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

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.

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Journal
Nature Communications
Published
2025-11-20
DOI
https://doi.org/10.1038/s41467-025-65019-0
Primary Topic
Hemoglobinopathies and Related Disorders
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Yuhua Ye, Peng Lin, Haoyang Huang, Shuhua Xu et al.
Nature Communications
Hemoglobinopathies and Related Disorders
article

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

Yuhua Ye, Peng Lin, Haoyang Huang, Shuhua Xu, Yi Gong, Xinghua Pan, Mark Stoneking, Qingming Luo, Boon‐Peng Hoh, Qianqian Zhang, Jialong Li, Xiangmin Xu, Xuan Shang, Lian Deng, Tizhen Yan, Wei Zhang
article en

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.

Nature CommunicationsVol. 16(1)
Université Claude Bernard Lyon 1 (FR), Macau University of Science and Technology (MO), Centre National de la Recherche Scientifique (FR), University of Macau (MO), Fudan University (CN), Nanfang Hospital (CN), Max Planck Institute for Evolutionary Anthropology (DE), Dongguan People’s Hospital (CN), Henan Provincial People's Hospital (CN), Laboratoire de Biométrie et Biologie Evolutive (FR), Southern Medical University (CN), IMU University (MY)
National Natural Science Foundation of China, Science and Technology Commission of Shanghai Municipality, Natural Science Foundation of Hainan Province, National Key Research and Development Program of China
Openalex Percentile: Top 49%
Hemoglobinopathies and Related Disorders
DOIOpen Access PDFOpenAlex
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