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Research team uncovers unusual changes in genomes of parasites

by CIFAR Jul 23 / 12

Recent technological advances have empowered biologists with new ways to study tiny organisms that inhabit our planet. For example, breakthroughs in the ability to quickly sequence whole genomes from a small number of cells have given scientists the ability to study the microbial world in ways that were not possible just a few years ago.

Recently, CIFAR Director Patrick Keeling (UBC) and Scholar Nicolas Corradi (University of Ottawa) led a collaborative team of researchers that used high-throughput genome sequencing to uncover an unusual process of genome change in parasites. Their findings were published online on July 16 in Proceedings of the National Academy of Sciences. The team found that a common ancestor of two parasites had acquired sets of genes from a variety of other organisms by a process called horizontal gene transfer (HGT), the movement of genetic material among non-mating species. And, these new genes contributed to a novel function in the cell – the ability to make essential nutrients called folate and purines.

This finding puzzled the team. While it is not unusual for parasites to acquire one or two genes from other organisms through HGT, this case involved several functionally related genes, which not all derived from the same donors. Some genes were bacterial in origin, others were from animals. This is the first time scientists have seen evidence of entire functional pathways being built in parasites from building blocks not related through evolution.

The parasites Encephalitozoon hellem and Encephalitozoon romaleae, who have a common ancestor, were the focus of this study. We spoke to Dr. Keeling, Director of CIFAR’s Integrated Microbial Diversity Program, to learn more about why his findings were so puzzling.

Why did you choose to study parasites in the species group Encephalitozoon?

Because parasites in the genus Encephalitozoon have the most reduced and compact nuclear genome of any cell with a nucleus, we were initially interested in understanding why their genome is so small and dense and how these characteristics affect genome function. We started by sequencing the entire genome for all the known species or family members in Encephalitozoon. But when we did this, we came across groups of genes in the species E. hellem and E. romaleae that were not found in the other parasites. These unfamiliar genes must have come from other organisms by HGT, which was surprising because we expected very little HGT in such small genomes.

How do you know that the groups of genes were derived by HGT?

The genomes of E. hellem and E. romaleae were similar to the genomes of other parasites in Encephalitozoon, except for the stand-out groups of genes we uncovered. Since these genes were not present in any other Encephalitozoon, this suggested that the genes “appeared” relatively recently in the common ancestor of E.hellem and E. romaleae.

Also, these parasites are eukaryotes, cells with a nucleus, and are related to fungi. We made phylogenetic trees of all these genes and found they were not similar to those seen in fungi or other eukaryotes. Some were actually related to bacteria, suggesting that the common ancestor of E.hellem and E. romaleae received the genes from bacteria by HGT. Other genes were related to animals, suggesting they might have come from the host organism.

The acquired genes gave their common ancestor the ability to make folate and purines. Why did this happen?

We don’t really know why, but we expect it might have something to do with giving the parasite new abilities to infect hosts or tissues that are folate deficient. As always though, we have to consider the order of events carefully. It is unlikely that the parasite was first folate deficient and then ‘fixed’ by HGT. More likely the groups of genes were acquired by chance, and their presence allowed the parasite to invade a new and previously off-limits hosts or tissues.

It’s important to point out that some of these genes have now lost their function. We discovered that all the genes that are supposed to produce folate in E. romaleae do not work, while they still do in the sister species E. hellem.

Do other organisms acquire groups of genes to produce coordinated functional pathways in the cell?

We know that some bacteria can pick up whole pathways from other organisms because they often have genes organized by function in co-expressed packages called operons. In eukaryotes, genes are mostly scattered randomly in the genome, so it is not likely that genes tied to one function get transferred together. But some fungi are known to have picked up a whole pathway as an operon from a bacterium. The strange thing about our findings is that the groups of genes in the pathways of the parasites did not come from the same organism. Although the genes produced a coordinated pathway in the cell to produce folate or purines, it looks like the genes responsible for different steps in the pathway came from different donor organisms.

How did you and Nicolas Corradi contribute to the study?

Nicolas and I started sequencing Encephalitozoon genomes several years ago, and when he started his own lab at the University of Ottawa, he and I both kept working on this genus. We each had a genome sequence that we were trying to decipher in our labs, and individually these were pretty interesting. But when we compared notes and put them together, we realized we had a much more interesting story than either genome on its own could tell. This was a real collaboration, and much of it happened because of CIFAR. We discussed our findings at two Integrated Microbial Biodiversity program meetings and also during the program review.

Nicolas’ appointment as a CIFAR Scholar played a major role in his decision to stay in Canada and accept a faculty position at the University of Ottawa. If it wasn’t for this, he might not have been working on Encephalitzoon anymore.

What do your findings mean for our understanding of parasites?

This study is mostly about how genomes change over time. But we also learned interesting things about the biology of the parasites, because observing the actual process of parasites gaining and loosing functions helps us understand their pathogenicity. To know how a parasite functions you need to know how it interacts with the host, since this is its ‘environment,’ in the same way the savannah is the environment of a zebra. It has to be able to extract all the nutrients and energy it needs from this environment and it has to be able to defend itself from environmental stresses. In the case of a parasite, this can include protecting itself from host defenses too. An intracellular parasite can always get nutrients and energy from the host cell that it lives within, and so sometimes it loses the ability to make things it can just acquire from elsewhere. But the more you lose, the more dependent you are on the host cell for getting you what you need, which can narrow down the range of possible host cells.

In the case of our study, the situation was reversed, such that the parasite acquired a new ability to make essential nutrients and therefore exploit previously off-limits host cells. These findings help us better understand the evolution of these parasites.

What are the next questions you want to answer?

One of these two species is an insect parasite and the other a vertebrate parasite. I think the next step is to figure out how these parasites with the same common ancestor became so different. Either a vertebrate parasite switched hosts to infect an insect, or insect parasite switched to infect vertebrates. To tell, we need to know more about the diversity of Encephalitozoon in nature and how parasites in the genus are related phylogenetically. This will require an environmental approach; going out into different geographical locations and sampling the diversity using molecular means. And if that is done in such a way that it also tells us what hosts they are infecting, maybe we can get an idea of how the two parasites switched hosts.