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<p>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 <i>GSDMD</i> for bone mineral density and one modern-human-specific SV in <i>WWP2</i> impacting height, weight, fat, craniofacial phenotypes and immunity. Our results suggest that the <i>GSDMD</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月10日

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  • 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,
  • Jingchun Luo,
  • Sijia Wang,
  • Jiucun Wang,
  • Guoqing Zhang,
  • Shuhua Xu,
  • Feng Qian,
  • Fang Zhou,
  • Huiru Tang,
  • Dali Li,
  • Fritz J. Sedlazeck,
  • Li Jin,
  • Yuting Guan,
  • Shaohua Fan

摘要

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.