Multi-centric origins and gene flow shape the diversity of β-thalassemia mutations in Southern East Asia

Qianqian Zhang, Jialong Li, Haoyang Huang, Xuan Shang, Yuhua Ye, Wei Zhang, Peng Lin, Yi Gong, Boon-Peng Hoh, Qingming Luo, Tizhen Yan, Xinghua Pan, Mark Stoneking, Shuhua Xu, Xiangmin Xu () and Lian Deng ()
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Qianqian Zhang: Postdoctoral Innovation Practice Base of Southern Medical University, Dongguan Maternal and Child Health Care Hospital
Jialong Li: Southern Medical University, Department of Medical Genetics, School of Basic Medical Sciences
Haoyang Huang: Southern Medical University, Department of Medical Genetics, School of Basic Medical Sciences
Xuan Shang: Southern Medical University, Department of Medical Genetics, School of Basic Medical Sciences
Yuhua Ye: Southern Medical University, Department of Medical Genetics, School of Basic Medical Sciences
Wei Zhang: Southern Medical University, Department of Medical Genetics, School of Basic Medical Sciences
Peng Lin: Dongguan Maternal and Children Health Care Hospital, Prenatal Diagnostic Center
Yi Gong: People’s Hospital of Zhengzhou University, Henan Provincial Key Laboratory of Genetic Diseases, Henan Provincial People’s Hospital
Boon-Peng Hoh: IMU University, Division of Applied Biomedical Sciences and Biotechnology, School of Health Sciences
Qingming Luo: Postdoctoral Innovation Practice Base of Southern Medical University, Dongguan Maternal and Child Health Care Hospital
Tizhen Yan: Dongguan Maternal and Children Health Care Hospital, Prenatal Diagnostic Center
Xinghua Pan: Postdoctoral Innovation Practice Base of Southern Medical University, Dongguan Maternal and Child Health Care Hospital
Mark Stoneking: Max Planck Institute for Evolutionary Anthropology, Department of Evolutionary Genetics
Shuhua Xu: Fudan University, State Key Laboratory of Genetics and Development of Complex Phenotypes, Center for Evolutionary Biology, School of Life Sciences
Xiangmin Xu: Southern Medical University, Department of Medical Genetics, School of Basic Medical Sciences
Lian Deng: Fudan University, State Key Laboratory of Genetics and Development of Complex Phenotypes, Center for Evolutionary Biology, School of Life Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Over 400 β-thalassemia mutations show population-differentiated spectra, yet their origins and evolution remain unclear. Focusing on targeted sequencing of 20,222 individuals and 510 β-thalassemia patients in southern China, we identified three major haplotype groups (HG) at the β-globin locus and observed highest haplotype diversity for CD41/42, -50, and HbE among 13 prevalent mutations in 993 carriers. Allele dating suggest these mutations emerged during agricultural expansions in the past 7420 years, represented by CD41/42 arising in mainland China. However, the -50 mutation likely originated on Hainan Island within 3900 years, subsequently spreading to the mainland and experiencing lineage-specific selection. HbE exhibits substantial haplotype heterogeneity in Yunnan, with network analyses indicating bidirectional disseminations between southern China and South/Southeast Asia. We further suggest an ameliorating effect of HG2, associated with elevated hemoglobin and fetal hemoglobin levels. These findings highlight multi-centric origins of β-thalassemia mutations and underscore the evolutionary context shaping their clinical impact.

Date: 2025
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DOI: 10.1038/s41467-025-65019-0

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