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

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. Subject terms: Population genetics, Population genetics, Haplotypes, Disease genetics