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

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 () and Shaohua Fan ()
Additional contact information
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
Jiucun Wang: Fudan University
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
Yuting Guan: East China Normal University
Shaohua Fan: Fudan University

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56661-9

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