ArticlebioRxiv : the preprint server for biology2025
Protein structure shapes natural genetic variation and
Article in bioRxiv : the preprint server for biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Protein structural context strongly influences the functional outcomes of mutations, but exploiting this intuition to interpret the consequences of natural variants has been limited by the paucity of structural information. Here, we show that simple molecular heuristics based on predicted protein structures-solvent accessibility and the local complexity of the protein fold-are strong predictors of protein-coding variation in genomes from yeast to plants to humans. Polymorphisms in structured and unstructured regions alike were subject to these constraints, revealing fine-grained selection across amino acid residues and secondary structures. The same analyses distinguished deleterious variants in datasets from existing deep mutational scans. Extending the metrics to
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