“From life’s school of war: What does not kill me makes me stronger.”—Friedrich Nietzsche
Nietzsche had no idea how right he was, but then he knew nothing of the genome’s internal struggles. One of these struggles, it turns out, has had no less a consequence than distinguishing the human genome from the genomes of other primates. This struggle, to get to the point, is that which is between the genes that would jump—viral remnants known as retrotransposons—and the genes that would repress them.
The jumping gene/repressor gene conflict isn’t exactly new. It has, for example, been studied in mice. But it has become a timely subject thanks to a study recently published by scientists at the University of California, Santa Cruz. These scientists have, for the first time, identified genes in humans that make repressor proteins to shut down specific jumping genes.
What’s more, they have traced the rapid evolution of the repressor genes in the primate lineage. According to these scientists, who were led by Sofie Salama, Ph.D., a research associate at the UC Santa Cruz Genomics Institute, the jumping gene/repressor gene conflict has the dynamics of an arms race. And, like other arms races, the intra-genomic arms race has “spun off” a side benefit. Specifically, repressor genes that originally evolved to shut down jumping genes have since come to play other regulatory roles in the genome.
“We have basically the same 20,000 protein-coding genes as a frog, yet our genome is much more complicated, with more layers of gene regulation,” said Dr. Salama. “This study helps explain how that came about.”
The study’s results appeared September 28 in Nature, in an article entitled, “An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons.” This title, which may be too compact, indicates that ZNF91 gene, which codes for a KRAB zinc-finger (KZNF) protein, evolved to repress SINE-VNTR-Alu (SVA), a retrotransposon currently active in the human genome. Similarly, the ZFN93 gene evolved to repress a different retrotransposon, the long interspersed nuclear element 1 (L1).
To derive these results, the researchers tested primate retrotransposons in nonprimate cells by using mouse embryonic stem cells that contain a single human chromosome. In the environment of a mouse cell, jumping genes that were repressed in primate cells became active. Then, the researchers were able to test individual zinc-finger proteins in the mouse cell environment for their ability to turn off a primate jumping gene.
Once the repressor proteins (and their genes) had been identified, the researchers painstakingly traced their evolution by analyzing primate genomes, which included reconstructed ancestral genomes.
“ZNF91 underwent a series of structural changes 8–12 million years ago that enabled it to repress SVA elements,” wrote the authors of the Nature study. “ZNF93 evolved earlier to repress the primate L1 lineage until ~12.5 million years ago when the L1PA3-subfamily of retrotransposons escaped ZNF93’s restriction through the removal of the ZNF93-binding site.”
Finally, and perhaps most intriguingly, the researchers speculated that by limiting the activity of newly emerging retrotransposon classes, KZNF gene expansion brought only temporary respite. Retrotransposons, not ready to admit defeat, developed mutations to evade repression, challenging KZNF genes to expand their capabilities yet again.
Because repression of a jumping gene also affects genes located near it on the chromosome, the researchers suspect that these repressors have been co-opted for other gene-regulatory functions, and that those other functions have persisted and evolved long after the jumping genes the repressors originally turned off have degraded due to the accumulation of random mutations.
“The way this type of repressor works, part of it binds to a specific DNA sequence and part of it binds other proteins to recruit a whole complex of proteins that creates a repressive landscape in the genome,” Dr. Salama explained. “This affects other nearby genes, so now you have a potential new layer of regulation available for further evolution.”