Functionally constrained human proteins are less prone to mutational instability from single amino acid substitutions

Area of Science:

• Genetics
• Biochemistry
• Computational Biology

Background:

• Missense mutations altering protein stability are a key cause of human genetic diseases.
• Understanding how protein constraint affects mutation impact is crucial for disease research.

Purpose of the Study:

• To quantify the impact of amino acid substitutions on protein stability.
• To investigate the relationship between functional constraint and susceptibility to stability-altering mutations.
• To explore the prevalence and implications of missense variants with large stability effects in human genetic variation.

Main Methods:

• Quantitative analysis of amino acid substitutions and their effects on protein structural stability.
• Assessment of intrinsic disorder and B-factors in functionally constrained proteins.
• Comparison of missense variant effects with loss-of-function mutations across human genes.

Main Results:

• Functionally constrained proteins exhibit reduced susceptibility to large stability changes from missense mutations.
• Constrained proteins show greater intrinsic disorder and higher B-factors in ordered regions.
• Missense variants with significant stability effects are prevalent in pathogenic variation, outnumbering unambiguous loss-of-function mutations.
• Stability-altering missense variants mirror functional constraint patterns of truncating mutations, aiding analysis in short genes.

Conclusions:

• Protein functional constraint modulates the impact of missense mutations on stability.
• Missense variants disrupting protein stability are a significant contributor to human genetic disease.
• The study provides a framework for understanding missense variant pathogenicity and functional constraint, particularly in challenging gene contexts.