Deforche Koen, Camacho Ricardo, Laethem Kristel Van, Shapiro Beth, Moreau Yves, Rambaut Andrew, Vandamme Anne-Mieke, Lemey Philippe
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium.
J Comput Biol. 2007 Oct;14(8):1105-14. doi: 10.1089/cmb.2007.0073.
The human immunodeficiency virus (HIV) has a genome that is rich in adenine, and its rapid evolution shows an observed bias of guanine (G) to adenine (A) mutations. Two mechanisms have been proposed to explain these properties: (1) an imbalance in dNTP pool concentrations which drives the misincorporation process during reverse transcription, and (2) cytidine deamination by the APOBEC3G/3F restriction factor, causing G to A mutations most notably in specific dinucleotide contexts. Although crucial to understanding HIV evolution, current estimates on misincorporation bias during the replication cycle are based on scarce in vitro measurements. In this work, HIV partial pol sequences obtained for drug resistance testing purposes are analyzed using likelihood methods to estimate various models of HIV misincorporation bias in vivo. The technique is robust to selection on the amino acid sequence and selection against CpG dinucleotides. A model where misincorporations are explained only by an imbalance in dNTP pool concentrations, together with a preference for transitions versus transversions, explained 98% (95% confidence interval [C.I.] 93-100) of the observed variation in freely estimated misincorporation rates. Although dinucleotide context was responsible for variation in misincorporation probabilities, this variation was not specific for G to A mutations implying that the footprint of APOBEC3G/3F editing could not be detected. These results indicate that an imbalance in dNTP pool concentrations explains most of the bias in HIV nucleotide misincorporations, while the effect of editing by APOBEC3G/3F on HIV evolution, based on its dinucleotide specificity, could not be observed in this study.
人类免疫缺陷病毒（HIV）的基因组富含腺嘌呤，其快速进化显示出观察到的鸟嘌呤（G）到腺嘌呤（A）突变的偏向性。已提出两种机制来解释这些特性：（1）dNTP池浓度的不平衡，这在逆转录过程中驱动错配掺入过程；（2）APOBEC3G/3F限制因子引起的胞嘧啶脱氨，最显著地在特定二核苷酸背景下导致G到A突变。尽管对于理解HIV进化至关重要，但目前对复制周期中错配掺入偏向性的估计是基于稀少的体外测量。在这项工作中，使用似然方法分析为耐药性测试目的获得的HIV部分pol序列，以估计体内HIV错配掺入偏向性的各种模型。该技术对氨基酸序列的选择和对CpG二核苷酸的选择具有鲁棒性。一种仅用dNTP池浓度不平衡以及对转换与颠换的偏好来解释错配掺入的模型，解释了自由估计的错配掺入率中观察到的变异的98%（95%置信区间[C.I.] 93 - 100）。尽管二核苷酸背景导致错配掺入概率的变异，但这种变异并非G到A突变所特有，这意味着无法检测到APOBEC3G/3F编辑的痕迹。这些结果表明，dNTP池浓度的不平衡解释了HIV核苷酸错配掺入中的大部分偏向性，而基于其二核苷酸特异性，在本研究中未观察到APOBEC3G/3F编辑对HIV进化的影响。
