Scheme: University Research Fellowship
Organisation: University of Oxford
Dates: Oct 2015-Sep 2018
Summary: Animal genomes contain the remnants of ancient viruses, known as endogenous viral elements (EVEs). These EVEs form a genomic ‘fossil record’ that can be used to reconstruct viral evolution, a field of research known as paleovirology. My work revealed that all known viral types exist as EVEs, extending the scope of paleovirology from retroviruses to all viruses. By looking back into the distant past through this record, I aim to better understand the viruses that infect animals in the present day.
The genomic fossil record has revealed that many viruses and their hosts have been engaged in evolutionary conflict that has spanned >100 million years. EVEs provide a crucial window into events that have long since passed. Some EVEs are stolen by the host and put to use as ‘domesticated’ viral genes to combat other incoming viruses. Conversely, viruses themselves can steal host genes and use them against their host. Thus, EVEs can be used to study the imprints of this ancient conflict, but can also be directly studied as active participants. The overarching aim of this project is to determine the role and nature of gene flow between viruses and their hosts, locked in an evolutionary arms race played out over millions of years. By understanding this evolutionary arms race, we will be better placed to design preventative and therapeutic strategies.
As viruses insert into the genome, they can disrupt the functions of the cell and can lead to cancer. I have shown that mammalian body size limits the number of endogenous retroviruses that an animal can carry, with larger organisms having fewer viruses. I proposed that this is because the risk that integrated viruses could lead to cancer should scale with the number of cells in an organism. I will determine whether the tumorigenic risk of viral integration has led to the evolution of mechanisms that control viral activity. This work could provide insights into cancer susceptibility.
Dates: Oct 2010-Sep 2015
Summary: Retroviruses are a group of viruses that infect the genomes of their hosts, and are
responsible for a wide range of diseases, most notably HIV/AIDS. In common with
other RNA viruses, retroviral evolution occurs very rapidly. This property has
greatly facilitated studies into the recent evolutionary biology of retroviruses, such
as dating the origin of the viruses responsible for the HIV pandemic. The rapid
rate of evolution of retroviruses has at the same time obscured their more distant
history due to the erosion of the evolutionary signal in viral genomes of events that
have occurred millions of years ago.
Retroviruses are unusual among mico-organisms in possessing a rich ‘fossil
record’, somewhat analogous to the palaeontological fossil record, resulting from
the integration of the viral genome into the DNA of the host. Occasionally, this
integration occurs in the reproductive tissue of the host, and the virus is
transmitted to the offspring. These inherited viruses are known as endogenous
retroviruses (ERVs), and can yield unique information about the evolution of
retroviruses that could not be obtained using contemporary sequence data. Once
in the genome, ERVs can copy themselves to other locations; ~5% of the human
genome is derived from ERVs, far more than codes for proteins (around 1%).
My research combines evolutionary biology, mathematical modelling, in vitro
experimental tests and sequencing, in order to answer fundamental questions
regarding retroviral biology. I aim to understand both the evolutionary dynamics of
ERVs within genomes, as well as the macroevolutionary processes that govern
retroviral evolution in general. Answering these questions will provide a valuable
tool for predicting the outcome of infection, and identifying potential sources of
future emerging infections. Furthermore, an understanding of the role of
retroviruses in shaping the host immune response could help guide future
treatments to retroviral infection.