Our DNA is locked in a constant battle with itself. It’s fighting to control mobile bits of genetic material that copy themselves and spread through the genome—so-called jumping genes. But that's a molecular game of Whac-A-Mole: For every bit it manages to suppress, another finds a way to break free. A new study has pinned down genes that have evolved to thwart these molecular intruders. The work paints a picture of the ongoing evolutionary struggle being waged within our genome.
“It’s very interesting, this yin and yang of evolutionary changes,” says Haig Kazazian, a geneticist from the University of Pennsylvania who was not involved with the study. “Nobody has looked at these proteins in the light of evolutionary change.” The work could have applications ranging from stem cell development to cancer prevention and may even lead to a deeper understanding of how the cell makes use of its genetic material.
Sequences of DNA that can self-replicate and then insert themselves into new locations in the genome are called transposons, or, more simply, jumping genes. They can cause problematic mutations if they jump into important genes: One that inserts itself into a gene used for slowing cell growth could cause cancer, for example. So our genomes have evolved countermeasures. Those countermeasures include a large family of genes that code for proteins known as KRAB zinc fingers. Establishing the link between a specific KRAB zinc finger and its target jumping gene has been a daunting task, though. The KRAB family contains approximately 170 different versions of the same basic protein.
To solve this problem, Frank Jacobs, a biologist from the University of California (UC), Santa Cruz, and colleagues studied cultured mouse cells that carry a human chromosome with transposons, but no human zinc finger genes. “In the absence of primate KRAB zinc fingers, the human [transposons] ran wild," Jacobs says.
Next, the team added 14 different zinc finger proteins to the mouse cells one by one, to see which ones could stop the jumping genes from jumping. Two KRAB zinc fingers (KZNF91 and KZNF93) worked against two kinds of human transposons. Jumping genes stopped jumping, the team reported online on 28 September in Nature.
Once the zinc fingers were paired with their target jumping genes, the team confirmed that indeed the zinc fingers had evolved shortly after the transposon emerged. When the experiment was repeated using a zinc finger from orangutans or macaques, the human transposons were able to escape. The result suggests that somewhere in our ancestry the jumping genes mutated to dodge the zinc fingers, but the zinc fingers also evolved to silence them once again. “We could actually look at when these zinc fingers arose in relation to when these transposons were active and could see this really interesting evolutionary story,” says Sofie Salama, a UC Santa Cruz biologist involved in the study. “It shows this sort of evolution in action.”
These zinc finger proteins turn off more than just the jumping genes. They also control other genes nearby and over evolutionary time can be incorporated into the cell’s program for regulating those genes’ activities, Jacobs says. This unintentional benefit may explain why many zinc finger genes persist in our DNA even after their target jumping genes lose the ability to copy themselves.
Primates in particular have shown explosive expansion in the KRAB zinc finger gene family; considerable differences exist in this family even between humans and chimpanzees. Our DNA is 98% identical to chimpanzees, but the big differences come from how and when that DNA is used. Jacobs suggests that many of our species’ distinctive features may have arisen because of changes in gene expression caused by zinc finger regulation. “[Zinc fingers] provide this potential regulatory landscape that can be used by the host to do something interesting and change in interesting ways,” Salama adds. By understanding that regulatory landscape, researchers may be better able to understand how, in various diseases, the way genes get used goes awry and find new ways to correct problems.