Malik Lab Maps Genetic Arms Races to Reveal Rules of Rapid Evolution and Antiviral Strategy

At the Fred Hutchinson Cancer Center, Harmit Malik runs a lab that thrives on competition, though the contest is between genomes rather than people. Malik, an HHMI investigator, and his team study rapid evolution: genetic change that unfolds over a few generations instead of thousands of years. Much of it, they argue, is driven by genetic conflicts, in which one entity maximizes its own success at another's expense.

The lab's premise is that these conflicts follow rules, and that learning them pays off in two directions. In Malik's words, the rules help researchers look back and understand how past arms races played out, and they also let researchers look forward and devise new strategies. The work is framed as a route to better disease treatments.

One conflict the team studies involves mosquito-borne alphaviruses such as Sindbis and chikungunya and the hosts they infect. These viruses manage to infect both insects and humans, even though the two hosts differ in body temperature and in immune system. Postdoc Tamanash Bhattacharya and colleagues recently identified a calibrated mechanism behind that versatility. It centers on a special stop codon in the viral genome, the signal that tells a cell to halt protein production. This codon, called the opal codon, produces what the team describes as a kinetic Goldilocks effect: the virus makes enough of a critical polyprotein to survive, but not so much that it disrupts other processes and drags down its own fitness.

Temperature determines how much the virus needs it. In humans, where bodies are hotter and replication moves fast, the virus relies on the opal codon to strike that balance. In mosquitoes, where temperatures are lower and replication slows, the balancing act is unnecessary, and the virus does not depend on the codon.

That raised a puzzle. Why does the opal codon persist in alphaviruses that infect only mosquitoes, where its special properties are not needed? In new research, again led by Bhattacharya, the team found that in both humans and insects the codon lets the virus build a compartment in which it can replicate unseen by the host's immune system. When the codon is lost, replication becomes more visible and more vulnerable to host immunity. Malik called it one of the simplest and most elegant ways to hide from immunity, and said its universal conservation among alphaviruses underlines its importance.

The team is now looking at other built-in strategies that let these viruses thrive in different hosts, including the ability to rapidly raise fitness in one host at the expense of the other. Malik says understanding these rules shows how much adaptive room these genomes have, and that any effort to design new antivirals will have to account for it.

The lab's second line of work addresses a counterintuitive pattern: essential genes, the ones organisms need to survive, grow and reproduce, are often among the fastest evolving. New research published in Science Advances, led by graduate student Jeremy Hollis, examines HJURP, a chaperone protein that marks the centromere, the site where chromosomes are pulled apart during cell division.

Despite that role, scientists had been unable to find HJURP in many animals. The Malik Lab combined remote homology detection, AlphaFold-based structural modeling and functional genetic techniques to show that most animals do have it. The protein evolves so quickly, possibly to keep pace with other fast-changing centromere components, that conventional search tools failed to recognize it.

Taken together, the two projects point the same way: rapid evolution can hide both a virus's vulnerabilities and a cell's essential machinery, and the lab's next steps include tracing further host-switching strategies in alphaviruses.