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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猴痘基因组与人类APOBEC3酶相互作用产生的进化潜力。
作者：
APOBEC3是一种酶亚家族，通过在特定DNA基序或突变“热点”上产生突变，在病毒限制中发挥作用，可以通过宿主特异性的优先热点突变驱动病毒诱变，从而导致病原体变异。虽然先前对2022年猴痘病暴发的病毒基因组的分析显示，TC基序上C b> T突变的频率很高，这表明最近的突变是人类apobec3介导的，但新出现的猴痘病毒（MPXV）毒株将如何作为apobec3介导的突变的结果进化仍然未知。通过测量热点代表性不足、同义位点的耗竭以及两者的结合，我们分析了apobec3在人类痘病毒基因组中驱动的进化，发现了不同的热点代表性不足模式。虽然本地的传染性软痘病毒表现出与人类APOBEC3广泛共同进化的特征，包括TC热点的枯竭，但天花病毒在根除时表现出与持续进化相一致的中间效应。MPXV可能是最近人畜共患病的结果，显示许多基因具有比预期更多的TC热点（过度代表性）和比预期更少的GC热点（代表性不足）。这些结果表明MPXV基因组：(1)可能在具有特定apbecc GC热点偏好的宿主中进化，(2)具有倒置末端重复（ITR）区域-可能在病毒复制过程中暴露于APOBEC3的时间更长-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诱导进化的潜力更高。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确定假定的药物靶点，也可以增加遏制人类m痘疾病传播和揭示病毒在其宿主中生态的紧迫性。
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.
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影响因子：
82.9
作者：
Isidro, Joana;Borges, Vitor;Pinto, Miguel;Sobral, Daniel;Santos, Joao Dourado;Nunes, Alexandra;Mixao, Veronica;Ferreira, Rita;Santos, Daniela;Duarte, Silvia;Vieira, Luis;Borrego, Maria Jose;Nuncio, Sofia;de Carvalho, Isabel Lopes;Pelerito, Ana;Cordeiro, Rita;Gomes, Joao Paulo
通讯作者：
Gomes, Joao Paulo
影响因子：
5.6
作者：
Lackey, Lela;Demorest, Zachary L.;Land, Allison M.;Hultquist, Judd F.;Brown, William L.;Harris, Reuben S.
通讯作者：
Harris, Reuben S.
影响因子：
5.4
作者：
Koning, Fransje A.;Newman, Edmund N. C.;Malim, Michael H.
通讯作者：
Malim, Michael H.
DOI：
10.3390/v2091933
发表时间：
2010-09
期刊：
Viruses
影响因子：
--
作者：
Hendrickson RC;Wang C;Hatcher EL;Lefkowitz EJ
通讯作者：
Lefkowitz EJ
影响因子：
4.8
作者：
Kremer, Melanie;Suezer, Yasemin;Schnierle, Barbara S.
通讯作者：
Schnierle, Barbara S.