Data from: A positively selected APOBEC3H haplotype is associated with natural resistance to HIV-1 infection

APOBEC3 genes encode cytidine deaminases endowed with the ability to inhibit retroviruses and retrotransposons. These genes have been targets of natural selection throughout primate evolutionary history. We analysed their selection pattern in human populations observing that APOBEC3F and 3G are neutrally evolving. Conversely, nucleotide diversity was extremely high for APOBEC3H, and most tests rejected the hypothesis of selective neutrality in Eurasian populations. Haplotype analysis and the derived intra-allelic nucleotide diversity test indicated that positive selection has driven the increase in frequency of one haplotype (Hap I) outside Africa. Consistently, population genetic differentiation between African and non-African populations was higher than expected under neutrality. A case/control association analysis indicated that Hap I is associated with protection from sexually transmitted HIV-1 infection. Hap I carries a protein-destabilizing variant and a residue conferring resistance to Vif-mediated degradation. Data herein suggest that lower protein stability might have been traded-off with a higher ability to circumvent Vif-mediated hijacking. Alternatively, transcription regulatory variants might represent the selection target. Our data represent an example of how the selective pressures exerted by extinct or unknown viral agents can be exploited to provide valuable information on the allelic determinants of susceptibility to modern infections.

APOBEC3基因（APOBEC3 genes）编码胞苷脱氨酶（cytidine deaminases），这类酶具备抑制逆转录病毒（retrovirus）与反转录转座子（retrotransposon）的能力。在整个灵长类动物的进化历程中，该类基因始终是自然选择（natural selection）的作用靶点。我们针对人类群体中该类基因的选择模式展开分析，结果发现APOBEC3F与APOBEC3G呈中性进化（neutral evolution）状态。与之相反，APOBEC3H的核苷酸多样性（nucleotide diversity）极高，且多数检验结果均推翻了欧亚人群中该基因受选择中性演化的假设。单倍型（haplotype）分析与衍生的等位基因内核苷酸多样性检验结果显示，正选择（positive selection）推动了非洲以外人群中某一单倍型（Hap I）的频率上升。与之相符的是，非洲人群与非非洲人群之间的群体遗传分化（population genetic differentiation）水平，高于中性演化预期下的理论值。病例-对照关联分析（case/control association analysis）结果表明，Hap I与性传播人类免疫缺陷病毒1型（HIV-1）感染的防护效应存在显著关联。Hap I携带一种可导致蛋白质不稳定的变异位点，以及一个能赋予病毒对Vif介导降解产生抗性的氨基酸残基（residue）。本研究数据表明，较低的蛋白质稳定性或许与更强的规避Vif介导的病毒劫持的能力形成了演化权衡。此外，转录调控变异（transcription regulatory variants）或许正是自然选择的作用靶点。本研究数据提供了一个典型案例：已灭绝或未知的病毒病原体所施加的选择压力，可被用于挖掘现代感染易感性的等位基因决定因素，从而为相关研究提供极具价值的信息。