Evolutionary potential of the monkeypox genome arising from interactions with human APOBEC3 enzymes.
Evolutionary potential of the monkeypox genome arising from interactions with human APOBEC3 enzymes.
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猴痘基因组因与人类 APOBEC3 酶相互作用而产生的进化潜力。
DOI：
10.1101/2023.06.27.546779
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
MacCarthy,Thomas
中科院分区：
文献类型：
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作者：
Delamonica,Brenda;Davalos,Liliana;Larijani,Mani;Anthony,SimonJ;Liu,Jia;MacCarthy,Thomas
APOBEC3 是一种酶亚家族，通过在特定 DNA 基序或突变“热点”处产生突变而在病毒限制中发挥作用，它可以通过导致病原体变异的宿主特异性优先热点突变来驱动病毒诱变。虽然之前对 2022 年 Mpox（以前称为猴痘）疾病爆发的病毒基因组分析显示，TC 基序上存在高频率的 C>T 突变，表明最近的突变是人类 APOBEC3 介导的，但新出现的猴痘病毒 (MPXV) 毒株将如何因 APOBEC3 介导的突变而进化仍然未知。通过测量热点代表性不足、同义位点的缺失以及两者的组合，我们分析了人类痘病毒基因组中 APOBEC3 驱动的进化，发现了不同的热点代表性不足模式。虽然天然传染性痘病毒表现出与人类 APOBEC3 广泛共同进化一致的特征，包括 TC 热点的消耗，但天花病毒表现出与根除时正在进行的进化一致的中间效应。 MPXV，可能是最近人畜共患病的结果，显示许多基因的 TC 热点比预期多（过度代表性），而 GC 热点比预期少（代表性不足）。这些结果表明MPXV基因组：（1）可能在具有特定APOBEC GC热点偏好的宿主中进化，（2）具有反向末端重复（ITR）区域——在病毒复制过程中可能更长时间地暴露于APOBEC3——并且更长的基因可能进化得更快，因此（3）随着病毒在人群中传播，未来人类APOBEC3介导的进化的潜力更大。我们对 MPXV 突变潜力的预测既可以帮助指导未来的疫苗开发和假定药物靶点的识别，也可以增加遏制人类 Mpox 疾病传播和揭示病毒在其储存宿主中的生态学的任务的紧迫性。
APOBEC3, an enzyme subfamily that plays a role in virus restriction by generating mutations at particular DNA motifs or mutational ‘hotspots’, can drive viral mutagenesis with host-specific preferential hotspot mutations contributing to pathogen variation. While previous analysis of viral genomes from the 2022 Mpox (formerly Monkeypox) disease outbreak has shown a high frequency of C>T mutations at TC motifs, suggesting recent mutations are human APOBEC3-mediated, how emerging monkeypox virus (MPXV) strains will evolve as a consequence of APOBEC3-mediated mutations remains unknown. By measuring hotspot under-representation, depletion at synonymous sites, and a combination of the two, we analyzed APOBEC3-driven evolution in human poxvirus genomes, finding varying hotspot under-representation patterns. While the native poxvirus molluscum contagiosum exhibits a signature consistent with extensive coevolution with human APOBEC3, including depletion of TC hotspots, variola virus shows an intermediate effect consistent with ongoing evolution at the time of eradication. MPXV, likely the result of recent zoonosis, showed many genes with more TC hotspots than expected by chance (over-representation) and fewer GC hotspots than expected (under-representation). These results suggest the MPXV genome: (1) may have evolved in a host with a particular APOBEC GC hotspot preference, (2) has inverted terminal repeat (ITR) regions—which may be exposed to APOBEC3 for longer during viral replication—and longer genes likely to evolve faster, and therefore (3) has a heightened potential for future human APOBEC3-meditated evolution as the virus spreads in the human population. Our predictions of MPXV mutational potential can both help guide future vaccine development and identification of putative drug targets and add urgency to the task of containing human Mpox disease transmission and uncovering the ecology of the virus in its reservoir host.