title: Classical sickle beta-globin haplotypes exhibit a high degree of long-range haplotype similarity in African and Afro-Caribbean populations.
abstract: BACKGROUND
  The sickle (betas) mutation in the beta-globin gene (HBB) occurs on five "classical" betas haplotype backgrounds in ethnic groups of African ancestry. Strong selection in favour of the betas allele - a consequence of protection from severe malarial infection afforded by heterozygotes - has been associated with a high degree of extended haplotype similarity. The relationship between classical betas haplotypes and long-range haplotype similarity may have both anthropological and clinical implications, but to date has not been explored. Here we evaluate the haplotype similarity of classical betas haplotypes over 400 kb in population samples from Jamaica, The Gambia, and among the Yoruba of Nigeria (Hapmap YRI).
  
  
  RESULTS
  The most common betas sub-haplotype among Jamaicans and the Yoruba was the Benin haplotype, while in The Gambia the Senegal haplotype was observed most commonly. Both subtypes exhibited a high degree of long-range haplotype similarity extending across approximately 400 kb in all three populations. This long-range similarity was significantly greater than that seen for other haplotypes sampled in these populations (P < 0.001), and was independent of marker choice and marker density. Among the Yoruba, Benin haplotypes were highly conserved, with very strong linkage disequilibrium (LD) extending a megabase across the betas mutation.
  
  
  CONCLUSIONS
  Two different classical betas haplotypes, sampled from different populations, exhibit comparable and extensive long-range haplotype similarity and strong LD. This LD extends across the adjacent recombination hotspot, and is discernable at distances in excess of 400 kb. Although the multi-centric geographic distribution of betas haplotypes indicates strong subdivision among early Holocene sub-Saharan populations, we find no evidence that selective pressures imposed by falciparum malaria varied in intensity or timing between these subpopulations. Our observations also suggest that cis-acting loci, which may influence outcomes in sickle cell disease, could lie considerable distances away from beta-globin.
authors: Tropical Metabolism Research Unit, Tropical Medicine Research Institute, University of the West Indies, Kingston, Jamaica. neil.hanchard@green-oxford.com
authors: Neil
authors: N
authors: Hanchard
authors: Abier
authors: A
authors: Elzein
authors: Clare
authors: C
authors: Trafford
authors: Kirk
authors: K
authors: Rockett
authors: Margaret
authors: M
authors: Pinder
authors: Muminatou
authors: M
authors: Jallow
authors: Rosalind
authors: R
authors: Harding
authors: Dominic
authors: D
authors: Kwiatkowski
authors: Colin
authors: C
authors: McKenzie
mesh_terms: D000328:Adult; D000483:Alleles; D000755:Anemia, Sickle Cell / Q000208:ethnology / Q000235:genetics*; D044383:Black People / Q000235:genetics*; D005714:Gambia / Q000453:epidemiology; D005914:Globins / Q000235:genetics*; D006239:Haplotypes; D006451:Hemoglobin, Sickle / Q000235:genetics*; D006801:Humans; D007563:Jamaica / Q000453:epidemiology; D009154:Mutation; D009549:Nigeria / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide; D012805:Sickle Cell Trait / Q000208:ethnology / Q000235:genetics
chemical_list: D006451:Hemoglobin, Sickle; D005914:Globins
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