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Decoding Missense Variants by Incorporating Phase Separation via Machine Learning

Author

Listed:
  • Mofan Feng

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

  • Xiaoxi Wei

    (Shanghai Jiao Tong University)

  • Xi Zheng

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

  • Liangjie Liu

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

  • Lin Lin

    (Shanghai Jiao Tong University)

  • Manying Xia

    (Shanghai Jiao Tong University)

  • Guang He

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

  • Yi Shi

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

  • Qing Lu

    (Shanghai Jiao Tong University
    Chongqing General Hospital
    Shanghai Jiao Tong University School of Medicine
    Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases)

Abstract

Computational models have made significant progress in predicting the effect of protein variants. However, deciphering numerous variants of uncertain significance (VUS) located within intrinsically disordered regions (IDRs) remains challenging. To address this issue, we introduce phase separation, which is tightly linked to IDRs, into the investigation of missense variants. Phase separation is vital for multiple physiological processes. By leveraging missense variants that alter phase separation propensity, we develop a machine learning approach named PSMutPred to predict the impact of missense mutations on phase separation. PSMutPred demonstrates robust performance in predicting missense variants that affect natural phase separation. In vitro experiments further underscore its validity. By applying PSMutPred on over 522,000 ClinVar missense variants, it significantly contributes to decoding the pathogenesis of disease variants, especially those in IDRs. Our work provides insights into the understanding of a vast number of VUSs in IDRs, expediting clinical interpretation and diagnosis.

Suggested Citation

  • Mofan Feng & Xiaoxi Wei & Xi Zheng & Liangjie Liu & Lin Lin & Manying Xia & Guang He & Yi Shi & Qing Lu, 2024. "Decoding Missense Variants by Incorporating Phase Separation via Machine Learning," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52580-3
    DOI: 10.1038/s41467-024-52580-3
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