A number of bacteria that infect insects have a simple and brutal way of increasing their transmission: they kill all the male offspring of the females they infect. There’s actually some evolutionary logic to this. The bacteria can be transferred to the eggs of the females they infect, but cannot be carried along on the sperm. That makes the male offspring a problem: they can’t spread the bacteria any further and they start competing with the females for food. It’s better to kill them then, just to make sure that never becomes a problem.
But it’s one thing to have something that is conceptually a good idea and quite another to develop an implementation that gets the job done. How exactly do you go about killing one sex while leaving the other untouched?
Thanks to a happy coincidence, two Swiss researchers (Toshiyuki Harumoto and Bruno Lemaitre) have identified the gene that allows one species of bacteria to kill males. While we don’t have all the details, it’s clear that the system takes advantage of something male flies have to do to cope with the fact that they only have a single copy of the X chromosome.
Accidents will happen
How do you accidentally make a discovery? Harumoto and Lemaitre studied a bacterium called Spiroplasma poulsonii, which lives in flies, is transmitted through eggs and kills male flies. However, in one of their collections, a few male flies began to survive. Some researchers would respond by assuming something messed up and tossing that collection in the trash. But Harumoto and Lemaitre did follow-up experiments that showed the bacteria were still there; they were just less adept at killing men.
A few decades ago, this would have caused a painstaking slog trying to identify the gene found in this strain of S. poulsonii. Now, however, the researchers have just sequenced the genome of the original strain and its male-tolerant relative. By comparing the two genomes, they were able to identify a suspicious-looking gene with much of it deleted in the altered strain.
To confirm that this was indeed the gene responsible, Harumoto and Lemaitre put a copy in flies and showed that it killed the males there. The forms of death were very similar: widespread cell death accompanied by nervous system problems. The researchers called the gene paidin front of “S. poulsonii androcidin.” (“Andro” means male, and “cidin” is a derivative of “cide” as in murder.)
The gene itself is about evenly split between things we’ve seen before and parts that look unfamiliar. In the known half, there is a stretch that codes for a stretch of protein that normally mediates interactions with other proteins (called an ankyrin domain). Removing this part of the gene and then inserting it into flies did not affect males, indicating it was essential for gene activity. A little further into the protein, there’s a part that looks like it’s performing a catalytic activity (removing ubiquitin tags). Versions of the gene with this part deleted still killed men, but they survived much later in development, suggesting that its loss weakened the protein.
Anything after these known parts doesn’t bear much resemblance to protein-coding regions of genes we’ve studied, so it’s hard to say what those bits do. The male-tolerant strain has a deletion that cuts off part of this unknown area. At this point, we cannot say whether the remaining male killing is due to the remaining portions of the protein retaining some activity or whether the bacteria have multiple pathways through which they kill males.
x marks the spot
This is not about how paid kills men. But Harumoto and Lemaitre found that a version of the gene with a fluorescent label caused the protein to stick to the X chromosome in male flies. Like humans, flies have an XX female/XY male system of sexing. In humans, the difference in X chromosome dose between males and females is made up for by cutting off one copy of the X chromosomes in females. Flies handle this dose difference by increasing the activity of genes on the single X chromosome in males.
This compensation relies on a set of proteins that form complexes on the male X chromosome. So Harumoto and Lemaitre developed women to make this complex and tested paid in them. With these ladies paid eventually located on the X chromosomes, just like in males. And the females also died in a similar way to males designed to express themselves paid. So the bacterial protein seems to have linked itself to a crucial cellular function in men.
How does it actually do its kills? A close look at the X chromosomes showed that they were fragmented, with breaks where the paid protein was present. It’s not clear whether the protein itself does the cutting or whether it recruits one of the fly’s own proteins to do it. What is clear is that the two known parts of the paid proteins are needed to get it located on the X chromosome – one to get it into the nucleus, the other to get it onto the X chromosome.
The last major mystery open is how the protein is made in the bacteria until it is introduced into the cells it affects. There is clearly still a lot of work to be done here. But the basic outlines are pretty clear and they paint a picture of how a parasite can use an organism’s own essential activities for the parasite’s own selfish purposes. The authors note that killing men has evolved at least five other times in different groups of bacteria. So if we can get the details of some of these other cases, we’ll have a clearer picture of the different ways selfish bacteria can exploit their hosts.
Nature2018. DOI: 10.1038/s41586-018-0086-2 (About DOIs).