A hidden genetic war is unfolding inside your DNA

That idea has long been used to describe evolutionary standoffs between species, such as hosts and the parasites or pathogens that attack them. But it also applies much closer to home. "Though we typically use this metaphor to describe evolutionary arms races between hosts and parasites or hosts and pathogens, the 'Red Queen Hypothesis' also characterizes the ongoing battles within our genome," says Mia Levine, a biologist at the University of Pennsylvania.

When DNA Turns Against Itself

Not all DNA works quietly for the benefit of the cell. Some sequences behave selfishly, Levine explains. Mobile genetic elements can copy or cut themselves out of one location and insert into another, sometimes damaging genes or other critical stretches of DNA in the process. Cells have evolved molecular defenses to counter these elements, using systems that detect them, shut them down, or physically block their movement.

This constant internal conflict raises a long-standing mystery. How can some of the most essential and reliable processes in life depend on proteins that must change rapidly in order to keep up with genetic threats?

Telomeres and Their Shape-Shifting Protectors

Levine and her colleagues set out to answer this question by studying fruit flies known as Drosophila melanogaster. They focused on genes involved in building telomeres, the protective caps at the ends of chromosomes that Levine compares to the plastic tips on shoelaces.

Their results, published in Science, show that although the role of these proteins remains the same, protecting chromosome ends, the proteins themselves are constantly evolving to defend against selfish DNA.

Chromosome ends must be shielded from sticking together, a failure that can trigger genetic instability, fertility problems, and even cell or organismal death. To prevent this, six proteins come together to form an end-protection complex that binds to telomeric DNA.

Fast Evolution in Essential Proteins

Among these six proteins, two stand out. The HipHop protein and its partner HOAP evolve much more quickly than the others, yet both are absolutely required for telomere protection.

"We offer a first glimpse of the fascinating biology faithfully preserved by an essential multiprotein complex whose subunits are under potent evolutionary pressure to change," says Levine.

To see whether these proteins must evolve together, or (coevolve), the team used gene-editing tools to replace the HipHop protein in D. melanogaster with the version from a closely related species, D. yakuba.

The outcome was dramatic. When the flies produced the D. yakuba version of HipHop instead of their own, they did not survive. Their cells showed widespread chromosome ends fusing together.

Six Amino Acids Make the Difference

The researchers then reversed part of the change. By switching just six adaptively evolving amino acids -- the building blocks of proteins -- in D. yakuba HipHop back to the D. melanogaster version, or by adding the D. yakuba form of HOAP, they were able to restore proper protein recruitment, protect telomeres, and keep the flies alive.

Levine explains that as HOAP changes to suppress internal genetic threats, HipHop is forced to adapt alongside it in order to maintain the partnership.

Exactly how selfish DNA interferes with these proteins is still unclear. "But similar evolutionary signatures in primates suggest this kind of compensatory evolution may be widespread and studying it could clarify how genomes retain ancient functions while adapting to ever-shifting threats," Levine says.

Research Team and Support

Mia T. Levine is an associate professor in the Department of Biology in the School of Arts & Sciences at the University of Pennsylvania. Additional authors include Briana N. Cruga, Hannah Futeran, Andrew Santiago-Frangos, and Sung-Ya Lin of Penn Arts & Sciences.

This research was supported by the National Institutes of Health (Grants R35GM124684 and R00GM147842.)