Scientists at the Pacific Northwest Research Institute (PNRI) have published findings in the Proceedings of the National Academy of Sciences (PNAS) that challenge a longstanding assumption in genetics. Their research suggests that inheriting two harmful variants within the same gene does not always worsen disease outcomes. Instead, they found that, in many cases, two such variants can combine to restore normal protein function.
The study centered on argininosuccinate lyase (ASL), an enzyme essential for removing toxic ammonia from the body. Variants that reduce ASL activity are linked to urea cycle disorders, which are rare and potentially serious metabolic diseases. By testing thousands of individual and combined genetic variants, PNRI researchers discovered that more than 60% of variant pairs—each damaging on their own—could together bring enzyme activity back to healthy levels.
"This work shows that genetic variants don't act independently in many important cases," said Michelle Tang, Ph.D., PNRI Staff Scientist and lead author of the study. "For a defined group of genes, the default assumptions we use to predict disease risk simply don't hold."
This phenomenon is known as intragenic complementation, where one variant's damage is offset by another variant located elsewhere within the same protein. Although this mechanism was first suggested by Francis Crick and Leslie Orgel in 1964, it had not previously been systematically tested or shown to be common across different genes.
The project was led by scientists from the Dudley Lab at PNRI with collaborators from Children's National Hospital, St. Jude Children's Research Hospital, George Mason University, and the University of Washington.
To help make these interactions predictable for other genes and proteins, the team developed an artificial intelligence-based model capable of accurately forecasting whether two variants would restore protein function. The model achieved nearly complete accuracy when predicting intragenic complementation for both ASL and another human enzyme called fumarase. This result suggests these types of interactions may be widespread across the human genome.
"We've shown that, in many cases, two damaging variants can work together to restore protein function," said Aimée Dudley, Ph.D., PNRI Senior Investigator who led the study. "This kind of genetic interaction is not an isolated exception but a widespread and underappreciated way that variants can interact, especially in rare disease contexts."
Researchers estimate about 4% of human genes have structural features allowing this type of interaction. For those genes, standard genetic predictions may overstate disease risk for individuals carrying two different variants within a single gene.
