichenowi. Three of these (the msp3/6-like genes PF10_0348 and PF10_0355 and the surf(4.1) gene PFD1160w) showed exceptionally high positive values of Tajima's D and Fu and Li's F indices and have the highest HKA ratios, indicating that they are under balancing selection and should be prioritized for studies of their protein products as candidate targets of immunity. Combined with earlier results, there is now strong evidence that high HKA ratio (as well as the frequency-independent ratio of Watterson's /K) is predictive of high values of Tajima's D. Thus, the former offers value for use in genome-wide screening when numbers of genome sequences within a species are low or in combination with Tajima's D as a 2D test on large population genomic samples.
平衡选择作用于地方病病原体特定基因座的特征可识别自然获得性免疫的候选靶标。在疟原虫中，当受到几种中性测试时，几个领先的候选疫苗都表现出这种特征，但发现受到类似选择影响的新靶标一直很缓慢。最近对 26 个恶性疟原虫裂殖阶段基因进行的研究表明，只有一小部分基因受到这种选择的影响，这些基因以前没有被列为疫苗候选基因，其中只有一个（PF10_0348 基因座）表现出强烈的特征。因此，为了将发现工作集中在多态性基因上，我们扫描了所有可用的恶性疟原虫实验室株的全基因组序列数据，并选择了六个每千碱基有超过五个单核苷酸多态性的基因座（包括 PF10_0348 基因座），用于在肯尼亚人群中进行基于频率的深入分析（每个基因座的等位基因样本大小>50），并比较黑猩猩寄生虫间日疟原虫的种群多样性（π）与种间分化（K）的哈德森-克里坦-阿加德（HKA）比值。这六个基因座中有三个（PF10_0348 和 PF10_0355 基因座的 msp3/6 样基因和 surf(4.1)基因 PFD1160w）表现出特别高的 Tajima 的 D 和 Fu 和 Li 的 F 指数的正值，并且具有最高的 HKA 比值，表明它们受到平衡选择的影响，应优先研究其蛋白质产物作为免疫的候选靶标。结合早期的结果，现在有强有力的证据表明，高 HKA 比值（以及 Watterson's /K 的频率独立比值）可预测 Tajima 的 D 的高值。因此，当一个物种内的基因组序列数量较少时，或者与 Tajima 的 D 一起作为大型人群基因组样本的二维测试时，前者具有用于全基因组筛选的价值。
