A hidden genetic war is taking place inside your DNA

This idea has long been used to describe evolutionary differences between species, such as hosts and the parasites or pathogens that attack them. But it also applies much closer to home. “Although we usually 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 in our genome,” says Mia Levine, a biologist at the University of Pennsylvania.

When DNA turns against itself

Not all DNA works silently to benefit the cell. Some sequences behave selfishly, Levine explains. Mobile genetic elements can be copied or cut from one location and inserted into another, sometimes damaging genes or other critical stretches of DNA in the process. Cells have developed molecular defenses against these elements with systems that detect them, shut them down, or physically block their movement.

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

Telomeres and their shape-changing protectors

Levine and his 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 likens to the plastic tips on shoelaces.

Their results, published in Scienceshow that although the role of these proteins remains the same, to protect the ends of chromosomes, the proteins themselves are constantly evolving to defend against selfish DNA.

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

Rapid development of essential proteins

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

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

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

The result was dramatic. When the flies produced D. Jacob version of HipHop instead of their own, they didn’t survive. Their cells showed extended 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 protein – in D. Jacob HipHop back to D. melanogaster version or addition D. Jacob 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 along with it in order to maintain the partnership.

It is still not clear how exactly the selfish DNA interferes with these proteins. “But similar evolutionary signatures in primates suggest that this kind of compensatory evolution may be widespread, and studying it could shed light on how genomes maintain ancient functions while adapting to ever-changing threats,” says Levine.

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.)