People and all other organisms are constantly involved in an arms race against genetic parasites such as retroviruses and transposons. Research on fruit flies now reveals how host cells make copies of the DNA parasites and smuggle these copies into the genome-defence system. This new knowledge can be used to understand the human genome-defence system and can help researchers learn how to correct malfunctions.
The human genome comprises 3 billion DNA building blocks, of which fewer than 2% are protein-coding genes. Of the remainder, about two thirds are genetic parasites such as retroviruses and transposable elements (transposons) and fragments thereof. In short, our genome is a genetic battlefield that is constantly being invaded by genetic parasites, which are then silenced by the genome-defence system.
“We have now identified some parts of how host cells counter-attack in this evolutionary battle. In 2017, we found the moonshiner gene and its Moonshiner protein in fruit flies that produce the illegal copies. Now we have discovered the bootlegger gene and its Bootlegger protein that disguise the transport of the small copies into the cell. By understanding these mechanisms in model organisms, we can build a knowledge framework that enables us to explore this biology in humans and thereby build a foundation for rectifying aberrations in the genome-defence system,” explains Peter Refsing Andersen, Assistant Professor, Department of Molecular Biology and Genetics, Aarhus University.
Dissecting ovaries from fruit flies
This molecular arms race occurs in virtually all forms of life. A species can die out as a result of massive damage to its DNA if its genome-defence system fails to control the genetic parasites. The host cells therefore have to silence the copying of the genomic parasites. Nevertheless, they need to recognize the genetic sequence of the parasites so they can differentiate between the parasitic genes and the host cell’s normal genes.
"The main weapon of genetic parasites is getting their host to copy their genome. Host cells therefore attempt to silence the copying process through the genome-defence system, which protects their DNA against the uncontrolled proliferation of transposons. However, the genome-defence system must use small copies of these DNA parasites to enable the cell to recognize them."
In 2017, Peter Refsing Andersen and his colleagues published the first landmark finding of the moonshiner gene in Nature. The new discovery is equally spectacular and has been published in Cell.
“In 2017, we discovered an alternative copying mechanism that permits the cell to make small RNA copies of the DNA from the genetic parasites. We have now identified the transport mechanism the cell uses to smuggle the small copies out of the nucleus past its own defence system: a smuggling pathway. This method has many similarities with how HIV evades a host’s defence system.”
The researchers found the new genes and their proteins in the reproductive cells of fruit flies. The reason they searched there is because that is where the genetic parasites attempt to replicate themselves so that they can propagate their new copies to the next generations. It is therefore remarkable that these defence systems have only been found there.
“These experiments are relatively simple in fruit flies, because the ovaries comprise one third of the bodies of females. We followed their journey through the cell by labelling the small RNA copies with fluorescent substances in the ovaries’ reproductive cells. Combined with the analysis of RNA and protein from dissected fruit fly ovaries, we have uncovered the entire molecular pathway that exports the RNA copies of the genetic parasites from the cell nucleus to the cytoplasm, where the genome defence is loaded with the small RNAs that guide it to the parasitic genes.”
Surprisingly rapid development
After the researchers discovered the smuggling pathway, they tried to remove this genetically in the fruit flies. The fruit flies’ reproductive cells became sterile as a result because they had been conquered by the genetic parasites. The researchers use fruit flies as a model because their genome is similar to that of humans, but it is still too early to determine whether the human system is identical.
“We use fruit flies to understand the molecular mechanisms of genetic activity, and although human genes are not completely identical, we have already found the genes that are key in the mechanisms of fruit flies in mice and humans. Since these genes are so similar, we can almost certainly say that the genes exist and that the concepts are conserved in humans.”
Peter Refsing Andersen very much looks forward to discovering even more similarities, as more and more people are genetically sequenced in the coming years. This is the only way we can become much wiser about how the human system functions and the significance of errors in the genome-defence system.
“We also need to learn how to correct these errors when they occur. Our results mainly testify to the constant and rapidly evolving arms race between host genomes, such as the human and its genetic parasites. It is extremely fascinating to discover how we decode each other’s mechanisms and how we have to bypass our own security systems through hacking and smuggling to win the war.”
“A heterochromatin-specific RNA export pathway facilitates piRNA production” has been published in Cell. In 2014, the Novo Nordisk Foundation awarded a postdoctoral fellowship to co-author Peter Refsing Andersen to carry out research abroad on the project Breaking Down the Rules of Transcription in Defence of the Genome. The postdoctoral fellowship involved a 4-year study period mainly at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna. He was recently awarded a Hallas-Møller Emerging Investigator grant of DKK 10 million to establish his own research group at the Department of Molecular Biology and Genetics, Aarhus University to study genetic parasites. Read more about the on-going research in the laboratory of Peter Refsing Andersen here.