Two harmful gene variants can combine to restore normal protein function

In a groundbreaking study published in the in Proceedings of the National Academy of Sciences (PNAS), scientists at Pacific Northwest Research Institute (PNRI) have overturned a long-held belief in genetics: that inheriting two harmful variants in the same gene always worsens disease. Instead, the team found that, in many cases, two harmful variants can actually restore normal protein function.

The research focused on a human enzyme called argininosuccinate lyase (ASL), which plays a critical role in removing toxic ammonia from the body. Variants in ASL that decrease its activity cause one of the urea cycle disorders, a set of rare and potentially life-threatening metabolic diseases.

By experimentally measuring the functional impact of several thousand individual variants and variant combinations, PNRI researchers discovered that over 60% of pairs that were individually damaging could, together, bring enzyme activity back to healthy levels.

This work shows that genetic variants don't act independently in many important cases. For a defined group of genes, the default assumptions we use to predict disease risk simply don't hold."

Michelle Tang, Ph.D., PNRI Staff Scientist and lead author of the study

This phenomenon is known as intragenic complementation. It occurs when damage caused by one variant is offset by another variant in a different part of the same protein. The mechanism was first proposed in 1964 by Francis Crick and Leslie Orgel, but until now had not been tested systematically or shown to be common or predictable at scale.

The study was led by scientists in the Dudley Lab at PNRI, in collaboration with clinicians and researchers at Children's National Hospital, St. Jude Children's Research Hospital, George Mason University, and the University of Washington.

To make these interactions predictable, the research team developed an AI-based model that accurately forecasted whether two variants would restore protein function. The model achieved nearly 100% accuracy in predicting intragenic complementation in ASL as well as in a second human enzyme, fumarase, suggesting these rules apply broadly 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."

The researchers estimate that approximately 4% of human genes have the structural features that allow this type of interaction. For these genes, standard genetic predictions can overestimate disease risk, particularly for people who carry two different variants in the same gene.