The Genetic Evolutionary Arms Race
Genes are tricky little buggers, the stuff that makes us up has fought the test of time to make it to where we are today. It is thought that our genes changed in an attempt to outpace other life, albeit random changes.That might only be half right however, new findings suggest that there is an evolutionary arms race going on within the genome against, of all things, itself. This inherent competition of primates drove the evolution of complex regulatory networks that orchestrate the activity of genes in every cell of our bodies
The arms race is between mobile DNA sequences known as “retrotransposons” (a.k.a. “jumping genes”, which are just as cool as they sound) and the genes that have evolved to control them. The researchers have, for the first time, identified genes in humans that make repressor proteins to shut down specific jumping genes. The researchers also traced the rapid evolution of the repressor genes in the primate lineage.
Their findings show that over evolutionary time, primate genomes have undergone repeated episodes in which mutations in jumping genes allowed them to escape repression, which drove the evolution of new repressor genes, and so on. Furthermore, their findings suggest that 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. This study helps explain how that came about,” said Sofie Salama, who led the study.
Retrotransposons are thought to be remnants of ancient viruses that infected early animals and inserted their genes into the genome long before humans evolved. Now they can only replicate themselves within the genome. Depending on where a new copy gets inserted into the genome, a jumping event can disrupt normal genes and cause disease. Often the effect is neutral, simply adding to the overall size of the genome. Very rarely the effect might be advantageous, because the added DNA can itself be a source of new regulatory elements that enhance gene expression. But the high probability of deleterious effects means natural selection favors the evolution of mechanisms to prevent jumping events.
Scientists estimate that jumping genes or “transposable elements” account for at least 50 percent of the human genome, and retrotransposons are by far the most common type.
“There have been successive waves of retrotransposon activity in primate evolution, when a transposable element changed to become expressed and replicated itself throughout the genome until something turned it off,” Salama said. “We’ve discovered a major mechanism by which the genome is able to shut down these mobile DNA elements.”
The repressors identified in the new study belong to a large family of proteins known as “KRAB zinc finger proteins.” These are DNA-binding proteins that repress gene activity, and they constitute the largest family of gene-regulating proteins in mammals. The human genome has over 400 genes for KRAB zinc finger proteins, and about 170 of them have emerged since primates diverged from other mammals.
The team’s findings support the idea that expansion of this family of repressor genes occurred in response to waves of retrotransposon activity. 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. This affects other nearby genes, so now you have a potential new layer of regulation available for further evolution,” Salama said.
KRAB zinc finger proteins are the subject of intensive research as scientists try to sort out their many regulatory roles within the genome. The idea that they are involved in repression of jumping genes is not new—previous studies by other researchers have shown that these proteins silence jumping genes in mouse embryonic stem cells. But until now, no one had been able to demonstrate that the same thing occurs in human cells.
The team developed a novel assay to test whether a particular KRAB zinc finger protein could shut down certain jumping genes. They then developed an assay for testing individual zinc finger proteins for their ability to turn off a primate jumping gene in the mouse cell environment.
“We did all our tests in mouse cells because they lack all of the primate zinc finger proteins, so when you put primate retrotransposons into a mouse cell they’re all active,” Salama explained.
The results demonstrated that two human proteins called ZNF91 and ZNF93 bind and repress two major classes of retrotransposons (known as SVA and L1PA) that are currently or recently active in primates.
Experiments with ZNF 93, which shuts down L1PA retrotransposons, provided a striking illustration of the arms race between jumping genes and repressors. The researchers found that, while it is good at shutting down many L1PA elements, there is one subset of a recently evolved lineage of L1PA that has lost a short section of DNA that includes the ZNF93 binding site. Without the binding site, these jumping genes evade repression by ZNF93. Interestingly, when the researchers put the missing sequence back into one of these genes and put it in a mouse cell without ZNF93, they found that it was better at jumping. So even though the sequence helps with jumping activity, losing it gives the jumping gene an advantage in primates by allowing it to escape repression by ZNF93.
“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.”
Proving once again that it isn’t the size of the genome that counts, it’s how you use it.
Jacobs, Greenberg, Nguyen, Haeussler, Ewing, Katzman, Paten, Salama & Haussler (2014). An evolutionary arms race betweenKRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons Nature : 10.1038/nature13760