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Koalas are facing multiple ecological and health issues which threaten their survival. Together with habitat loss – accelerated by last year’s devastating bush fires — domestic dog attacks and road accidents, they suffer from fatal chlamydial infections and extremely high frequency of cancer.
The results are reported in the journal Nature Communications.
The koala retrovirus (KoRV) is a virus which, like other retroviruses such as HIV, inserts itself into the DNA of an infected cell. At some stage in the past 50,000 years, KoRV has infected the egg or sperm cells of koalas, leading to offspring that carry the retrovirus in every cell in their body.
The whole koala population of Queensland and New South Wales in Australia now carry copies of KoRV in their genome. All animals, including humans, have gone through similar”germline” infections by retroviruses at some point in their evolutionary history and contain several ancient retroviruses in their genomes.
These retroviruses have, over millions of years, mutated into degraded, inactive forms which are no longer detrimental to the host. Since in most animal species this procedure occurred millions of years ago, the immediate health effects on the host at the time are unknown but it has been suspected for some time that the invasion of a genome by a retrovirus may have considerable detrimental health consequences.
The koala is in a very early stage of this process when the retrovirus remains active and these health effects can be studied.
Since retroviruses can cause cancer, it had been thought that there’s a connection between KoRV and the high frequency of lymphoma, leukaemia and other cancers in koalas from northern Australia. To investigate this link, scientists at the Leibniz-IZW sequenced DNA from wild koalas experiencing cancer.
This allowed them to correctly detect the number of copies of KoRV from the koala genomes and identify the precise locations where the retrovirus had inserted its DNA. By comparing this information between healthy and tumour cells in single koalas, and by comparing insertion sites between koala people, they found multiple links between KoRV and genes known to be involved in the kind of cancers to which koalas are prone.
“Each koala carries around 80 – 100 inherited copies of KoRV in its genome. The genomic locations of most of these are not shared between koalas, indicating a rapid growth and accumulation of KoRV copies in the population. Every time a retrovirus reproduces and re-inserts itself into the genome, it causes a mutation, possibly disrupting gene expression, which might be harmful to the host,” says Prof Alex Greenwood, Head of Department of Wildlife Diseases at the Leibniz-IZW.
This means that by copying itself to new locations in the genome, KoRV is now conferring a high mutational load on the koala population. Tumour tissues contain several new copies of KoRV, indicating that KoRV is significantly more active in tumour cells.
These copies generally were found close to genes related to cancer. New KoRV insertions in tumour cells affected the expression of genes within their area. These changes in gene expression associated with cancer can cause increased cell growth and proliferation, which leads to tumours.
Although other factors may also lead to cancer in koalas, the mutational burden from KoRV likely increases the frequency of cells becoming cancerous and may shorten the time for cancer to develop.
In one koala, a replica of KoRV was discovered that had incorporated an entire cancer-related gene in the koala genome to its DNA sequence. This considerably increased the expression of the gene and probably caused cancer in this specific koala.
If this mutated virus is transmissible, it would be of grave concern for koala conservation efforts. Comparing the genomic location of KoRVs between koalas also suggests that KoRV may predispose related koalas to particular tumours, with koalas sharing KoRV insertions in particular cancer-related genes experiencing similar types of cancer that they can pass on to their offspring.
Across all koalas examined, there were”hot spots” in the genome where KoRV frequently matches itself. These hot spots were also found in proximity to genes related to cancer.
In summary then, we find multiple links at the genomic level between cancer-related genes and KoRV, revealing ways in which KoRV underlies the high frequency of cancer in koalas.”
Gayle McEwen, Scientist, Leibniz Institute for Zoo and Wildlife Research (IZW)
The results highlight the detrimental health consequences that wildlife species can suffer after germline infection by retroviruses.
Germline invasions have been experienced during vertebrate evolution and have formed vertebrate genomes, including the lineage leading to modern humans. These were probably associated with acute detrimental health effects, which must be endured and overcome to ensure species survival.
The scientists in the Leibniz-IZW have previously demonstrated that old retroviruses present in the koala genome assist the rapid degradation of KoRV. Considering the numerous threats to koalas, it’s a race they will need to win.
Leibniz Institute for Zoo and Wildlife Research (IZW)
McEwen, G. K., et al. (2021) Retroviral integrations contribute to elevated host cancer rates during germline invasion. Nature Communications. doi.org/10.1038/s41467-021-21612-7.
