Surveying the genetic battlefield to uncover the rules of rapid evolution

The Malik Lab thrives on competition. But for HHMI investigator Harmit Malik and his team at the Fred Hutchinson Cancer Center, it’s the genomes—not the people—that are in conflict. The lab studies rapid evolution—the genetic changes that happen in a species over a few generations rather than thousands of years. These fast changes are often fueled by genetic conflicts—competitions between different entities trying to maximize their success at the expense of another.

By uncovering the evolutionary rules that guide these conflicts, Malik and his team are revealing insights that could help in the development of better disease treatments.

“Not only do these rules help us to look back in evolution and understand how these arms races played out, but these rules also let us look forward and come up with new strategies,” Malik says.

Discovering a viral thermometer

One of the competitions the lab studies is the conflict between mosquito-borne alphaviruses like Sindbis and chikungunya and their hosts. These viruses are successful at infecting both insects and humans despite the different body temperatures and immune systems of these hosts.

The team, including postdoc Tamanash Bhattacharya, recently uncovered a carefully calibrated system that helps enable this versatility. A special stop codon in the virus’s genome, which signals the cell to halt protein production, enables a “kinetic Goldilocks”: It allows the virus to produce just enough of a critical polyprotein to survive, but not too much to slow down other processes that would lead to a decline in the virus’s fitness.

In humans, where body temperatures are hotter and replication happens quickly, the virus relies on this codon, called the opal codon, to enable this production balancing act. In mosquitoes, where temperatures are colder and replication slows down, this balancing act isn’t necessary, and the virus does not need to rely on this special stop codon.

Hiding from the immune system

These insights led the team to another question: Why is the opal codon still found in alphaviruses that only infect mosquitoes, even though its special properties aren’t needed?

In new research, also led by Bhattacharya, the team found that in both humans and insects, the opal codon enables the virus to create a compartment where it can replicate without being seen by the host’s immune system. If the opal codon is lost, viral replication becomes more visible and more susceptible to host immunity.

“This is one of the simplest and most elegant ways to hide yourself from immunity, and the fact that it is universally conserved in alphaviruses just reinforces how important it is,” Malik says.

Now, the team is working to understand other built-in strategies these viruses use to thrive in different hosts, including the ability to quickly ramp up fitness in one host at the expense of the other.

“Learning the rules by which they do this gives us insight into the sheer adaptive possibilities that these genomes can experience,” Malik says. “That’s important because any attempts to make new antivirals will have to take this into account.”

Evolution of essential genes

It might seem counterintuitive, but essential genes that organisms need to survive, grow and reproduce are often among the fastest evolving. The Malik Lab is uncovering these changes and why they occur.

New research, published in Science Advances and led by graduate student Jeremy Hollis, examines HJURP, a chaperon protein that marks the centromere, the site where chromosomes are pulled apart during cell division.

Despite its importance, scientists couldn’t find HJURP in many animals. The Malik Lab used remote homology detection, AlphaFold-based structural modeling and functional genetic techniques to show that most animals do have HJURP. Because the protein evolves so rapidly, possibly to keep pace with other fast-changing centromere components, conventional tools couldn’t detect it.

Separate research, also published in Science Advances led by former postdoc Ching-Ho Chang, investigated Mst77F, a protamine that packages DNA in fruit fly sperm. Protamines, which are essential for male fertility, are among the fastest-evolving genes in animals, and scientists couldn’t figure out why. The Malik Lab found that Mst77F is rapidly evolving to suppress a form of genetic cheating that kills X-bearing sperm and skews broods toward sons.

Who’s behind this story?

Sadie Harley

BSc Life Sciences & Ecology. Microbiology lab background with pharmaceutical news experience in oil, gas, and renewable industries.

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Robert Egan

Bachelor’s in mathematical biology, Master’s in creative writing. Well-traveled with unique perspectives on science and language.

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