Dissecting disease inheritance modes in a three-dimensional protein network challenges the "guilt-by-association"...

Area of Science:

• Genetics
• Molecular Biology
• Bioinformatics

Background:

• Understanding disease-associated mutations is crucial for human health.
• Classifying mutations by inheritance and molecular type provides insights into their effects.
• Protein interactions are central to cellular function and disease.

Purpose of the Study:

• To investigate the relationship between mutation types, inheritance modes, and disease causation.
• To analyze mutation effects within a 3D protein interactome network.
• To clarify the molecular mechanisms of disease-associated mutations, particularly truncating ones.

Main Methods:

• Classified 82,833 disease mutations by inheritance (recessive/dominant) and type (in-frame/truncating).
• Examined mutation effects in a 3D protein interactome network with atomic-resolution interfaces.
• Analyzed mutation enrichment in interface regions versus inter-interface regions.

Main Results:

• Recessive mutations at interaction interfaces often lead to the same disease ('guilt-by-association').
• This principle does not hold for dominant mutations.
• Recessive truncating mutations at interfaces are more likely to cause the same disease than dominant truncating mutations, which are enriched between interfaces.
• Dominant truncating mutations can result in partially functional proteins.

Conclusions:

• The 'guilt-by-association' principle is limited, especially for dominant mutations.
• Truncating mutations are not always 'knockout' alleles and can yield functional proteins.
• Findings aid in understanding disease mechanisms for numerous genes and mutations.