Researchers find a gene that lets bacteria kill all male flies

A number of bacteria that infect insects have a simple and brutal way of increasing their transmission: they kill off all the male progeny of the females that they infect. There’s actually some evolutionary logic to this. The bacteria can get transmitted to the eggs of the females they infect but can’t get carried along on the sperm.

That makes the male offspring a problem: they can’t spread the bacteria further, and they’ll compete with the females for food. Better to kill them off, then, just to ensure that never becomes a problem.

But it’s one thing to have something that’s a good idea conceptually and another entirely to evolve an implementation that gets the job done. How, exactly, do you go about killing one sex while leaving the other untouched?

Thanks to a lucky accident, two Swiss researchers (Toshiyuki Harumoto and Bruno Lemaitre) have identified the gene that allows one species of bacteria to kill off males. Although we don’t have all the details, it’s clear that the system leverages something that male flies need to do to cope with the fact that they only have a single copy of the X chromosome.

Accidents will happen

How do you make a discovery by accident? Harumoto and Lemaitre were studying a bacteria called , which lives in flies, is transmitted via eggs, and kills off male flies. In one of their collections, however, some male flies started to survive. Some researchers would respond to this by assuming something got screwed up and chucking that collection in the trash. But Harumoto and Lemaitre did follow-up experiments that showed that the bacteria were still there; they had just become less adept at killing males.

A few decades ago, this would have triggered a laborious slog to try to identify the gene that was altered in this strain of . Now, however, the researchers 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 that had a big chunk deleted in the altered strain.

To confirm that this was in fact the gene responsible, Harumoto and Lemaitre inserted a copy into flies and showed that it killed males there. The form of death looked very similar: widespread cell death accompanied by problems with the nervous system. The researchers named the gene , for ” androcidin.” (“Andro” means male, and “cidin” is a derivative of “cide” as in homicide.)

The gene itself is roughly evenly split between things we’ve seen before and parts that look unfamiliar. In the familiar half, there’s a stretch that encodes a piece of protein that normally mediates interactions with other proteins (called an ankyrin domain). Deleting this portion of the gene and then inserting it into flies didn’t affect males, indicating it was essential for gene activity. A bit further into the protein, there’s a part that looks like it performs a catalytic activity (removing ubiquitin tags). Versions of the gene with this part deleted still killed males, but they survived much later into development, suggesting its loss weakened the protein.

Everything after these familiar parts doesn’t show much similarity to protein-coding regions of genes we’ve studied, so it’s hard to tell what those bits are doing. The male-tolerant strain has a deletion that cuts off part of this unknown region. At this point, we can’t say whether the residual male killing is the result of the remaining portions of the protein retaining some activity or whether the bacteria have multiple pathways by which they kill males.

X marks the spot

This doesn’t get at the issue of how kills males. But Harumoto and Lemaitre noticed that a version of the gene carrying a fluorescent tag resulted in the protein sticking to the X chromosome in male flies. Like humans, flies have an XX female/XY male system of sex determination. In humans, the difference in X chromosome dose between males and females is handled by shutting down one copy of the X chromosomes in females. Flies handle this dose difference by raising the activity of genes on the single X chromosome in males.

This compensation depends on a set of proteins that form complexes on the male X chromosome. So Harumoto and Lemaitre engineered females to make this complex and tested in them. In these females, ended up localized to the X chromosomes, just as it is in males. And the females also died in a similar manner to males engineered to express . So the bacterial protein seems to have linked itself to a critical cellular function in males.

How does it actually do its killing? A close look at the X chromosomes showed they had fragmented, with breaks appearing at the sites where the 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 protein are needed to get it localized to the X chromosome—one to get it into the nucleus, the other to get it onto the X chromosome.

The last big outstanding mystery is how the protein gets from being made in the bacteria to being inserted into the cells it effects. So there’s clearly a lot of work to do here still. But the basic outlines are pretty clear, and they provide a picture of how a parasite can harness an organism’s own essential activities for the parasite’s own selfish ends. The authors note male killing has evolved at least five other times in distinct groups of bacteria. So, if we can get the details on some of these other instances, we’ll have a clearer picture of the different ways in which selfish bacteria can exploit their hosts.

, 2018. DOI: 10.1038/s41586-018-0086-2 (About DOIs).

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