Evidence for multiple origins of the beta E-globin gene in Southeast Asia.

Abstract

To investigate whether recurrent mutation has contributed to the high frequency of the '3E-globin gene in Southeast Asia, we used the haplotypes at three-polymorphic restriction sites within and. to the 3' side of the ,B-globin gene to predict the framework of 23 JE-globin genes. These haplotypes suggested that jE-globin genes are present in two different g-globin gene frameworks. DNA sequence determination of one gene representing each framework demonstrated that the same mutation (GAG -+ AAG at codon 26) was present in both frameworks. Moreover, the frameworks differed at three nucleotide positions known to be polymorphic in Mediterraneans. These polymorphicsites are located 70 nucleotides to the 5' side of the 1E mutation and 382 and 1032 nucleotides to the 3' side of it. The existence of the ,#E mutation in these two .3-globin gene frameworks can be explained by (i) recurrent mutation giving rise to #E-globin, (ii) a double crossing-over event, or (nii) two single crossing-over events. Mathematical analysis suggests that the first alternative, recurrent mutation of G -*A at the first nucleotide ofcodon 26, is most likely.

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

“…Importantly, of the three different haplotypes identified by us to be associated with the Hb S gene, at least three different restriction site polymorphisms distinguish each from the others. The polymorphism differences between any two of the haplotypes occur both 5' and 3' to the putative "hot spot" for recombination that has been postulated to exist for some ethnic groups between the 3' pseudo-f3-globin HincII site and the HinfI site 5' to the /3-globin gene (5,7).…”

“…The conceptual basis for the use of DNA polymorphisms located in the ,3globin gene cluster stems from the discovery of at least 11 sites accessible to detection by restriction endonucleases and several other sites detectable, at this point, only by sequence analysis (5)(6)(7)(8) be closely linked to the p-globin gene, and if the mutational event is reasonably recent a 3-globin gene mutation should be accompanied by a defined haplotype formed by the set of polymorphic DNA sequences found in the ,B-globin-like gene cluster. This set of sequences would be those preexisting in the chromosome before the mutational event.…”

Structural analysis of the 5' flanking region of the beta-globin gene in African sickle cell anemia patients: further evidence for three origins of the sickle cell mutation in Africa.

“…In contrast to the normal pA chromosome, the 5' and 3' subhaplotypes linked to ,-gene mutations were found to be nonrandomly associated (11)(12)(13)(14)(15). The sickle mutation is associated with more than 30 haplotypes, but most of these are rare.…”

“…The patients were selected from previously reported groups of SCA individuals; they were homozygotes for the S mutation and for the associated specific haplotype. They originated from three different countries in Africa: 13 from Benin, 12 from Senegal, and 15 from the Central African Republic (CAR) (15). DNAs were prepared from leukocytes by standard methods as described (17).…”

Variation at the 87A heat shock locus in Drosophila melanogaster

“…The study of DNA-level variation in nuclear genes is technically more complex and to date three systematic population surveys have been completed-one on the ,B-globin region in man (11) and two on the alcohol dehydrogenase (Adh) locus in Drosophila melanogaster (12,13). Much information has been collected at other loci in man (14)(15)(16)(17)(18) but, in general, those studies were conditioned by the prior discovery of variation and do not provide an unbiased estimate of its overall level. In this paper I present the results of a survey on variation in restriction map at the 87A7 heat shock locus in a single natural population of D. melanogaster.…”