A unified analysis of evolutionary and population constraint in protein domains highlights structural features and pathogenic sites
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Abstract
Protein evolution is constrained by structure and function, creating patterns in residue conservation that are routinely exploited to predict structure and other features. Similar constraints should affect variation across individuals, but it is only with the growth of human population sequencing that this has been tested at scale. Now, human population constraint has established applications in pathogenicity prediction, but it has not yet been explored for structural inference. Here, we map 2.4 million population variants to 5885 protein families and quantify residue-level constraint with a new Missense Enrichment Score (MES). Analysis of 61,214 structures from the PDB spanning 3661 families shows that missense depleted sites are enriched in buried residues or those involved in small-molecule or protein binding. MES is complementary to evolutionary conservation and a combined analysis allows a new classification of residues according to a conservation plane. This approach finds functional residues that are evolutionarily diverse, which can be related to specificity, as well as family-wide conserved sites that are critical for folding or function. We also find a possible contrast between lethal and non-lethal pathogenic sites, and a surprising clinical variant hot spot at a subset of missense enriched positions.
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Unified inference of missense variant effects and gene constraints in the human genome
Huang, Y.-F. (2020) · PLoS Genetics · doi:10.1371/journal.pgen.1008922 · Cited by 31 · see citing works
Huang, Y.-F., & Golding, G. B. (2014) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003429 · Cited by 25 · see citing works
Three-dimensional missense tolerance ratio analysisPreprint
Perszyk, R. E., Kristensen, A. S., Lyuboslavsky, P. N., & Traynelis, S. F. (2021) · Genome Research · doi:10.1101/gr.275528.121 · Cited by 25 · see citing works
Melloni, G. E. M., de Pretis, S., Riva, L., Pelizzola, M., Ceol, A. G. M., Costanza, J., Müller, H., & Zammataro, L. A. (2016) · BMC Bioinformatics · doi:10.1186/s12859-016-0935-7 · Cited by 19 · see citing works
MacGowan, S. A., Madeira, F., Britto‐Borges, T., Schmittner, M. S., Cole, C., & Barton, G. J. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/127050 · Cited by 18 · see citing works
Self-citationAnkyrin repeats in context with human population variation
Utgés, J. S., Tsenkov, M. I., Dietrich, N. J. M., MacGowan, S. A., & Barton, G. J. (2021) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1009335 · Cited by 13 · see citing works
Self-citationRichard Dickerson, Molecular Clocks, and Rates of Protein Evolution
Alvarez‐Ponce, D. (2020) · Journal of Molecular Evolution · doi:10.1007/s00239-020-09973-x · Cited by 10 · see citing works
Utgés, J. S., MacGowan, S. A., Ives, C. M., & Barton, G. J. (2024) · Communications Biology · doi:10.1038/s42003-024-05970-8 · Cited by 10 · see citing works
Self-citationZhang, X., Theotokis, P. I., Li, N., the SHaRe Investigators, Wright, C. F., Samocha, K. E., Whiffin, N., & Ware, J. S. (2022) · medRxiv · doi:10.1101/2022.02.16.22271023 · Cited by 8 · see citing works
MacGowan, S. A. (2024) · Zenodo (CERN European Organization for Nuclear Research) · doi:10.5281/zenodo.10731678 · Cited by 1 · see citing works
Self-citationBorges, T. B., Madeira, F., & MacGowan, S. A. (2024) · Zenodo (CERN European Organization for Nuclear Research) · doi:10.5281/zenodo.10732460 · Cited by 1 · see citing works
Self-citationMacGowan, S. A. (2024) · Zenodo (CERN European Organization for Nuclear Research) · doi:10.5281/zenodo.10731990 · Cited by 1 · see citing works
Self-citationMadeira, F. (2024) · Zenodo (CERN European Organization for Nuclear Research) · doi:10.5281/zenodo.10732088 · Cited by 1 · see citing works
Self-citation
Flagged first, then by citations
Cited by
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LIGYSIS-web: a resource for the analysis of protein-ligand binding sites
Utgés, J. S., MacGowan, S. A., & Barton, G. J. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf411 · Cited by 12 · see citing works
Self-citationUtgés, J. S., MacGowan, S. A., Ives, C. M., & Barton, G. J. (2024) · Communications Biology · doi:10.1038/s42003-024-05970-8 · Cited by 10 · see citing works
Self-citationIntroduction to androgenetics: terminology, approaches, and impactful studies across 60 years
Akbari, A., Kasak, L., & Laan, M. (2025) · Andrology · doi:10.1111/andr.13835 · Cited by 2 · see citing works
CharacTERT: A Machine Learning Tool for Classifying hTERT Missense VariantsPreprint
Parra, G. B., Pan, Q., Myung, Y., Portelli, S., Nelson, N. E., Dickinson, J. L., Lucas, S. E. M., Holien, J. K., Bryan, T. M., & Ascher, D. B. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.05.18.725793 · Cited by 1 · see citing works
(2026) · doi:10.1098/rsob.250230
Self-citationFei, X.-Y., Gu, J., Zhou, C., Liu, Y., Li, Z., & Kang, Y.-L. (2026) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.6c00969
Evolutionary constraint and population variation across coagulation genes
Seidizadeh, O., Chand, H., Cairo, A., & Peyvandi, F. (2026) · Research and Practice in Thrombosis and Haemostasis · doi:10.1016/j.rpth.2026.106980
Characteristics of predicated pathogenic missense variants in human genes for Mendelian disorders
Song, R., Bai, X., & Fan, X. (2026) · Frontiers in Bioinformatics · doi:10.3389/fbinf.2026.1947929
Network analysis of correlated conformational dynamics across the evolution of influenza A virus NS1Preprint
Bastiray, A., Gonzales, J. E., Hwang, W., & Cho, J.-H. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.09.29.755463
- Authors
- MacGowan, S. A., Madeira, F., Britto-Borges, T., & Barton, G. J.
- Affiliations
- University of Dundee (GB)
- European Bioinformatics Institute (GB)
- Corresponding author
- Barton, Geoffrey J.
- Venue
- Communications Biology
- Published
- 2024-04-11
- Volume
- 7
- Issue
- 1
- Pages
- 447-447
- ISSN
- 2399-3642 (ISSN-L)
- PMC
- PMC11009406
- OpenAlex
- W4394724740
- Cited by
- 8
- References
- 105
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 1
- FWCI
- 2.12
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Communications Biology (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- RCUK | Biotechnology and Biological Sciences Research Council (BB/J019364/1, BB/R014752/1)
- Wellcome Trust (101651/Z/13/Z, 218259/Z/19/Z, 100150/Z/12/Z)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- protein domains, population constraints, missense mutations, amino acid conservation, protein structure prediction, pathogenicity prediction, buried residues, protein binding sites
- MeSH terms
- Protein Domains, Base Sequence, Humans, Protein Binding, Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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