Mapping Long-Read Sequences to a Complete Reference Genome Reveals Uncaptured Variants Across the β-Globin Cluster in Africans With Sickle Cell Disease

Authors

• Pamela Lurie
• Medhat Mahmoud
• Aparna Haldipur
• Yixing Han
• Qing Li
• Edmond Wonkam Tingang
• Natalie Asmus
• Emilyn Banfield
• Nancy J Hall
• Bamidele Tayo
• Richard Cooper
• Titilola Akingbola
• George Ayodo
• Stephen Obaro
• Guillaume Lettre
• Qing Meng
• Shalini Jhangiani
• R Alan Harris
• Kim C Worley
• Juyhun Kim
• Arang Rhie
• Adam M Phillippy
• Fritz Sedlazeck
• Ambroise Wonkam
• Neil A Hanchard

Language

English

Publication Date

10-8-2026

Journal

Human Genetics and Genomics Advances

DOI

10.1016/j.xhgg.2026.100669

PMID

42693638

PMCID

PMC13651657

PubMedCentral® Posted Date

10-8-2026

PubMedCentral® Full Text Version

Post-print

Abstract

African genomes are marked by extensive complexity in the number and distribution of variants yet remain under-represented in genetic databases and the human reference genome. This gap in representation limits the broad application of genomic medicine. Sickle cell disease (SCD)-one of the most common monogenic diseases-has its highest prevalence in Africa, and variation in disease severity has consistently been linked to the β-globin locus, including levels of fetal hemoglobin (HbF). Modulation of HbF is central to current SCD gene therapies; however, the inherent complexity and variation at the locus in African genomes present a challenge to translating these advances to Africa. Here, we align single-molecule long-read sequencing (LRS) targeted to the β-globin region to the human genome build 38 (hg38) and telomere-to-telomere (T2T)-CHM13.v2 genome references in 40 individuals with SCD, predominantly recruited from three African countries. We demonstrate that the expanded T2T-CHM13.v2 reference sequence at this locus reduces structural variant (SV) calls by 70% and uncovers uncaptured single-nucleotide variants (SNVs). Across the cluster, we report 343 SVs and 196 SNVs that have not been previously reported, including in LRS data from the All of Us project. By including African populations from ethnolinguistic groups that have not been previously surveyed, we improve variant resolution and bolster evidence for observed variation. Finally, we identify a common ∼4 kb insertion locus overlapping the HBB promoter among individuals with high HbF. These results demonstrate the utility of combining a comprehensive reference genome with LRS in African populations to uncover genomic variation at disease-associated loci.

Keywords

Humans, Anemia, Sickle Cell, beta-Globins, Genome, Human, Genetic Variation, Polymorphism, Single Nucleotide, Black People, Multigene Family, Fetal Hemoglobin, Sub-Saharan African People, T2T-CHM13, African genomics, fetal hemoglobin, HBB, genomic diversity, cis-regulatory variation, structural variation, sickle haplotypes, human genome

Published Open-Access

yes

Recommended Citation

Lurie, Pamela; Mahmoud, Medhat; Haldipur, Aparna; et al., "Mapping Long-Read Sequences to a Complete Reference Genome Reveals Uncaptured Variants Across the β-Globin Cluster in Africans With Sickle Cell Disease" (2026). Faculty, Staff and Students Publications. 8663.
https://digitalcommons.library.tmc.edu/baylor_docs/8663