Evidence for the multicentric origin of the sickle cell hemoglobin gene in Africa.

Abstract

Previous studies of the Hpa I cleavage site-sickle cell hemoglobin gene linkage in various African populations suggested that the sickle gene arose independently more than once. In the present study we have performed restriction endonuclease haplotype analysis for the beta-globin-like gene cluster from four separate geographic areas in Africa, all of which possess the sickle gene. In Benin (Central West Africa) and Algeria (Arab North Africa) all chromosomes carrying the sickle gene possess an identical haplotype as defined by 11 different polymorphic restriction endonuclease sites within the 60-kilobase region of the beta-globin-like gene cluster. In the Central African Republic (Bantu-speaking Africa) and in Senegal (Atlantic West Africa) a very large proportion of the sickle gene chromosomes were associated with a haplotype specific for each country. Thus, three different haplotypes are shown to be associated with the sickle gene in Africa, and each is present at a very high frequency in geographically separate regions. Since the three haplotypes differ from each other by at least three sites residing both 5' and 3' to a putative hot spot for recombination, it is most likely that the sickle gene arose at least three times on separate preexisting chromosomal haplotypes. This may have implications for a better understanding of the variable nature of the expression of sickle cell anemia, because clinically relevant sequences (for example, gamma-globin gene regulatory sequences responsive to anemia) might be linked polymorphically to these haplotypes.

Mutations and polymorphisms in hemoglobin genes and the risk of pulmonary hypertension and death in sickle cell disease

“…The absence of a strong effect for a-thalassemia in SCD pulmonary hypertension was unexpected in contrast to the findings with Hb SC, despite the increased statistical power from the presence of the a 3.7 allele at nearly three times the frequency of Hb C. Still, the magnitude of a 3.7 's effect may be sufficiently small to be below the threshold for detection for the statistical power in this study. Likewise, haplotypes of the b-globin locus have been used in the past to study both the variation in SCD severity and the evolutionary history of the b S mutation [47][48][49][50]27]. In particular, some of the variability in Hb F expression is attributable to functional alleles in the fetal hemoglobin genes inherited on specific b S -globin haplotypes [48,[51][52][53].…”

Variantes genéticas asociadas con niveles de hemoglobina fetal muestran diversos orígenes étnicos en pacientes colombianos con anemia falciforme

“…The prevalence of allele 'A', tagging mostly the 'Senegal' sickle haplotype and a few atypical haplotypes (28), is due to the specific origin of the African ancestors of our patients, which might have included individuals from Senegal or Sierra Leone, where this allele is more frequent (29).…”

Dominique Labie (1920-2016)

“…pointe de génétique moléculaire et accès à des cohortes de patients africains et indiens soigneusement phénotypés, qui la conduira avec son équipe à la contribution scientifique la plus marquante de sa carrière, la démonstration de l'origine multicentrique de la mutation drépano-cytaire [1]. Il est juste d'associer à cette découverte Ronald Nagel de l'Albert Einstein College of Medicine à New York, disparu quelques jours après elle.…”