Carrying Ancient History In The Gut

It is a day to write about Giardia, and I am happy to say that I cannot do so from firsthand experience. Friends of mine have suffered infections of Giardia in their gut, but they haven't been terribly forthcoming about the details. It's not fun, they assure me, and it can last for months. Unpleasant as it may be up close, though, Giardia is one of the most fascinating, most enigmatic creatures on the planet (from a safe distance). Scientists do not yet quite know what to make of this single-celled parasite, but one possibility is that Giardia holds secrets to some of the key steps in the evolution of our own ancestors billions years ago. [cont. below the fold]

Giardia is, like us, a eukaryote. In other words, it shares some key features with a group of other species that includes animals, plants, fungi, slime molds, and many other creatures. The most obvious feature is the nucleus, in which eukaryotes keep their DNA balled up. Bacteria and archaea, on the other hand, don't squirrel away their genes this way. Eukaryotes have other compartments as well, inside of which they break down food, tailor new molecules, and generate energy. The genomes of eukaryotes are peculiar as well. Their genes are broken up by chunks of non-coding DNA. In order to make a protein, a eukaryotic cell has to make an RNA copy of a gene and edit out all those extra chunks. Eukaryote genes are also separated by lots of non-coding DNA. Bacteria and archaea, by contrast, have sleek, compact genomes.

The origin of eukaryotes remains one of the most intriguing questions for evolutionary biologists. It's not clear what the forerunners of eukaryotes looked like or how they took on the nucleus and the other features that make them so different from other species. There is no non-eukaryote that resembles eukaryotes more than any other. Some scientists have looked for clues within eukaryotes, trying to draw their evolutionary tree. The deepest branches might be more primitive than newer ones, not having acquired the full eukaryote package of traits.

Giardia, many researchers suspected, was one of those early-branching eukaryotes. This suspicion was generated at first by simply eyeballing the creatures. They are quite weird. Their teardrop-shaped bodies have eight tails for swimming and a suction pad to clamp onto the wall of the intestines. They also carry two nuclei, each with its own DNA. How i>Giardia manages to keep all those genes coordinated--and why it even has two nuclei--remain mysteries. Bizarre single-celled eukaryotes are pretty easy to find. What set Giardia apart from most other eukaryotes was what it lacked. Scientists could not find a lot of those compartments in which the business of most eukaryote cells takes place.

Most significantly, it was missing mitochondria. Lots of things take place inside these sausage-shaped structures, most importantly the generation of ATP, the energy-bearing molecule found in all living things. Mitochondria started out as free-living bacteria and later evolved into permanent symbionts inside the eukaryote cell. (Mitochondria still carry some DNA of their own, which bears a strong resemblance to one group of free-living bacteria.) The fact that Giardia seemed to be missing mitochondria hinted that it was a transitional eukaryote. Its ancestors branched off before other eukaryotes acquired mitochondria.

It was a cool idea, but scientists eventually discovered evidence that weighed against it. While Giardia may not have mitochondria, scientists knew that it had odd compartments of its own, now called mitosomes. After a lot of probing, scientists realized that mitosomes are in fact vestigial mitochondria. While they may no longer be able to make ATP, they still do other mitochondrial jobs, such as building clusters of iron and sulfur atoms. The discovery of vestigial mitochondria raised a different possibility for Giardia's place among eukaryotes. Perhaps it was not frozen in time, but a highly evolved parasite. Its ancestors acquired new traits (such as its sucker) for feeding on hosts, while losing other traits (full-blown mitochondria) that they no longer required. In other words, Giardia's mitosomes are like the stump of a tail at the base of our spines. No biologists would call us ancient relicts because we lack a full-blown tail.

A good evolutionary tree of eukaryotes might help solve the mystery of Giardia's true nature. But that tree has offered its own challenges. Many studies of eukaryote DNA agree that they belong to five clear-cut branches. Land plants, for example, share a common ancestor with green algae and red algae. We, on the other hand, are closer kin to fungi. But most recent studies of the eukaryote tree find those five branches all seem to burst from the tree's base all at once. It's possible that scientists just haven't found the right eukaryotes that still preserve evolutionary clues in their genomes that will reveal which branch is most closely related to which. But it's also possible that all five branches separated from a common ancestor over the course of a few million years, in a rapid burst of evolution. In either case, the eukaryote tree does not yet help scientists figure out whether Giardia is a relict or a cutting-edge parasite.

It's these sorts of puzzles--combined with Giardia's nasty toll on our guts--that motivated a Giardia Genome Project. A team of scientists from the United States and Europe sequenced all 11.7 million base pairs of Giardia's DNA. In this week's issue of Science, they report their results.

There's all sorts of fascinating stuff lurking in Giardia's genome. As they surveyed its 6470 genes, the genome team was struck by how simple Giardia is, compared to other eukaryotes. I think this diagram in particular does a nice job of illustrating Giardia's simplicity. The top drawing shows what happens when Giardia is done copying a gene from DNA into a messenger molecule of RNA. The parasite has to lop off the end of the RNA molecule when it reaches the end of the gene. (It's a process known as polyadenylation.) Four proteins (the small white circles) come to the aid of the RNA-building machine (marked here as RNAPII) when it reaches the end of a gene.

Below the diagram of Giardia's proteins is one showing the proteins that yeast uses to lop off its RNA. While yeast is single-celled eukaryote like Giardia, it's much more typical as eukaryotes go. Along with the same four proteins Giardia uses (marked in green), yeast needs another 20 proteins to do the same job.

Same job, six times more proteins.

If you just looked at the polyadenylation complex of yeast (or humans), you might think that it was a marvelously complex system that could not work if any part was missing. But it turns out that it still works in Giardia with most of those proteins missing. The new genome paper demonstrates several other cases in which Giardia does what other eukaryotes do, only with a lot fewer genes. In these cases, personal disbelief won't get you far.

These simple systems only makes the original question about the evolutionary history of Giardia all the more interesting. Does its simple RNA-lopping system represent the early evolution of eukaryotes, or the ancestors of Giardia strip down a complex system to the bare essentials?

There are several ways to hunt for the answer. The genome team chose one way: by drawing a new version of the eukaryote tree, using the new data they have about Giardia DNA. They conclude that Giardia is, in fact, an old survivor. It's at the tip of a branch that split off very early in the history of eukaryotes. Much of its simplicity is due to the fact that its ancestors had already diverged from other eukaryotes before many of the eukaryotic bells and whistles evolved.

But the scientists are very tentative about that conclusion. Drawing the eukaryote tree is very tricky for a number of reasons. One is that scientists are trying to reconstruct events that occurred billions of years ago. Another is that Giardia has about 100 genes that its ancestors picked up at one point or another from distantly related species. So the scientists grant that Giardia may turn out to be a stripped-down parasite belonging to a much younger lineage. A new round of tests, taking advantage of the genomes of other eukaryotes that are soon to be published, might confirm the deep ancestry of Giardia.

In the meantime, drug-developers might want to take a look at several dozen genes that the scientists identified as potential targets in the fight against Giardia. I know some people who would be able to wait a little more patiently if there was a fast cure for Giardia.

Source: Morrison et al, "Genomic Minimalism in the Early Diverging Intestinal Parasite Giardia lamblia," Science 317:1921 doi:10.1126/science.1143837

(Image courtesy of 3D Science)