Examination of retroviruses within the Queensland koala population has revealed how they integrate and rewrite the koala genome, ultimately resulting in cancer.
Retroviruses and the koala
Retrovirus-like elements are highly abundant in vertebrate genomes, comprising 8% of the human genome. They originate from exogenous retroviruses that infect the host germline and are subsequently inherited by offspring as endogenous retroviruses (ERVs). Most mammalian ERVs are derived from germline infections that occurred millions of years ago. Therefore, our understanding of the immediate effects on host health are unclear.
Retroviruses are insertional mutagens. They can impact the host in a number of deleterious ways, including disrupting or altering gene expression. As a result, a general consequence of ongoing germline invasion is predicted to be increased host cancer rates. However, this has not yet been directly observed in outbred wild species.
The koala (Phascolarctos cinereus) enables researchers to study the early stages of retroviral endogenisation in a wild, outbred, large-bodied mammal. Currently, koalas are undergoing active germline invasion, a process which likely began in the last 50,000 years. This means that the retrovirus is still active, allowing health effects to be studied. The koala retrovirus (KoRV-A) is endogenous in all koalas from northern Australia. KoRV is a member of a retroviral lineage associated with lymphoma and leukaemia. Both of these cancers occur at high prevalence in koalas.
Host cancer rates
In this study, published in Nature Communications, researchers examined retroviral endogenisation during its earliest stages in the koala. They characterised KoRV integration sites in tumours and health tissues from 10 koalas.
The team showed that northern koalas harbour ~80-100 inherited proviral copies in their germlines. None of these copies were found to be fixed across the population and few were shared between koalas. Shared insertion sites corresponded to geographical proximity. This indicated a rapid expansion and accumulation of KoRV copies in the population. They specifically found 1,002 unique insertion sites, with hotspots in the vicinity of known cancer genes. In addition, they found that tumours accumulated novel insertion sites, with proximate genes overrepresented for cancer associations. In one koala, they detected a KoRV provirus that had transduced a host oncogene, with the oncogene displaying markedly increased expression. It can be inferred that the high mutational burden from KoRV is likely to increase the frequency of cells becoming cancerous and shorten the time for cancers to develop.
This study demonstrates multiple links at the genomic level between cancer-related genes and KoRV. The results highlight the detrimental consequences that wildlife species can suffer following germline infection. These consequences have shaped vertebrate genomes and have been repeatedly experienced during vertebrate evolution. However, the team noted that the immediate health effects on a species, including increased cancer rates, must first be endured and overcome.
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