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Whole genome sequence-based haplotypes reveal a single origin of the 1393 bp HBB deletion
Xunde Wang1, Julia Z Xu1, Anna Conrey1
1Sickle Cell Branch, NIH, Bethesda, Maryland, USA.
Insights
Large deletions causing beta-thalassaemia are rare. Our study suggests these 1393bp HBB deletions in three unrelated individuals likely share a common ancestral origin, impacting hemoglobin disorders.
Area of Science:
- Genetics
- Molecular Biology
- Hematology
Background:
- Mutations in the HBB gene cause sickle cell disease (SCD) and beta-thalassaemia.
- Beta-thalassaemia is typically caused by point mutations or small insertions/deletions in HBB, with large deletions being rare.
- This study identified three individuals with hemoglobin S beta(0)-thalassaemia resulting from a large HBB deletion.
Purpose of the Study:
- To investigate the origin of a specific 1393bp HBB deletion causing beta(0)-thalassaemia using whole genome sequence data.
- To determine if the identified large deletions in unrelated individuals share a common ancestral origin.
Main Methods:
- Confirmed unrelatedness of three individuals using pairwise SNP comparison and identity by descent analysis.
- Generated phased haplotypes for 683 individuals using Eagle V.2.4.
- Constructed a haplotype network using the Neighbor-Net method in SplitsTree V.4.13.1.
Main Results:
- Identical 1393bp deletions, spanning the beta-promoter, exons 1-2, and part of intron 2, were found in all three unrelated individuals.
- While individuals had different beta(S) haplotypes, they shared the same haplotype for the 1393bp deletion.
- The breakpoints of the deletion were identical across all three cases.
Conclusions:
- The consistent haplotype associated with the 1393bp HBB deletion suggests a single ancestral origin.
- It is proposed that all reported cases of this specific 1393bp HBB deletion likely stem from the same ancestral source.
- This finding contributes to understanding the genetic basis and evolutionary history of beta-thalassaemia mutations.
Background:
Mutations of HBB give rise to two prevalent haemoglobin disorders-sickle cell disease (SCD) and β-thalassaemia. While SCD is caused by a single base substitution, nearly 300 mutations that downregulate expression of HBB have been described. The vast majority of β-thalassaemia alleles are point mutations or small insertion/deletions within the HBB gene; deletions causing β-thalassaemia are very rare. We have identified three individuals with haemoglobin Sβ0-thalassaemia in which the β0-thalassaemia mutation is caused by a large deletion.
Objective:
To use whole genome sequence data to determine whether these deletions arose from a single origin.
Methods:
We used two approaches to confirm unrelatedness: pairwise comparison of SNPs and identity by descent analysis. Eagle, V.2.4, was used to generate phased haplotypes for the 683 individuals. The Neighbor-Net method implemented in SplitsTree V.4.13.1 was used to construct the network of haplotypes.
Results:
All three deletions involved 1393 bp, encompassing the β-promoter, exons 1 and 2, and part of intron 2, with identical breakpoints. The cases were confirmed to be unrelated. Haplotypes based on 29 SNPs in the HBB cluster showed that the three individuals harboured different βS haplotypes. In contrast, the haplotype harbouring the 1393 bp deletion was the same in all three individuals.
Conclusion:
We suggest that all the reported cases of the 1393 bp HBB deletion, including the three cases here, are likely to be of the same ancestral origin.
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