Trimodality in the proportion of hemoglobin G Philadelphia in heterozygotes: evidence for heterogeneity in the number of human alpha chain loci.

Abstract

The extent of variability in the number of human Hb .alpha.-chain loci has not yet been conclusively determined. Individuals may possess 2 .alpha.-chain loci, while in other populations only 1 locus is present. Electrophoresis of peripheral blood from 53 heterozygotes for Hb G Philadelphia (.alpha.68 Asn.fwdarw.Lys) revealed that the proportion of Hb G is trimodally distributed, with modes at approximately 20, 30 and 40% Hb G. Familial, hematologic and statistical studies suggests that the proportion of Hb G is not random but is genetically controlled and inversely correlated with mean cell volume. Two alternative genetic models are proposed to explain these findings: 1 assumes .alpha.-thalassemia, while the other postulates variability in the number of .alpha.-chain loci in the American black population. Biosynthetic studies of blood from 15 subjects revealed balanced synthesis of .alpha. and .beta. globin chains in heterozygotes from all 3 classes, strongly supporting variable gene dosage rather than .alpha.-thalassemia as the mechanism underlying the observed trimodality in the proportion of Hb G. Incompatibilities between the results and current concepts of .alpha.-thalassemia are discussed in the context of differences between black compared with Oriental and Italian forms of Hb H disease.