Adaptive defenses against malicious jumping genes

The word mutation can mean different things in different situations. Putting aside for a second the image you might have of superheroes or monsters, in the real world, mutations are simply changes in the genes of an organism. These can happen as an organism reproduces offspring, and when these mutations lead to a slightly modified trait that improves the offspring's chances of survival, the trait will spread within the population. But mutations are often harmful and lead to diseases, including cancer.

While there are many things which cause mutations, something that caught the attention of Professor Yukihide Tomari from the University of Tokyo's Institute for Quantitative Biosciences are so-called jumping genes, technically known as transposons or transposable elements (TEs). These can spontaneously insert themselves into random locations along the genome, causing disruptions. Help is at hand, however, as organisms, including silkworms, mice, and even humans, can silence jumping genes by producing countermeasures called PIWI-interacting ribonucleic acid (piRNA). The way these are made however seems overly complex and the reason for their widespread conservation across species remains unclear, but Tomari and his team decided to pick this apart and discovered what is going on.

"PIWI-interacting RNAs not only silence TEs but are also amplified during the silencing process," said Tomari. "How this occurs is when piRNA targets and cuts up the TE, it also creates new piRNA from the cut-up fragments, essentially reproducing. This process is called the ping-pong pathway, and it ensures a set of protective piRNAs is robustly maintained."

But there's more going on than just amplification of the piRNA when it comes to combating jumping genes. As, like many things in biology, jumping genes can change over time.

"By comparing the genes from different generations of silkworm-derived cultured cells, we found that the sites on TEs the piRNAs attack are not fixed, but fluctuate over time," said Tomari. "This means that there is a kind of competition between these sites, when one site becomes inefficient, neighboring sites can emerge and replace it, potentially improving overall efficiency. In other words, piRNA rapidly catches up with any changes in the TEs, keeping them subdued. This unique property of piRNA was confirmed not only in silkworms but also in flies and mice."

The team discovered this not by a meticulously planned strategy, but almost by chance due to the lockdowns during the pandemic, when it wasn't possible to carry on experimental work as usual. Instead, during that time, they explored some old data on silkworm piRNAs, which led to them making comparisons with current data, and that in turn resulted in their unexpected discovery. Their next steps in this area include seeing how this newly discovered mechanism might work over multiple generations in living organisms. While still early days, their findings could help medical researchers, especially since piRNA malfunctions have been linked to conditions such as human male infertility, opening the door to potential diagnostic and therapeutic strategies against unwanted genetic mutations.