Two pedigrees, each exhibiting the presence of two distinct thalassemia genes are described. Though indistinguishable by their hematologic stigmata the genes in each pedigree differed in their effect on the quantitative behavior of the minor hemoglobin components A2 and F. One gene produced the usual pattern of elevated values for the A2 fraction with minimal if any increases in the proportion of hemoglobin F. Another gene failed to produce increases in the A2 fraction but gave rise to substantial increments in the amounts of fetal hemoglobin. Still another gene produced a similar pattern but with less marked elevations of hemoglobin F though still well above the usual levels for thalassemic heterozygotes. There were intrafamilial similarities with respect to these features. In one family, the combination of two dissimilar genes had produced the picture of thalassemia major in the propositus.
For the particular thalassemia genes observed a reciprocal relationship in the quantitative behavior of the two minor components could be shown on the basis of comparisons including a larger case material studied by the authors. The apparent vagaries in the quantitative behavior of fetal hemoglobin in thalassemic heterozygotes could thus be explained as related to the presence or absence of an elevated A2 fraction. In general, levels of fetal hemoglobin in the former type rarely exceed 3.5 per cent, in the latter they are rarely below 4.0 per cent.
In accordance with other genetic information the findings are compatible with the assumption that both types of thalassemia genes represent mutations of β genes affecting the synthesis of β chains and thus represent a series of multiple alleles at the β chain locus. This interpretation fits the hypothesis of Ingram and Stretton regarding the nature of the defect in thalassemia.
The factor determining whether predominantly δ or γ chains and consequently hemoglobin A2 or hemoglobin F (or still other fractions) are formed appears to be the nature of the particular amino-acid substitutions in the anomalous β chain, resulting in the utilization of one or another metabolic pathway leading to the formation of different by-products of a metabolic block. The genetic implications of this hypothesis are presented with a view to establishing that current genetic theory does not yet fully account for the observations.
The interpretation of γ chains of fetal hemglobin as primitive β chains produced under the control of the same pair of genes which in normal adult life regulate the synthesis of β chains is offered as the basis for a unifying concept concerning the nature and genetic control of fetal hemoglobin. If valid, this concept appears applicable to all conditions thus far known, normal or abnormal, in which fetal hemoglobin occurs.