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Impact of rare non-coding variants on human diseases through alternative polyadenylation outliers

Author

Listed:
  • Xudong Zou

    (Shenzhen Bay Laboratory)

  • Zhaozhao Zhao

    (Fudan University)

  • Yu Chen

    (Fudan University)

  • Kewei Xiong

    (Shenzhen Bay Laboratory)

  • Zeyang Wang

    (Shenzhen Bay Laboratory)

  • Shuxin Chen

    (Shenzhen Bay Laboratory)

  • Hui Chen

    (Shenzhen Bay Laboratory)

  • Gong-Hong Wei

    (Shanghai Medical College of Fudan University)

  • Shuhua Xu

    (Fudan University
    Fudan University)

  • Wei Li

    (Irvine)

  • Ting Ni

    (Fudan University
    Fudan University
    Inner Mongolia University)

  • Lei Li

    (Shenzhen Bay Laboratory)

Abstract

Although rare non-coding variants (RVs) play crucial roles in complex traits and diseases, understanding their mechanisms and identifying disease-associated RVs continue to be major challenges. Here we constructed a comprehensive atlas of alternative polyadenylation (APA) outliers (aOutliers), including 1334 3′ UTR and 200 intronic aOutliers, from 15,201 samples across 49 human tissues. These aOutliers exhibit unique characteristics from transcription or splicing outliers, with a pronounced RV enrichment. Mechanistically, aOutlier-RVs alter poly(A) signals and splicing sites, and perturbation indeed triggers APA events. Furthermore, we developed a Bayesian-based APA RV prediction model, which successfully pinpointed a specific set of 1799 RVs impacting 278 genes with significantly large disease effect sizes. Notably, we observed a convergence effect between rare and common cancer variants, exemplified by regulation in the DDX18 gene. Together, this study introduced an APA-enhanced framework for genome annotation, underscoring APA’s role in uncovering functional RVs linked to complex traits and diseases.

Suggested Citation

  • Xudong Zou & Zhaozhao Zhao & Yu Chen & Kewei Xiong & Zeyang Wang & Shuxin Chen & Hui Chen & Gong-Hong Wei & Shuhua Xu & Wei Li & Ting Ni & Lei Li, 2025. "Impact of rare non-coding variants on human diseases through alternative polyadenylation outliers," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55407-3
    DOI: 10.1038/s41467-024-55407-3
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