Viral Genes In Our Brain

How did a gene from a virus end up in our brain? That's just one of the interesting questions raised by a pair of recent studies investigating a gene which is crucial for our nerves to develop properly.

Nerves carry electrical signals throughout the body, but, unlike electric wires, they don't need to be insulated from each other to prevent a short circuit. Some of them are insulated anyway, since it makes the signal travel faster. While we insulate wires by wrapping plastic around them, insulated nerves are ensheathed in a fatty layer called myelin. In 2009, researchers discovered that a gene called MYRF is essential for myelin to properly form around nerve cells (a process called myelination). MYRF encodes a transcription factor, a protein which binds to the DNA of other genes and switches them on or off. Without it, many of the genes needed for myelination don't get turned on and the whole process goes awry, leading to major neurological problems. Recently, two research teams independently teased apart how MYRF works and discovered that a core part of the gene originally came from a virus which preys upon bacteria.

Many transcription factors live within the nucleus or freely shuffle in and out, but not MYRF. MYRF starts its life outside the nucleus, far from the DNA it's supposed to regulate. It's part of a class of transcription factors which are bound to the membranes of organelles in the cell, stuck outside the nucleus until something frees them. Trapping these transcription factors is one way to control their activity. A network of molecular machines constantly monitors the cell, cutting free transcription factors when they're needed; the freed transcription factor can then move into the nucleus and bind to its target DNA. To their surprise, the researchers discovered that MYRF doesn't wait for help. Instead, it just cuts itself free.

MYRF is able to cut itself loose thanks to a region tucked in between the part that binds to its target DNA and the bit that attaches it to a membrane. This region, called the "intramolecular chaperone domain" (ICD), does two things. First, it enables three MYRF proteins to come together as a single unit. Then, remarkably, it cuts itself in two, liberating the rest of the protein. Cut loose, the business end of MYRF (the DNA-binding domain) is free to migrate into the nucleus, leaving behind the ICD and the part of MYRF anchored to the membrane.

When they examined the sequence of the ICD, both research groups discovered that it was similar to part of the tailspike protein in bacteriophage, viruses that infect bacteria. Phage attack a bacterium by using their tailspike proteins to latch onto the surface and break through the cell wall. The ICD-like part of the tailspike protein does the same thing it does in MYRF; it brings together three proteins before cleaving itself to free the part of the protein that will break down the bacterium's wall.

Its viral origin isn't the only interesting thing about MYRF. Another important question is why it starts out stuck to a membrane. Being bound to a membrane usually offers a way to regulate a transcription factor, but the liberation of MYRF doesn't seem to be regulated — it always cuts itself out of the membrane. MYRF goes to great lengths to get free, so it seems likely that there's a reason why it starts in the membrane. MYRF-like genes (with an ICD) are also found in a wide range of organisms, including non-vertebrates which lack myelin and even creatures without a nervous system, like the slime mold Dictyostelium discoideum. There's clearly still a lot to learn about MYRF, including what it does in these various organisms, but its basic design -- dating back to an ancient insertion of viral DNA — must be quite useful to show up in so many evolutionary lineages.

This is hardly the only example of viruses shaping our evolution. In fact, viral DNA is littered across our (and other!) genomes. Carl Zimmer has written about the importance of viral genes in the evolution of the placenta and in totipotency, and earlier this year I wrote about their role in regulating gene activity in the evolution of primates. All in all, a picture of evolution is emerging that looks less like the branches of a tree and more like the reticulated pattern of veins on a leaf.