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

Author

Listed:
  • Maryam May

    (The Australian National University)

  • Aaron Chuah

    (The Australian National University
    National Cancer Centre Singapore)

  • Nicole Lehmann

    (The Australian National University)

  • Llewelyn Goodall

    (The Australian National University
    The Australian National University)

  • Vicky Cho

    (The Australian National University)

  • T. Daniel Andrews

    (The Australian National University
    The Australian National University)

Abstract

Missense mutations that disrupt protein structural stability are a common pathogenic mechanism in human genetic disease. Here, we quantify potential disruption of protein stability due to amino acid substitution and show that functionally constrained proteins are less susceptible to large mutational changes in stability. Mechanistically, this relates to greater intrinsic disorder among constrained proteins and to increased B-factors in the ordered regions of constrained proteins. This phenomenon means that constrained proteins exhibit smaller stability effects due to missense mutations, and partly explains why overtransmission of pathogenic missense variation is less prevalent in genetic disorders characterised by protein truncations. We show that the most functionally constrained proteins are depleted of both destabilising and overly-stabilising amino acid variation in disease-free populations. Despite this, amino acid substitutions with large stability effects in functionally constrained proteins are still highly prevalent among pathogenic human genetic variation. Importantly, we observe that there are approximately five times more missense variants with large stability effects than there are unambiguous loss-of-function mutations. Missense variants with disruption of stability effects recapitulate the per-gene patterns of functional constraint observed with protein truncating loss-of-function variation, yet their relative abundance abrogates difficulties encountered when estimating functional constraint for the shortest human genes.

Suggested Citation

  • Maryam May & Aaron Chuah & Nicole Lehmann & Llewelyn Goodall & Vicky Cho & T. Daniel Andrews, 2025. "Functionally constrained human proteins are less prone to mutational instability from single amino acid substitutions," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57757-y
    DOI: 10.1038/s41467-025-57757-y
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    1. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    2. Monkol Lek & Konrad J. Karczewski & Eric V. Minikel & Kaitlin E. Samocha & Eric Banks & Timothy Fennell & Anne H. O’Donnell-Luria & James S. Ware & Andrew J. Hill & Beryl B. Cummings & Taru Tukiainen , 2016. "Analysis of protein-coding genetic variation in 60,706 humans," Nature, Nature, vol. 536(7616), pages 285-291, August.
    3. Bian Li & Dan M. Roden & John A. Capra, 2022. "The 3D mutational constraint on amino acid sites in the human proteome," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
    5. Ni Huang & Insuk Lee & Edward M Marcotte & Matthew E Hurles, 2010. "Characterising and Predicting Haploinsufficiency in the Human Genome," PLOS Genetics, Public Library of Science, vol. 6(10), pages 1-11, October.
    6. Siwei Chen & Laurent C. Francioli & Julia K. Goodrich & Ryan L. Collins & Masahiro Kanai & Qingbo Wang & Jessica Alföldi & Nicholas A. Watts & Christopher Vittal & Laura D. Gauthier & Timothy Poterba , 2024. "A genomic mutational constraint map using variation in 76,156 human genomes," Nature, Nature, vol. 625(7993), pages 92-100, January.
    7. Siwei Chen & Laurent C. Francioli & Julia K. Goodrich & Ryan L. Collins & Masahiro Kanai & Qingbo Wang & Jessica Alföldi & Nicholas A. Watts & Christopher Vittal & Laura D. Gauthier & Timothy Poterba , 2024. "Author Correction: A genomic mutational constraint map using variation in 76,156 human genomes," Nature, Nature, vol. 626(7997), pages 1-1, February.
    8. Konrad J. Karczewski & Laurent C. Francioli & Grace Tiao & Beryl B. Cummings & Jessica Alföldi & Qingbo Wang & Ryan L. Collins & Kristen M. Laricchia & Andrea Ganna & Daniel P. Birnbaum & Laura D. Gau, 2020. "The mutational constraint spectrum quantified from variation in 141,456 humans," Nature, Nature, vol. 581(7809), pages 434-443, May.
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