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Junkyard genius

Basic Sciences researchers find unexpected evolution in a heterochromatin protein's control of mobile genetic elements

Aug. 18, 2005
Dr. Danielle Vermaak

Dr. Danielle Vermaak and colleagues study heterochromatin, a genetic region often dismissed as a 'junkyard.' They found that a heterochromatin protein called Rhino may prevent mobile genetic elements from inserting themselves into the genome.

Photo by Todd McNaught

The genetic blueprints of plants, animals and fungi are organized into two types of regions: euchromatin, which contains most of the organism's genes, and heterochromatin, a gene-poor region full of repeated stretches of DNA and mobile genetic elements — stretches of DNA that can jump from place to place in the genome.

Although heterochromatin — a characteristic that helps ward off malfunctions that can lead to cancer or Down syndrome — is very important for chromosome structure, it's sometimes dismissed as a junkyard. With few active genes and a mobile — elements haven, many researchers have assumed that it has not been changed much by evolution.

Drs. Danielle Vermaak, Steven Henikoff, and Harmit Malik of the Basic Sciences Division argue otherwise in the inaugural issue of the open-access journal Public Library of Science Genetics. Their study shows that an important heterochromatin protein called Rhino has gone through drastic changes in the evolution of fruit flies.

The researchers think that Rhino might be involved in controlling mobile genetic elements, making sure that these pieces are inserted into heterochromatin instead of into active genes, where they could disrupt the cell's normal processes. As these mobile elements evolve and devise new ways to insert themselves into the genome, the scientists hypothesize, Rhino must also evolve quickly to come up with new ways to stop them.

If heterochromatin were "really just a trash can," Malik said, "we wouldn't expect the sort of innovation that we've seen."

Studying proteins instead of DNA

It's very difficult to determine the sequence of heterochromatic DNA, largely because the sequence is so repetitive, Vermaak said. Heterochromatin makes up about 30 percent of the human and fly genomes but, Malik pointed out, most "complete" genome projects have actually sequenced very little heterochromatin.

Because of the technical difficulties, most researchers interested in heterochromatin study proteins that interact with it. Heterochromatin protein 1 (HP1) binds directly to heterochromatin and is required to maintain heterochromatic structure, so HP1 can be used as a "mirror image" of heterochromatin, Malik explained.

"We're studying the proteins that bind heterochromatin, hoping that their evolution is going to clue us in to what's going on at the heterochromatin itself," Malik said.

Many organisms have HP1 and often have more than one version of it. Most vertebrates have three versions, while fruit flies have five. Vermaak, Henikoff and Malik compared these five versions of HP1 between two closely related species of Drosophila.

They found that three of the five genes have undergone very little evolutionary change between the two species. This extreme sequence conservation — called purifying selection — is expected for HP1 proteins, the authors said, because they are so important for normal segregation of chromosomes before cell division. If their sequences change too much, then cells could end up with the wrong number of chromosomes, an outcome often fatal for the cell.

The HP1 called Rhino seems to be different, though. First, Rhino is found predominantly in the ovaries, whereas the first three HP1s are found everywhere in the fly body, Vermaak said.

Also, Rhino has gone through many evolutionary changes in the past few million years — its sequence is fairly different in different species of Drosophila.

There are two possibilities for why Rhino's sequence has changed so much. The first is that Rhino has not been under strong evolutionary pressure — perhaps because its function is not that important — so it has been free to evolve away from its original sequence. The second possibility is that Rhino has been pressured to change its sequence, likely because the job it needed to do kept changing.

Using a method that compares different types of sequence changes, Vermaak and her co-workers examined Rhino's sequence in a variety of different species of Drosophila. They found that sequence change, rather than preservation, has indeed been favored in several regions of Rhino.

Fighting a genetic conflict

A change in protein sequence might be favored by evolution if, for example, a species moves to a new climate and needs slightly different proteins to thrive in that climate, Malik said.

Another possibility, though, is that the changing protein is responding to some kind of genetic conflict — for example, competition against the mobile genetic elements that are known to amass in heterochromatin.

"There's a lot of control to keep these elements dormant and silent," Malik said, but the elements themselves must figure out a way to keep inserting into new spots of the genome if they are to survive.

When people think about these mobile elements, they usually think about viruses like HIV, Malik said, but not all inserted genetic elements make us sick. "We have a whole batch of transposable elements that are sitting dormant in our genome," Malik said, and so do most other organisms.

Discovery of fifth protein

The authors speculate that, as transposable genetic elements evolve in different ways and try to insert themselves into new places of the genome, Rhino evolves in response and develops new ways to keep these elements dormant, perhaps by ensuring they insert into heterochromatin rather than euchromatin.

"That would explain why Rhino could be under such strong positive selection," Vermaak said.

It makes sense that this genetic battle would take place in the ovaries, Malik said, since inserting into germline cells is how transposable elements propagate themselves to the next generation.

Vermaak also discovered the fifth Drosophila HP1, which was not known before, based on its sequence similarity to the other HP1s. This protein is expressed mainly in the fly testes, so the researchers are looking at it next, to see if it shares any similarities with Rhino.

Public Library of Science Genetics, where this work appears, is the latest journal from the Public Library of Science series, which already publishes PLoS Biology, PLoS Medicine, and PLoS Computational Biology. The series was started in 2003 with the goal of promoting open access to scientific work.

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