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Long-read sequencing of 945 Han individuals identifies structural variants associated with phenotypic diversity and disease susceptibility

Author

Listed:
  • Jiao Gong

    (Fudan University)

  • Huiru Sun

    (Fudan University)

  • Kaiyuan Wang

    (East China Normal University)

  • Yanhui Zhao

    (Fudan University)

  • Yechao Huang

    (Fudan University)

  • Qinsheng Chen

    (Fudan University)

  • Hui Qiao

    (Fudan University)

  • Yang Gao

    (Fudan University)

  • Jialin Zhao

    (Fudan University)

  • Yunchao Ling

    (University of the Chinese Academy of Sciences, Chinese Academy of Sciences)

  • Ruifang Cao

    (University of the Chinese Academy of Sciences, Chinese Academy of Sciences)

  • Jingze Tan

    (Fudan University)

  • Qi Wang

    (Fudan University)

  • Yanyun Ma

    (Fudan University)

  • Jing Li

    (Fudan University)

  • Jingchun Luo

    (Fudan University)

  • Sijia Wang

    (University of Chinese Academy of Sciences, Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Jiucun Wang

    (Fudan University
    Chinese Academy of Medical Sciences)

  • Guoqing Zhang

    (University of the Chinese Academy of Sciences, Chinese Academy of Sciences)

  • Shuhua Xu

    (Fudan University)

  • Feng Qian

    (Fudan University)

  • Fang Zhou

    (East China Normal University)

  • Huiru Tang

    (Fudan University)

  • Dali Li

    (East China Normal University)

  • Fritz J. Sedlazeck

    (Baylor College of Medicine)

  • Li Jin

    (Fudan University
    Chinese Academy of Medical Sciences)

  • Yuting Guan

    (East China Normal University)

  • Shaohua Fan

    (Fudan University)

Abstract

Genomic structural variants (SVs) are a major source of genetic diversity in humans. Here, through long-read sequencing of 945 Han Chinese genomes, we identify 111,288 SVs, including 24.56% unreported variants, many with predicted functional importance. By integrating human population-level phenotypic and multi-omics data as well as two humanized mouse models, we demonstrate the causal roles of two SVs: one SV that emerges at the common ancestor of modern humans, Neanderthals, and Denisovans in GSDMD for bone mineral density and one modern-human-specific SV in WWP2 impacting height, weight, fat, craniofacial phenotypes and immunity. Our results suggest that the GSDMD SV could serve as a rapid and cost-effective biomarker for assessing the risk of cisplatin-induced acute kidney injury. The functional conservation from human to mouse and widespread signals of positive natural selection suggest that both SVs likely influence local adaptation, phenotypic diversity, and disease susceptibility across diverse human populations.

Suggested Citation

  • Jiao Gong & Huiru Sun & Kaiyuan Wang & Yanhui Zhao & Yechao Huang & Qinsheng Chen & Hui Qiao & Yang Gao & Jialin Zhao & Yunchao Ling & Ruifang Cao & Jingze Tan & Qi Wang & Yanyun Ma & Jing Li & Jingch, 2025. "Long-read sequencing of 945 Han individuals identifies structural variants associated with phenotypic diversity and disease susceptibility," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56661-9
    DOI: 10.1038/s41467-025-56661-9
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