Role of APOBEC3 in genetic diversity among endogenous murine leukemia viruses.
Role of APOBEC3 in genetic diversity among endogenous murine leukemia viruses.
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DOI：
10.1371/journal.pgen.0030183
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发表时间：
2007-10
期刊：
影响因子：
4.5
通讯作者：
Coffin JM
中科院分区：
文献类型：
--
作者：
Jern P;Stoye JP;Coffin JM
人和鼠APOBEC（特别是APOBEC 3）抑制感染逆转录病毒和某些移动的元件逆转录转座的能力正在建立。不太清楚的是它们对人类和小鼠基因组中内源性前病毒建立的影响。我们使用小鼠基因组序列来研究非嗜性小鼠白血病病毒（多嗜性[Pmv]、修饰的多嗜性[Mpmv]和异嗜性[Xmv]亚组）的多样性和遗传特征，这些病毒是最近整合的最具特征的大型前病毒。我们发现了49个前病毒。在系统发育分析中，Pmvs和Mpmvs是单系的，而Xmvs分为几个分支，这意味着更多的复制周期之间的整合事件。四种不同的引物结合位点类型（Pro，Gln 1，Gln 2和Thr）分散在同源性内，表明频繁的错误引发。我们分析了G-to-A突变的频率和背景，以了解mA 3在这些前病毒形成中的作用。在Pmv和Mpmv（而不是Xmv）组中，归因于mA 3的突变占总数的很大一部分。大量的无义突变表明突变后不存在纯化选择。相对于C至T的变化，观察到G至A的强偏倚，这意味着只能在整合之前发生的链特异性。G-to-A突变的最佳序列背景TTC与mA 3一致。至少在Pmv组中，G-to-A突变的显著5′至3′梯度与mA 3编辑一致。总而言之，我们的结果首次表明，在整合事件之前立即编辑mA 3，导致逆转录病毒内源化，从而导致感染性失活。脊椎动物的基因组中充满了早期逆转录病毒感染的残留物，以内源性逆转录病毒（ERV）的形式存在。先前已经描述了针对逆转录病毒的细胞宿主防御，包括胞苷脱氨酶的APOBEC 3家族。已显示APOBEC 3蛋白在其复制期间通过在负链合成期间将C脱氨为U来编辑一些逆转录病毒和其他逆转录转座元件，从而导致有义链中的G至A突变。在这里，我们研究了APOBEC蛋白家族在建立ERVs中可能产生的影响。我们确定了49个内源性（nonecotropic）小鼠白血病病毒，分为三组：嗜多性，修改的嗜多性，异嗜性，在测序的C57 BL/6 J小鼠基因组。我们分析了亚组内和亚组之间的遗传变异，发现突变模式与Pmv和Mpmv的APOBEC 3编辑一致，但与Xmv前病毒不一致。证据如（i）与对照相比显著更高的G至A突变频率和导致失活终止突变的大部分，（ii）突变位置周围的最佳序列环境，和（iii）逆转录病毒复制时程后的编辑梯度，暗示APOBEC 3是促成小鼠基因组中这些ERV失活的因素。
The ability of human and murine APOBECs (specifically, APOBEC3) to inhibit infecting retroviruses and retrotransposition of some mobile elements is becoming established. Less clear is the effect that they have had on the establishment of the endogenous proviruses resident in the human and mouse genomes. We used the mouse genome sequence to study diversity and genetic traits of nonecotropic murine leukemia viruses (polytropic [Pmv], modified polytropic [Mpmv], and xenotropic [Xmv] subgroups), the best-characterized large set of recently integrated proviruses. We identified 49 proviruses. In phylogenetic analyses, Pmvs and Mpmvs were monophyletic, whereas Xmvs were divided into several clades, implying a greater number of replication cycles between the integration events. Four distinct primer binding site types (Pro, Gln1, Gln2 and Thr) were dispersed within the phylogeny, indicating frequent mispriming. We analyzed the frequency and context of G-to-A mutations for the role of mA3 in formation of these proviruses. In the Pmv and Mpmv (but not Xmv) groups, mutations attributable to mA3 constituted a large fraction of the total. A significant number of nonsense mutations suggests the absence of purifying selection following mutation. A strong bias of G-to-A relative to C-to-T changes was seen, implying a strand specificity that can only have occurred prior to integration. The optimal sequence context of G-to-A mutations, TTC, was consistent with mA3. At least in the Pmv group, a significant 5′ to 3′ gradient of G-to-A mutations was consistent with mA3 editing. Altogether, our results for the first time suggest mA3 editing immediately preceding the integration event that led to retroviral endogenization, contributing to inactivation of infectivity. Vertebrate genomes are littered with remnants from earlier retroviral infections, in the form of endogenous retroviruses (ERVs). Cellular host defenses against retroviruses, including the APOBEC3 family of cytidine deaminases, have been described previously. APOBEC3 proteins have been shown to edit some retroviruses and other retrotransposing elements during their replication by deamination of C to U during negative-strand synthesis, resulting in G-to-A mutations in the sense strand. Here, we studied the possible effects that the APOBEC-protein family might have had in the establishing ERVs. We identified 49 endogenous (nonecotropic) murine leukemia viruses, divided into three groups; polytropic, modified polytropic, and xenotropic, in the sequenced C57BL/6J mouse genome. We analyzed genetic variation within and among subgroups and found mutation patterns consistent with APOBEC3 editing of Pmv and Mpmv, but not Xmv proviruses. Evidence such as (i) significantly higher G-to-A mutation frequencies compared to controls and large fractions leading to inactivating stop mutations, (ii) optimal sequence contexts surrounding the mutation positions, and (iii) editing gradient following the time course of retroviral replication, implicate APOBEC3 as a factor contributing to inactivation of these ERVs in the mouse genome.
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作者：
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