Origin and evolution of papillomavirus (onco)genes and genomes

Abstract

Papillomaviruses (PVs) are ancient viruses infecting vertebrates, from fish to mammals. Although the genomes of PVs are small and show conserved synteny, PVs display large genotypic diversity and ample variation in the phenotypic presentation of the infection. Most PVs genomes contain two small early genes E6 and E7. In a bunch of closely related human PVs, the E6 and E7 proteins provide the viruses with oncogenic potential. The recent discoveries of PVs without E6 and E7 in different fish species place a new root on the PV tree, and suggest that the ancestral PV consisted of the minimal PV backbone E1-E2-L2-L1. Bayesian phylogenetic analyses date the most recent common ancestor of the PV backbone to 424 million years ago (Ma). Common ancestry tests on extant E6 and E7 genes indicate that they share respectively a common ancestor dating back to at least 184 Ma. In AlphaPVs infecting primates, the appearance of the E5 oncogene 53-58 Ma concurred with i) a significant increase in substitution rate, ii) a basal radiation, and iii) key gain of functions in E6 and E7. This series of events was instrumental to build the extant phenotype of oncogenic human PVs. Our results assemble the current knowledge on PV diversity and present an ancient evolutionary timeline punctuated by evolutionary innovations in the history of this successful viral family.

Ecological opportunity, radiation events and genomic innovations shaped the episodic evolutionary history of papillomaviruses

“…Regarding the evolution of substitution rates, it does not seem that PV evolution has reached an evolutionary stasis, as the PV substitution rates still vary after more than 400 million years of virus-host co-evolution (Supplementary File 1). Episodic and rare events eventually triggering an elevated substitution rate such as host jumps, switch of tissue tropism (Van Doorslaer et al, 2015; Willemsen & Bravo, 2019) and gene gain/loss events (Van Doorslaer & McBride, 2016; Willemsen et al, 2019) might prevent PVs from reaching an evolutionary stasis with their hosts, thus maintaining recent increased substitution rates.…”

“…This discovery challenged our perspective on the origin of this viral family. Phylogenetic dating studies including this single fish PV genome date back the time to the most recent common ancestor (tmrca) of PVs to 481 (95% HPD: 326─656; Van Doorslaer, Ruoppolo, et al, 2017) and 424 million years ago (95% HPD: 402─446; Willemsen & Bravo, 2019), and thus more ancient than previously thought.…”

“…Proteins in the early region are involved in viral replication and cell transformation, while the capsid proteins self assemble to yield virions and encapsidate the genome. During PV evolution, at different time points and in different linages, the viral genomes have acquired, and in cases subsequently lost, the E5 , E6 and E7 oncogenes (Van Doorslaer & McBride, 2016; Willemsen et al, 2019; Willemsen & Bravo, 2019). In chronic infections by certain viruses and in certain hosts, these genes are directly involved in the onset of cancer and behave thus as oncogenes.…”

The oncogenic pathways of papillomaviruses

“…Moreover, it is considered that the E5 oncogene has been present for 53 to 58 million years in Alphapapillomaviruses , which infecting “Old World” monkeys and apes. In light of these recent findings, it has been suggested that these interrelated events led to oncogenic high‐risk (HR) HPVs 31 …”

Modelling the evolution of viral oncogenesis

“…Human oncoviruses are not monophyletic which implies that oncogenic traits evolved separately in a case of convergent evolution. Even in the case of HPVs, the two types responsible for the majority of cancers globally, HPV16 and HPV18, belong to different HPV species and the other genotypes in their species are significantly less oncogenic [4,35]. Oncoviruses can be classified based on their genetic make up and replication modes.…”