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Mutation Edgotype Drives Fitness Effect in Human
1Department of Bioengineering, McGill University, Montreal, QC, Canada.
Frontiers in Bioinformatics
|October 28, 2022
Summary
Missense mutations can alter protein-protein interaction networks. This study reveals that mutations not disrupting these networks are mostly neutral, while those affecting protein stability are often detrimental, impacting organismal fitness.
Area of Science:
- Genomics
- Systems Biology
- Biophysics
Background:
- Missense mutations can affect protein-protein interaction networks (interactome networks) in various ways.
- The impact of different interactome perturbation patterns, termed 'edgotypes,' on organismal fitness is not well understood.
Purpose of the Study:
- To estimate the fitness effects of missense mutations based on their distinct interactome perturbation patterns in humans.
- To classify mutations as quasi-wild-type (no PPI disruption), edgetic (interface disruption), or quasi-null (stability disruption).
Main Methods:
- Mapping pathogenic and common non-pathogenic mutations onto human protein-protein interaction structural models.
- Employing structure-based calculations to categorize mutations into quasi-wild-type, edgetic, or quasi-null.
- Estimating fitness effects using predicted and experimental interactome perturbation data.
Main Results:
- Over 40% of quasi-wild-type mutations appear neutral, with the rest being mildly deleterious.
- >75% of edgetic mutations are only mildly deleterious.
- Up to 75% of quasi-null mutations may be strongly detrimental to fitness.
Conclusions:
- Mutations not disrupting interactomes are generally neutral.
- Most human protein-protein interactions are under strong purifying selection.
- Protein stability is crucial for human survival.
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