High-density SNP genotyping to define β-globin locus haplotypes

Li Liu, Shalini Muralidhar, Manisha Singh, Caprice Sylvan, Inderdeep S. Kalra, Charles T. Quinn, Onyinye C. Onyekwere, Betty S. Pace

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Five major β-globin locus haplotypes have been established in individuals with sickle cell disease (SCD) from the Benin, Bantu, Senegal, Cameroon, and Arab-Indian populations. Historically, β-haplotypes were established using restriction fragment length polymorphism (RFLP) analysis across the β-locus, which consists of five functional β-like globin genes located on chromosome 11. Previous attempts to correlate these haplotypes as robust predictors of clinical phenotypes observed in SCD have not been successful. We speculate that the coverage and distribution of the RFLP sites located proximal to or within the globin genes are not sufficiently dense to accurately reflect the complexity of this region. To test our hypothesis, we performed RFLP analysis and high-density single nucleotide polymorphism (SNP) genotyping across the β-locus using DNA samples from healthy African Americans with either normal hemoglobin A (HbAA) or individuals with homozygous SS (HbSS) disease. Using the genotyping data from 88 SNPs and Haploview analysis, we generated a greater number of haplotypes than that observed with RFLP analysis alone. Furthermore, a unique pattern of long-range linkage disequilibrium between the locus control region and the β-like globin genes was observed in the HbSS group. Interestingly, we observed multiple SNPs within the HindIII restriction site located in the Gγ-globin intervening sequence II which produced the same RFLP pattern. These findings illustrated the inability of RFLP analysis to decipher the complexity of sequence variations that impacts genomic structure in this region. Our data suggest that high-density SNP mapping may be required to accurately define β-haplotypes that correlate with the different clinical phenotypes observed in SCD.

Original languageEnglish (US)
Pages (from-to)16-24
Number of pages9
JournalBlood Cells, Molecules, and Diseases
Volume42
Issue number1
DOIs
StatePublished - Jan 1 2009
Externally publishedYes

Keywords

  • Haplotype
  • Haploview
  • Sickle cell disease
  • Single nucleotide polymorphism
  • β-locus

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Hematology
  • Cell Biology

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  • Cite this

    Liu, L., Muralidhar, S., Singh, M., Sylvan, C., Kalra, I. S., Quinn, C. T., Onyekwere, O. C., & Pace, B. S. (2009). High-density SNP genotyping to define β-globin locus haplotypes. Blood Cells, Molecules, and Diseases, 42(1), 16-24. https://doi.org/10.1016/j.bcmd.2008.07.002