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Raiding the Oldest Arsenal

Life on this planet has existed for at least 3.5 billion years. For most of that time, it was microscopic. Bacteria and other microbes had the world to themselves, but since they still had to compete, they evolved a wide arsenal of weapons for scuppering and killing their rivals. Humans have spent the last century plundering these arsenals. The vast majority of our antibiotics come from chemicals that microbes use on each other.

But you don’t need Alexander Fleming, the scientific method, or a pharmaceutical industry to exploit a microbe’s antimicrobial weapons. All you need is time and a little luck.

Seemay Chou and Matthew Daugherty from the University of Washington School of Medicine have found that one group of antibiotic genes have repeatedly jumped from bacteria into eukaryotes—the catch-all term for complex life forms, including animals, plants, fungi, and more. The genes made these crossings on at least six separate occasions, and they are now part of their hosts’ immune systems.

In an instant, these hosts acquired what scientists take decades of research to develop: a new tool for controlling microbes and protecting against infections.

kclkdpayub7roood8nmlChou and Daugherty made their discovery by accident. They were studying the tae genes, which make proteins that can digest a bacterium’s outer wall, causing it to leak and rupture. These are weapons built by bacteria, for use against bacteria. So why, when Chou and Daugherty searched for these genes, did they find them all over the tree of life? Why were these bacterial genes also in ticks, mites and scorpions? In limpets, water fleas, sea slugs, oysters, and sea anemones? In the lancelet, a close relative of back-boned animals like us? In weird single-celled pond creatures like Naegleria and Oxytricha?

The genes certainly hadn’t come from contaminating bacteria, since they were riddled with junk sequences that are only ever found in eukaryotic DNA. They were genuine parts of their hosts, so the team called them dae genes, with the ‘d’ standing for domesticated. They then compared the dae genes with their bacterial tae counterparts to reconstruct their origins.

Let’s take just one example. This family tree shows that the dae2 genes of ticks and mites (dark green box) are most closely related to tae2 in Burkholderia bacteria (red arrow). The next closest relatives are more dae2 genes in water fleas (light green).

Dae2 family tree. Credit: Chou et al, 2014, Nature.
Dae2 family tree. Credit: Chou et al, 2014, Nature.

If these genes were just passing down from parent to offspring, there is no way you’d get a pattern like this. Instead, the tick and water flea genes would be on neighbouring branches, while the bacterial genes would all sit on some very distant part of the family tree. The only explanation for the actual pattern is that tae2 genes have jumped into animals at least twice, once in the common ancestor of all ticks and mites and again in the common ancestor of water fleas.

Among bacteria, these kinds of “horizontal gene transfers” are very common. Among eukaryotes, they are relatively rare. Scientists have documented many examples, but the transferred genes are often just useless flotsam. In rare cases, they can plug into their new hosts in valuable ways, allowing a beetle pest to destroy coffee plants or allowing caterpillars to resist poisonous meals.

The dae genes belong to this elite club. Chou and Daugherty found that the genes are switched on in deer ticks, lancelets, and Naegleria amoebas, and they all still make proteins that can sunder bacterial walls. Even though they left bacteria hundreds of millions of years ago, they still carry out their ancient destructive roles.

The team reasoned that the hosts must be using these genes as part of their immune systems, and they confirmed this idea by focusing on the deer tick. This parasite makes Dae2 proteins in its salivary glands and guts—the organs most likely to encounter fresh microbes from a victim’s blood.

The protein is very specific. It degrades the walls of certain bacteria, including the cause of Lyme disease—Borellia burgdoferi. When the team switched off the dae2 gene, ticks were no longer able to control this particular microbe. If they fed on infected mice, they ended up with 10,000 times more B.burgdoferi in their bodies. This borrowed gene matters to them—and to us too! Lyme disease affects hundreds of thousands of people every year, and the tick that spreads it relies on a bacterial gene to control the microbe that causes it.

In hindsight, we should probably have expected something like this. Chou says that the tae genes are “prime candidates for horizontal gene transfer”. They make small, potent proteins that don’t require a supporting cast to work. And they are universally useful, since every living thing has to contend with bacteria. It’s no coincidence that a different group recently found another antibiotic gene that has hopped all over the tree of life. The war between bacteria, which had raged for billions of years, has created a reservoir of genetic weapons that latecomers can exploit.

Reference: Chou, Daugherty, Peterson, Biboy, Yang, Jutras, Fritz-Laylin, Ferrin, Harding, Jacobs-Wagner, Yang, Vollmer, Malik & Mougous. 2014. Transferred interbacterial antagonism genes augment eukaryotic innate immune function. http://dx.doi.org/10.1038/nature13965

Find out more about horizontal gene transfers here

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