"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 Sophie Salama, a research associate at the University of California, Santa Cruz, Genomics Institute, where researchers are studying the complex processes of human evolution. How then, did humans and other primates evolve to have so many more complex cellular and genetic processes than frogs? The answer may lie in the idea of an evolutionary arms race that has occurred between elements of the genome throughout history.

The study, appearing in the journal Nature, suggests that there has always been a conflict between mobile DNA sequences known as retrotransposons (also called "jumping genes"), which can "jump" to different parts of the genome to create or reverse a mutation, and the genes that have evolved to control them — these genes produce proteins that halt jumping gene activity. The UCSC scientists have not only identified these genes in their new study but also found that the repressor genes have evolved to play a role in other important cellular processes.

Jumping genes form nearly 42 percent of the human genome, while DNA transposons constitute around two to three percent. They are believed to be remnants of ancient viruses that inserted their genes into the genome long before humans evolved. Since there are hardly any advantages to jumping genes, natural evolutionary processes led to the development of repressor genes that produce proteins to disrupt their activity. The study found that these repressors belong to a large family of proteins known as "KRAB zinc finger proteins." The nearly 400 genes that encode these DNA-binding proteins are arranged in clusters in the human genome, and about 170 genes have emerged since primates diverged from other mammals.

The study suggests that these repressor proteins grew in quantity after an increase in jumping gene activity. Because their repression also affected other genes closeby on the chromosome, the researchers believe it could have caused other genomic effects, pushing evolution along. "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," Salama said in a press release. "This affects other nearby genes, so now you have a potential new layer of regulation available for further evolution."

Previous studies had shown that KRAB zinc finger proteins could silence jumping genes in mouse embryonic stem cell models. So, researchers introduced primate jumping genes to non-primate cells with the help of mouse embryonic stem cells containing a single human chromosome. Because mouse cells lack the repressor genes, the primate jumping genes became active. The researchers also found two human zinc finger proteins called ZNF91 and ZNF93 that bind and repress two major classes of jumping genes either currently or recently active in primates, called SVA and L1PA. Their research showed that ZNF91 underwent structural changes eight to 12 million years ago, enabling it to repress elements of SVA.

Meanwhile, experiments with ZNF93, which shuts down some L1PA jumping genes, found that some elements of an L1PA subset recently evolved without a short section of DNA. That short section is where ZNF93 would normally bind. Without it, ZNF93 can't bind, thus preventing it from repressing the subset of L1PA. When the researchers added the DNA back and inserted it into mouse cells, they found that it was better at jumping. Although that's better for the gene, going without the extra DNA allows it to avoid repression, which is a better advantage.

"That's kind of the icing on the cake for aficionados of molecular evolution, because it demonstrates that this is a never-ending race," Salama said. "KRAB zinc finger proteins are a rare class of proteins that is rapidly expanding and evolving in mammalian genomes, which makes sense because the transposable elements are themselves continually evolving to escape repression."

Source: Jacobs F, Haussler D, Salama S, et al. An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons. Nature. 2014.