Papillomaviruses (PVs) have a wide host range, infecting mammals, birds, turtles, snakes and fish. Certain PVs are a major public health concern as in humans they are responsible for virtually all cases of cervical cancer, and for a fraction of cancers on the anus, penis, vagina, vulva and oropharynx. But oncogenic PVs are actually an unfortunate exception, as most PVs cause asymptomatic infections, and a few cause benign, wart-like lesions. Despite the efforts directed towards the understanding of the different clinical manifestations of infection, our knowledge on PV evolution remains fragmentary. A better understanding of the evolutionary history of PVs will expand our current knowledge on the origin of these viruses and on the evolutionary changes that make these viruses oncogenic.
The main aim of this project was to better understand the factors that differentiate between oncogenic and non-oncogenic PVs. To investigate this, we have combined computational and experimental methods to study specific events that occurred during PV genome evolution. In WP1 the goal was to resurrect the ancestral oncogenes and experimentally test hypotheses about the function of the ancestral proteins in different environmental contexts. In WP2 the goal was to computationally generate comprehensive scenario of all the events that led to the PV genomes that we observe today, such as the emergence of the viral oncogenes. We further investigated how the presence of these oncogenes is linked to the phenotype we observe. In WP3 the goal was to explore the evolutionary origin of PVs and test whether they share a common ancestor with other closely related viruses.
Here, we conclude that ancestral PVs existed already 430 million years ago. Moreover, we inferred that the ancestral PV genome did not contain any of the oncogenes (E5, E6 and E7) and thus these were acquired later during PV evolution. The E6 and E7 oncogenes, that are present in most PV genomes we observe today, appear to have evolved from a common ancestor. The E5 oncogene, that is present in only a few PV genomes, does not appear to have evolved from a common ancestor, and thus evolved independently multiple times. The mechanism that best explains the independent origin is de novo gene evolution in a long non-coding region in the PV genome. As little is known about the functions of E5, we have shown that E5 displays the properties of a genuine gene. In addition, the role of E5 in the differential oncogenic potential of human PVs is supported by the sharp match between the type of E5 protein encoded in the PV genome and the infection phenotype we observe. Our results compile the current knowledge on PV diversity and present an ancient evolutionary timeline punctuated by evolutionary innovations in the history of this successful viral family.
