Battle of the Hole Punchers

One of the most exciting lines of research in evolution today is how parasites have become so good at making us sick. A case in point appears in the latest issue of Genome Biology (full text of paper here). It appears that parasites have stolen one of our best lines of defense and now use it against us.

When bacteria or other pathogens try to invade our bodies, we marshall an awesome system of biochemistry to ward them off. Recently, a group of French and German molecular biologists took a look at a key piece of that system, a molecule studding the surface of our cells called alpha-2-macroglobulin. Parasites penetrate a host cell by releasing enzymes that can punch a hole through the cell wall. But alpha-2-macroglobulin can snag these enzymes before they do damage, tucking them away in a cage where they can be destroyed.

You can find the gene for alpha-2-macroglobulin not only in humans but in other animals. The French and German researchers have identified a number of other versions of the gene in invertebrates by trawling through genome databases, looking for sequences that are similar to the alpha-2-macroglobulin gene. In some cases, other animals have evolved much more sophisticated variations on this particular defense than we have. Mosquitoes, for example, use 15 different versions of the gene. When you suck blood for a living, there’s a high premium on eradicating the parasites you slurp up as well.

It is now clear that the common ancestor of all animals on Earth evolved an ancestral version of alpha-2-macroglobulin, which was then passed down and gradually altered over a billion years of animal evolution. But the European researchers found some surprises as they hauled up their genomic nets. They found many versions of the alpha-2-macroglobulin gene in bacteria as well. Not in all bacteria, mind you, but in a wide range of species, most of which live inside animals. When the researchers looked at a family tree of bacteria, the ones carrying versions of alpha-2-macroglobulin were scattered across its branches. In many cases, their closest relatives lacked the gene.

Here’s the hypothesis that the researchers came up with to explain this weird pattern. An early animal equipped with alpha-2-macroglobulin was infected with a bacterium. The microbe accidentally acquired the animal gene and wove it into its own genome. (This has been documented happening many times among bacteria. They can scoop up genes from dead microbes, and viruses hopping between bacteria can deliver genes as well. But the exchange from animals to microbes hasn’t been studied very well till now.)

The stolen alpha-2-macroglobulin gene turned out to give the pathogen an advantage over others that lacked the gene. Specifically, it was able to use this host-defense molecule to defend itself from the host. It just so happens that animals also use enzymes to punch holes in the cell walls of their enemies. But while bacteria punch holes to invade a cell, animals do so in order to rip open pathogens and kill them. After one species of bacteria stole the alpha-2-macroglobulin gene from animals, it began to use the gene to trap their host’s hole-punchers. Later, it handed off the gene to other species of bacteria also living in animal cells. They also used it to defend themselves against their hosts.

The scientists point out that they still have to rule out the possibility (unlikely as they consider it) that the transfer went the other way: that animals acquired their alpha-2-macroglobulin defense from bacteria. But there’s a straightforward way to do that. They need to make a large-scale comparison of the version of the gene in bacteria, as well as in animals. If they’re right, then the tree will show that all of the bacterial versions descend from animal versions of the gene. If they’re wrong, the opposite pattern will emerge.

Either result would, however, point to one important conclusion: gene-swapping has been a big deal in the history of life. Scientists have known for a long time that it’s important for the rise of antibiotic resistance in bacteria. They’ve also known that the energy-generating mitochondria of our cells are actually captured degenerate bacteria. But it was hard to know how important gene-swapping was beyond these examples until entire genomes became available for study. When scientists first began to analyze genomes for evidence of gene-swapping, they sometimes claimed evidence for it that disappeared when more data came in. The most glaring example came in 2001, with the publication of the rough draft of the human genome. The authors of the draft claimed that a few percent of the human genome consisted of genes imported from bacteria. A comparison with more genomes later showed that this was not true.

The Genome Biology paper is an example of today’s more thorough tests for gene-swapping. (In this case, they studied 32 species of bacteria, not to mention a wide range of animals.) It’s also an example of why this sort of research matters. Bacterial versions of alpha-2-macroglobulin could become excellent targets for drugs that would prevent the microbes from defending themselves against our hole-punching.