Felez-Sanchez, M. | bioRxiv Science

bioRxiv2018

Genome plasticity in Papillomaviruses and de novo emergence of E5 oncogenes

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 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 non-coding 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 humans. 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 non-coding 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, and that display 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.

evolutionary biology↗

bioRxiv2017

Macroecology suggests cancer-causing papillomaviruses form non-neutral communities

Chronic infection by oncogenic Human papillomaviruses (HPVs) leads to cancers. Public health interventions, such as cancer screening and mass vaccination, radically change the ecological conditions encountered by circulating viruses. It is currently unclear how HPVs communities may respond to these environmental changes, because little is known about their ecology. Predicting the impact on viral diversity by the introduction of HPV vaccines requires answering the unresolved question of how HPVs interact. Although it is commonly believed that they do not interact (neutral theory), there are suggestions that HPV types may compete for resources or via the immune response (niche-based or non-neutral theory). Here, we applied for the first time established biodiversity measures and methods to epidemiological data in order to assess whether niche-partitioning or neutral processes are shaping HPV diversity patterns at the population level. We find that as infections progress toward cancer, HPVs communities become more uneven and a few HPVs play a stronger dominance role. By fitting species abundance distributions, we found that neutral models were always out-performed by non-neutral distributions, both in asymptomatic infections and in cancers. Our results suggest that temporally moving from a more even to a less even community implies an increase in competition, probably due to environmental changes linked to infection progression. More ecological thinking will be required to understand present-day interactions and to anticipate the future of the long lasting interactions between HPVs and humans.\n\nSIGNIFICANCE STATEMENTHuman papillomaviruses (HPVs) are very diverse. Infections by HPVs are very common and chronic infections may lead to cancers. The more oncogenic HPVs are now targetted by effective vaccines, and this has raised the question of whether there may be a viral replacement if these dominant types were removed. This is a medical version of a classical ecological controversy, namely how much biodiversity distributions and community dynamics are explained by neutral theory plays out across ecosystems. For HPVs, epidemiologic studies before and after the vaccination have led to the widespread belief that these viruses do not interact. Here, we apply different methods developed in macroecology to the best available epidemiologic data to address this issue. Consistently, we find that HPVs form non-neutral communities. Instead, competitive niche-partitioning process and dominance explain best HPVs communities. We also find that the vaccine might not change such competitive niche processes. Beyond clinical implications, this garners support that niche processes often best explain biodiversity patterns, even in human viral communities.

ecology↗