News from Dudley Lab
A recent study from PNRI’s Dudley Lab published in Proceedings of the National Academy of Sciences is challenging a long-held assumption in genetics: that two harmful variants in the same gene always make disease worse.
Instead, the researchers found that in many cases, two damaging variants can actually work together to restore protein function–a phenomenon known as intragenic complementation. Long theorized but rarely demonstrated at scale, this interaction has important implications for how genetic risk is predicted, particularly in rare disease.
The findings quickly drew attention from both scientific and mainstream media. The Scientist highlighted how the team systematically tested thousands of variant combinations, revealing that many variants considered harmful in isolation can behave very differently together.
The work also reached a broader audience through Popular Mechanics, which explored how this discovery reshapes how we think about inherited disease and so-called “bad genes.”
Within the rare disease community, the study resonated strongly. The National Urea Cycle Disorders Foundation shared the research with families and clinicians, underscoring its relevance for people affected by ASL deficiency and related urea cycle disorders.
Additional coverage from Phys.org and Technology Networks further amplified the message: genetic variants don’t always act alone, and those interactions matter.
Taken together, this coverage points to a growing shift in how genetic risk is understood. For a subset of genes—estimated to be about 4% of the human genome—standard models can overestimate disease risk by treating variants in isolation. Paying attention to how variants interact gives a more accurate picture of what’s happening biologically, and moves us closer to truly personalized care.
Learn more:
- PNRI’s press release on the findings
- The study in Proceedings of the National Academy of Sciences