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Updated: Jun 24, 2026
06:41
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
Allostery is a widespread cause of loss-of-function variant pathogenicity
Xiaotian Liao1,2, Ben Lehner3,4,5,6
1Wellcome Sanger Institute, Cambridge, UK.
Nature Communications
|June 22, 2026
Summary
Allosteric mutations, which affect protein function without direct contact, are a major cause of human genetic diseases. Understanding these effects is crucial for predicting disease and protein evolution.
Area of Science:
- Molecular Biology
- Genetics
- Biophysics
Background:
- Allosteric communication is vital for protein regulation and drug action.
- Gain-of-function allosteric variants drive oncogene activation, but their role in genetic disease and evolution is less understood.
Purpose of the Study:
- To develop a framework to distinguish functional disruption from destabilization caused by mutations.
- To investigate the role of allosteric effects in human genetic diseases and protein evolution.
Main Methods:
- Developed a comparative framework to analyze mutation effects.
- Applied the framework to diverse datasets including experimental measurements and proteome-wide evolutionary data.
- Utilized biophysical stability predictions.
Main Results:
- Allosteric mechanisms are a significant cause of loss-of-function variant pathogenicity in human genetic diseases.
- A conserved distance-dependent decay of allosteric mutational effects was observed outside active sites.
- Allosteric effects are widespread across the human proteome.
Conclusions:
- Allosteric effects are a critical, underappreciated mechanism in genetic disease.
- Mapping and predicting allosteric effects is essential for understanding protein function and disease.
- Further research into allosteric mechanisms can inform therapeutic strategies.
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