Perpetual War

In the American Civil War, the United States fought itself in a bloody struggle that dragged on for four years. A new study out of the University of California, Santa Cruz shines light on an even longer – and seemingly endless – conflict within ourselves.

This internal struggle takes place within our genome, between an onslaught of antagonists and our own genes that try to control them. The antagonists are called “jumping genes,” stretches of DNA that jump around to different locations in our genomes. Think of a jumping gene as an oddball guest at a dinner party who leaps up and changes seats without warning. That would be a rather disruptive guest, and the same can be said for jumping genes. As they leap from location to location, jumping genes can disrupt other genes in the genome, turning genes on or off or even ripping genes to shreds.

Obviously, this behavior is not healthy for a genome, particularly given that our (non-jumping) genes are best kept intact and well-regulated. After all, our genes are instructions for making and maintaining cells, tissues and organs. They also help us respond to our environments. Left unchecked, jumping genes have an enormous potential to disrupt large swathes of the human genome, which cannot be good for us.

“Jumping genes have been invading [our] genomes throughout evolution,” said Frank Jacobs, a member of the UC Santa Cruz team who is now a professor at the University of Amsterdam. “They have been pretty successful too, considering that over 50 percent of the human genome actually consists of… jumping genes.”

To counteract this chaos, our genomes try to suppress jumping genes. But, sometimes jumping genes evolve to escape our control. This is the key to the protracted clash: genes constantly evolve to fight jumping genes, and vice versa. The field of battle, our DNA, is littered with the corpses of this struggle. These include genes that tried and failed to suppress jumpers, jumping genes that were long ago beaten and permanently silenced, and genes ripped apart by jumping gene activity. But, most of these corpses are ancient, predating even our ape ancestors. There are few examples of more recent struggles between jumping genes and their would-be suppressors, few snapshots from this war’s stormy present.

But, Jacobs and his colleagues at UC Santa Cruz captured just such a snapshot. As they reported in the journal Nature, they identified two genes in the human genome that have been evolving to fight jumping genes, with varying degrees of success.

The team, a collaboration between UC Santa Cruz professors Sofie Salama and David Haussler, specifically wanted to find genes that were recently – perhaps even currently – trying to counteract jumping genes.

To accomplish this, “we had to restrict our question to what is repressing… jumping genes that are still active in the human genome,” explained Jacobs.

Jacobs and co-author David Greenberg searched for genes that try to fight two types of jumping genes, L1 retrotransposons and SVAs. Their search was not easy, but eventually they found two genes that try to keep these jumping genes from disrupting the dinner party.

“Long days, long nights, all driven by the perspective that if we hit the right one, it’s going to be great… And it was!” said Jacobs.

The two genes Jacobs and Greenberg identified are soldiers on the frontline of this genomic conflict. They are genes that have been repressing jumping genes just as our species was emerging. Interestingly, one gene has been more successful in this battle than the other. One gene, ZNF91, gained a new function several million years ago that enabled it to repress SVA jumping genes. The timing of ZNF91’s transformation (8-12 million years ago, a mere blink of an eye in evolutionary timescales) is critical: ZNF91 gained this new ability shortly after SVA jumping genes invaded our genomes and began to spread. In essence, Jacobs and his colleagues captured evolution in action. They have found a problem (an invasion of SVA jumping genes), as well as a solution (ZNF91 evolving the ability to suppress SVA jumping genes).

The same cannot be said for the second gene, ZNF93. ZNF93 was once able to silence L1 retrotransposons. But, about 12 million years ago (again, blink of an eye), L1s gained a mutation that let them evade ZNF93. Since then, L1s have jumped and copied themselves around our genomes, even today.

So, the UC Santa Cruz team captured two steps in this protracted civil war. The ZNF91 gene evolved to repress one class of jumping genes, while an entirely separate class of jumping genes evolved to escape ZNF93.

These processes are not simply an abstraction for Santa Cruz’s finest nerds to fawn over. Jumping genes have left fingerprints across our evolutionary history, and they play a role in our identity that we do not fully understand.

“We simply don’t know the full extent to which they have contributed to our… species,” said Jacobs.

Famously, jumping gene activity may have helped our immune systems learn to produce protective antibodies, and played a central role in the evolution of the placenta. This war, it seems, is not just about mounting casualties.

Jacobs is continuing to investigate jumping genes, probing how they may have shaped our unique identity as human beings.

“I will start exploring how the jumping genes that are still active in the human genome have contributed to the evolution to the human brain,” he said. “Seems like a big question, and it is.”

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