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），这类酶可抑制逆转录病毒（retroviruses）与反转录转座子（retrotransposons）的活性。该基因家族在灵长类进化史中始终处于自然选择（natural selection）的作用靶标之列。我们针对人群中该基因的选择模式展开分析，结果显示APOBEC3F与APOBEC3G呈现选择中性进化特征。与之相反，APOBEC3H的核苷酸多样性（nucleotide diversity）极高，且多数检验均拒绝欧亚人群（Eurasian populations）中该基因处于选择中性（selective neutrality）的假说。单倍型分析（haplotype analysis）与等位基因内核苷酸多样性检测（intra-allelic nucleotide diversity test）结果表明，正选择（positive selection）推动了非洲以外人群中某一单倍型（Hap I）的频率升高。与此一致，非洲与非非洲人群间的群体遗传分化（population genetic differentiation）高于中性进化预期水平。病例-对照关联分析（case/control association analysis）显示，Hap I与性传播HIV-1感染（sexually transmitted HIV-1 infection）存在显著保护性关联。Hap I携带一种蛋白质不稳定变异体（protein-destabilizing variant）以及一个可赋予Vif介导降解（Vif-mediated degradation）抗性的氨基酸残基。本研究数据提示，较低的蛋白质稳定性或许与规避Vif介导劫持（circumvent Vif-mediated hijacking）的能力提升存在进化权衡。此外，转录调控变异体（transcription regulatory variants）也可能是自然选择的作用靶标。本研究数据清晰展示了：已灭绝或未知病毒媒介施加的选择压力，可被用于挖掘现代感染易感性的等位基因决定因素，为相关研究提供宝贵信息。