Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
J Virol. 2021 May 24;95(12). doi: 10.1128/JVI.00144-21.
APOBEC3 proteins play pivotal roles in defenses against retroviruses, including HIV-1, as well as retrotransposons. Presumably due to the evolutionary arms race between the hosts and retroelements, APOBEC3 genes have rapidly evolved in primate lineages through sequence diversification, gene amplification and loss, and gene fusion. Consequently, modern primates possess a unique set or "repertoire" of APOBEC3 genes. The APOBEC3 gene repertoire of humans has been well investigated. There are three types of catalytic domains (Z domain; A3Z1, A3Z2, and A3Z3), 11 Z domains, and 7 independent genes, including 4 genes encoding double Z domains. However, the APOBEC3 gene repertoires of nonhuman primates remain largely unclear. Here, we characterize APOBEC3 gene repertoires among primates and investigated the evolutionary scenario of primate APOBEC3 genes using phylogenetic and comparative genomics approaches. In the 21 primate species investigated, we identified 145 APOBEC3 genes, including 69 double-domain type APOBEC3 genes. We further estimated the ages of the respective APOBEC3 genes and revealed that APOBEC3B, APOBEC3D, and APOBEC3F are the youngest in humans and were generated in the common ancestor of Catarrhini. Notably, invasion of the LINE1 retrotransposon peaked during the same period as the generation of these youngest APOBEC3 genes, implying that LINE1 invasion was one of the driving forces of the generation of these genes. Moreover, we found evidence suggesting that sequence diversification by gene conversions among APOBEC3 paralogs occurred in multiple primate lineages. Together, our analyses reveal the hidden diversity and the complicated evolutionary scenario of APOBEC3 genes in primates. In terms of virus-host interactions and coevolution, the APOBEC3 gene family is one of the most important subjects in the field of retrovirology. APOBEC3 genes are composed of a repertoire of subclasses based on sequence similarity, and a paper by LaRue et al. provides the standard guideline for the nomenclature and genomic architecture of APOBEC3 genes. However, it has been more than 10 years since this publication, and new information, including RefSeq, which we used in this study, is accumulating. Based on accumulating knowledge, APOBEC3 genes, particularly those of primates, should be refined and reannotated. This study updates knowledge of primate APOBEC3 genes and their genomic architectures. We further inferred the evolutionary scenario of primate APOBEC3 genes and the potential driving forces of APOBEC3 gene evolution. This study will be a landmark for the elucidation of the multiple aspects of APOBEC3 family genes in the future.
APOBEC3 蛋白在防御逆转录病毒（包括 HIV-1）和逆转座子方面发挥着关键作用。由于宿主和逆转录元件之间的进化军备竞赛，APOBEC3 基因在灵长类动物的进化过程中通过序列多样化、基因扩增和缺失以及基因融合而迅速进化。因此，现代灵长类动物拥有独特的 APOBEC3 基因集或“库”。人类的 APOBEC3 基因库已经得到了很好的研究。有三种催化结构域（Z 结构域；A3Z1、A3Z2 和 A3Z3），11 个 Z 结构域和 7 个独立基因，包括 4 个编码双 Z 结构域的基因。然而，非人类灵长类动物的 APOBEC3 基因库在很大程度上仍不清楚。在这里，我们描述了灵长类动物中的 APOBEC3 基因库，并使用系统发育和比较基因组学方法研究了灵长类动物 APOBEC3 基因的进化情况。在所研究的 21 种灵长类动物中，我们鉴定了 145 个 APOBEC3 基因，包括 69 个双结构域 APOBEC3 基因。我们进一步估计了各自 APOBEC3 基因的年龄，并揭示 APOBEC3B、APOBEC3D 和 APOBEC3F 在人类中是最年轻的，并且是在灵长类动物的共同祖先中产生的。值得注意的是，LINE1 逆转座子的入侵在这些最年轻的 APOBEC3 基因产生的同期达到顶峰，这表明 LINE1 入侵是这些基因产生的驱动力之一。此外，我们发现了一些证据，表明 APOBEC3 基因的序列在多个灵长类动物谱系中通过基因转换发生多样化。总之，我们的分析揭示了灵长类动物 APOBEC3 基因的隐藏多样性和复杂的进化情况。在病毒-宿主相互作用和共同进化方面，APOBEC3 基因家族是逆转录病毒学领域最重要的课题之一。APOBEC3 基因根据序列相似性由一系列亚类组成，LaRue 等人的一篇论文为 APOBEC3 基因的命名和基因组结构提供了标准指南。然而，自该出版物发表以来已经过去了 10 多年，包括我们在本研究中使用的 RefSeq 在内的新信息正在不断积累。基于不断积累的知识，APOBEC3 基因，特别是灵长类动物的 APOBEC3 基因，应该得到细化和重新注释。本研究更新了灵长类动物 APOBEC3 基因及其基因组结构的知识。我们进一步推断了灵长类动物 APOBEC3 基因的进化情况以及 APOBEC3 基因进化的潜在驱动力。这项研究将成为未来阐明 APOBEC3 家族基因多个方面的一个里程碑。
