Scientists from the University of Nottingham are part of an international group of experts who have used cutting edge genomic technology to predict which koalas are at high risk of getting cancer, based on which retroviruses they inherited in their genes.
The findings of the new study, which are published in Nature Communications, could also be used to predict koala breeding success, which could give experts the tools to select the best animals for captive breeding, which in turn will help with species conservation.
Retroviruses integrate into the host genome when they infect cells. If this happens in the germline, the integrated viruses can be passed on from generation to generation by inheritance rather than relying on infection.
Repeated retroviral infections of vertebrate germlines have made endogenous retroviruses abundant and prominent features of all animal genomes, including humans, though ours are very old and not infectious anymore.
Koalas are at the earliest stages of genome colonisation by the Koala Retrovirus (KoRV) with infectious and germline versions and suffer high cancer prevalence as a result.
Experts at the University of Nottingham worked alongside colleagues at the Leibniz Institute for Zoo and Wildlife Research in collaboration with the San Diego Zoo and Wildlife Alliance (SDZWA), and the biotechnology company Illumina. The team examined large US and European zoo koala pedigrees with matching whole genome sequencing to understand what happens to the virus and the koala individuals over generations.
This has been a really exciting collaboration bringing cutting edge genomic technology and research to a real world use in breeding programmes for endangered wildlife species. We hope to see this work making a big impact on mitigating disease problems in koalas."
A large pedigree of over 100 koalas from SDZWA representing 46 family groups and four koala generations were sequenced by the biotechnology company Illumina. An additional smaller European Zoo pedigree representing nine family groups and three generations were sequenced PacBio sequencing technology.
The genome information was combined with very detailed life history and health information from each koala in the pedigrees. Bioinformatician Guilherme Neumann and colleagues analyzed the data and observed that in one part of the pedigree, animals that had a harmful KoRV integrated into a cancer gene all the family group died of cancer with both the family group and the virus integration dying out.
In some cases, however, KoRVs integrated in genes showed signs of being favorable to koala health such as association with longevity or higher number of offspring. Such KoRVs tended to increase in number over time.
The scientists also observed the spread of new integrations within a single generation. Some offspring had germline integrations that were not found in either parent. This means that a novel germline integration had occurred in the parents cells that produce sperm or eggs and was transmitted to their offspring while the parents lacked the integration in any other cell in their bodies. This new integration could then be passed on to further generations by their offspring. Such rapid generation of new copies of the retrovirus in the genome demonstrates it has not been "tamed" yet like most human endogenous retroviruses and still represents a health risk to koalas.
Such a large dataset with so much associated life history and health data allowed the scientists to produce genetic risk scores (GRS). This means one could examine individual integrations and determine if they were a risk for negative outcomes, positive outcomes or had no effect on koala health at all. In one case, an animal with the highest GRS for developing leukemia died of this while the project was underway emphasizing how the GRS can be used in breeding decisions to reduce disease.
Professor Tarlinton said: "Having a new retrovirus hopping around is not generally very good for genome stability and in koalas we see very high rates of cancers like leukaemia (up to 60% of captive animals and 3% of wild animals die of this). This project allowed us the unique chance to combine the very detailed health and pedigree records from koalas at San Diego zoo and a number of European Institutes with whole genome sequencing from historical tissue archives kept by the zoo (Funded and sequenced by biotech company Illumina's iconserve wildlife charity arm) from multi generation family trees of koalas. This lets us see what is happening to the koalas as the virus enters.
"New KoRV insertions are still accumulating faster than they are lost. A lot appear only once in an individual and are not passed on. Some of the most damaging ones (like one in a known cancer oncogene) are rapidly eliminated from the population as all animals with it die at a young age with leukaemia. When we used the retroviral insertions to calculate genetic risk scores (commonly used in livestock breeding programmes but not yet in wildlife), we could see big risk factors from certain inherited KoRVs for leukaemia and poor fertility, allowing us to develop recommendations for which animals would be most suitable for breeding in this population.
"One insertion that is widespread in many animals appears to have a positive effect (decreasing cancer risk). How this works and whether more insertions like it accumulate with time (gradually controlling the virus) are things we need to understand better, both for the koalas sake and to understand how this fundamental bit of genome evolution works."
The full study can be found here.
