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Using a parathyroid hormone (PTH) cDNA probe we found a common Pst I polymorphic restriction site 3' to the PTH gene in all ethnic groups examined. Because the PTH, insulin, and beta-globin loci have been localized to the short arm of chromosome 11 (11p) we used DNA polymorphisms adjacent to each of these three loci to determine whether they are genetically linked and to determine their order. We found that the PTH and beta-globin loci are closely linked (estimated recombination fraction, 0.07; 95% confidence limits, 0.05-0.10; lod score, 4.63; odds favoring linkage, 42,000:1). Furthermore, our findings strongly indicate that the beta-globin gene cluster lies between the PTH and insulin loci. Therefore, the gene order on 11p is centromere-PTH-beta-globin-insulin.

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