Laboratory MIVEGEC (UMR CNRS IRD Uni Montpellier), Centre National de la Recherche Scientique (CNRS), Montpellier, France.
Infections and Cancer Laboratory, Catalan Institute of Oncology (ICO), Barcelona, Spain.
Genome Biol Evol. 2019 Jun 1;11(6):1602-1617. doi: 10.1093/gbe/evz095.
The clinical presentations of papillomavirus (PV) infections come in many different flavors. While most PVs are part of a healthy skin microbiota and are not associated to physical lesions, other PVs cause benign lesions, and only a handful of PVs are associated to malignant transformations linked to the specific activities of the E5, E6, and E7 oncogenes. The functions and origin of E5 remain to be elucidated. These E5 open reading frames (ORFs) are present in the genomes of a few polyphyletic PV lineages, located between the early and the late viral gene cassettes. We have computationally assessed whether these E5 ORFs have a common origin and whether they display the properties of a genuine gene. Our results suggest that during the evolution of Papillomaviridae, at least four events lead to the presence of a long noncoding DNA stretch between the E2 and the L2 genes. In three of these events, the novel regions evolved coding capacity, becoming the extant E5 ORFs. We then focused on the evolution of the E5 genes in AlphaPVs infecting primates. The sharp match between the type of E5 protein encoded in AlphaPVs and the infection phenotype (cutaneous warts, genital warts, or anogenital cancers) supports the role of E5 in the differential oncogenic potential of these PVs. In our analyses, the best-supported scenario is that the five types of extant E5 proteins within the AlphaPV genomes may not have a common ancestor. However, the chemical similarities between E5s regarding amino acid composition prevent us from confidently rejecting the model of a common origin. Our evolutionary interpretation is that an originally noncoding region entered the genome of the ancestral AlphaPVs. This genetic novelty allowed to explore novel transcription potential, triggering an adaptive radiation that yielded three main viral lineages encoding for different E5 proteins, displaying distinct infection phenotypes. Overall, our results provide an evolutionary scenario for the de novo emergence of viral genes and illustrate the impact of such genotypic novelty in the phenotypic diversity of the viral infections.
人乳头瘤病毒 (PV) 的临床表现多种多样。虽然大多数 PV 是健康皮肤微生物群的一部分，与身体损伤无关，但其他 PV 会引起良性病变，只有少数 PV 与特定的 E5、E6 和 E7 癌基因的恶性转化有关。E5 的功能和起源仍有待阐明。这些 E5 开放阅读框 (ORF) 存在于少数多系 PV 谱系的基因组中，位于早期和晚期病毒基因盒之间。我们通过计算评估了这些 E5 ORF 是否具有共同的起源，以及它们是否具有真正基因的特性。我们的结果表明，在乳头瘤病毒科的进化过程中，至少有四个事件导致 E2 和 L2 基因之间存在长的非编码 DNA 片段。在这三个事件中，新的区域进化出了编码能力，成为现存的 E5 ORF。然后，我们专注于感染灵长类动物的α型 PV 中 E5 基因的进化。α型 PV 编码的 E5 蛋白类型与感染表型（皮肤疣、生殖器疣或肛门生殖器癌）之间的强烈匹配，支持 E5 在这些 PV 不同致癌潜力中的作用。在我们的分析中，最支持的情况是，α型 PV 基因组中现存的 5 种 E5 蛋白可能没有共同的祖先。然而，E5 在氨基酸组成方面的化学相似性使我们无法自信地拒绝共同起源的模型。我们的进化解释是，一个原本非编码的区域进入了祖先α型 PV 的基因组。这种遗传新颖性允许探索新的转录潜力，引发适应性辐射，产生了三种主要的病毒谱系，编码不同的 E5 蛋白，显示出不同的感染表型。总的来说，我们的结果提供了一个病毒基因从头出现的进化情景，并说明了这种基因型新颖性对病毒感染表型多样性的影响。
