Shaffer Esther, Boso Guney, Sadjadpour Reza, Yedavalli Venkat V S R K, Lam Oscar, Kozak Christine A
Viral Biology Section, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
Department of Biological Sciences, Salisbury University, Salisbury, Maryland, USA.
J Virol. 2025 Sep 16:e0125125. doi: 10.1128/jvi.01251-25.
Apobec3 (A3, apolipoprotein B editing complex 3) is a cytidine deaminase with broadly antiretroviral activity. A3 is packaged in virions and converts cytidines to uracil (C > U) in viral minus-strand DNA during reverse transcription, resulting in guanosine to adenosine (G > A) mutations in the viral plus strand. Mouse Apobec3 (mA3) mutagenizes numerous infectious retroviruses and some families of endogenous retroviruses. Here we show that endogenous mouse mammary tumor viruses, termed , show a range of mA3 hypermutation from trace levels to an extreme example, that sustained a catastrophic, genome-wide reduction of G content to 10.8%; this level is associated with the contemporaneous generation of new preferred trinucleotide target sites by mutagenesis of consecutive cytidines. Although newly inserted proviruses have identical long terminal repeats (LTRs), mA3 can disproportionately generate G > A substitutions specific to the 3' LTR. Individual hypermutated display two different mA3 target site context preferences that correspond to those of the two mA3 alleles found among inbred strains of laboratory mice. positive subspecies screened for these mA3 alleles unexpectedly revealed 20 distinct mA3 haplotypes with different combinations of replacement mutations at the 15 sites that distinguish the two inbred strain alleles, 11 of which show signatures of positive selection. These data show that mA3 deamination can have a major impact on the genomic integrity of , and that mA3 is actively evolving within this single mouse species suggestive of high-impact genetic conflicts over a short evolutionary time frame.IMPORTANCEThe antiviral cytidine deaminase Apobec3 (apolipoprotein B editing complex 3) mutates retroviral DNA copies generated during new infections. Although such mutagenesis of replicating mouse retroviruses has been reported to be modest, here we show that many germline copies of mouse mammary tumor viruses () have sustained significant to massive levels of mouse Apobec3 (mA3) editing. mA3 hypermutation can also disproportionally affect one of the two otherwise identical viral long terminal repeats and can create new preferred target sites in the viral genome substrate by mutating successive cytosines. The edits in individual correspond to the different target sequence preferences of the two inbred mouse strain mA3 alleles, but examination of allelic variation in wild mice of the species identified 18 additional variants and signatures of diversifying selection, a display of unusually rapid evolution within a single species over a short time frame.
载脂蛋白B编辑复合体3（A3）是一种具有广泛抗逆转录病毒活性的胞嘧啶脱氨酶。A3被包装在病毒粒子中，并在逆转录过程中将病毒负链DNA中的胞嘧啶转化为尿嘧啶（C>U），导致病毒正链中鸟嘌呤到腺嘌呤（G>A）的突变。小鼠载脂蛋白B编辑复合体3（mA3）可诱变多种传染性逆转录病毒和一些内源性逆转录病毒家族。在这里，我们表明，内源性小鼠乳腺肿瘤病毒，称为，显示出一系列从痕量水平到一个极端例子的mA3超突变，该极端例子维持了全基因组范围内G含量的灾难性降低至10.8%；这个水平与通过连续胞嘧啶的诱变同时产生新的优先三核苷酸靶位点有关。虽然新插入的前病毒具有相同的长末端重复序列（LTR），但mA3可以不成比例地产生特定于3'LTR的G>A替换。单个超突变显示出两种不同的mA3靶位点上下文偏好，这与在实验室小鼠近交系中发现的两个mA3等位基因的偏好相对应。对这些mA3等位基因进行筛选的阳性亚种意外地揭示了20种不同的mA3单倍型，在区分两个近交系等位基因的15个位点上具有不同的替换突变组合，其中11种显示出正选择的特征。这些数据表明，mA3脱氨作用可对的基因组完整性产生重大影响，并且mA3在这一单一小鼠物种内正在积极进化，这表明在短时间进化框架内存在高影响的遗传冲突。重要性抗病毒胞嘧啶脱氨酶载脂蛋白B编辑复合体3（A3）可使新感染期间产生的逆转录病毒DNA拷贝发生突变。虽然据报道，复制型小鼠逆转录病毒的这种诱变作用不大，但在这里我们表明，许多小鼠乳腺肿瘤病毒（）的种系拷贝已持续受到显著到大量水平的小鼠载脂蛋白B编辑复合体3（mA3）编辑。mA3超突变也可不成比例地影响两个原本相同的病毒长末端重复序列之一，并可通过对连续胞嘧啶进行诱变在病毒基因组底物中产生新的优先靶位点。个体中的编辑对应于两个近交小鼠品系mA3等位基因的不同靶序列偏好，但对该物种野生小鼠的等位基因变异进行检查时发现了另外18种变异和多样化选择的特征，这显示了在短时间框架内单一物种内异常快速的进化。
