Publisher Summary This chapter reviews that spectacular progress has been made in the recognition and study of biological differences between hemoglobin types. Many aspects of variations in hemoglobins such as the worldwide distribution of human hemoglobin types and their epidemiologic implications, animal hemoglobin types, and others have not been discussed. It may be expected that through the continuous efforts of investigators of various backgrounds, the next decade will prove as fertile as the last. The chapter discusses that the biochemist and geneticist will need to ask in what precise way the normal and abnormal hemoglobin types are synthesized. Others will continue their efforts to relate structural abnormalities and functional aberrations. The chapter explores that thalassemia has remained one of the most challenging disease states and presents a number of puzzles that are of importance and interest to the general physician, the hematologist, the pediatrician, the biochemist, the geneticist, the epidemiologist, and perhaps even the geographer, historian, and others. The same seems true for the fetal hemoglobin as it occurs in the newborn and in adults under various hematologic abnormalities; the function of this normal hemoglobin type, although the senior under the hemoglobin variants, is still incompletely known.

Normal and abnormal human hemoglobins.

Abnormal hemoglobins in a quarter million people

The proportion of Hb G Philadelphia (alpha68-Asn leads to Lys) in heterozygotes has been found to have a well-defined bimodal distribution around means of 33% and 46% Hb G. microcytosis and hypochromia are consistently associated with the latter group, who also have a decreased ratio of alpha/beta-chain synthesis in the peripheral blood, but these characters are not linked to the Hb-Galpha gene, because a parent with microcytosis and 46% Hb Galpha may have offspring with 33% Hb G without significant microcytosis. In one family a subject with Hb G and Hb G2 but no Hb A or Hb A2 is presumably a homozygote for alphaG. This subject has microcytosis and a decreased ratio of alpha/beta chain synthesis. In another family a subject with Hbs H, G and G2 but without Hbs A or A2 is heterozygous for both Hb G and alpha thalassaemia I. These findings are compatible with the hypothesis that the alphaG mutation occurs on a chromosome with only a single alpha-chain locus and that the expression in heterozygotes as 46% or 33% Hb G is determined by the homologous chromosome in trans having either one or two normal alphaA genes respectively. The significance of this polymorphism for chromosomes carrying alpha-chain genes is discussed.

Studies of the proporation and synthesis of haemoblogin C Philadelphia in red cells of heterozygotes, a homozygote, and a heterozygote for both haemoglobin G and alpha thalassaemia.

(1997). International Hemoglobin Information Center Variant List. Hemoglobin: Vol. 21, No. 6, pp. 505-506.

International Hemoglobin Information Center Variant List

The prevalence of multiple loci governing a-chain synthesis in many other animal species has been adequately documented by earlier papers in this volume. Until rather recently the world of the human geneticist has been relatively simple, there being only one structural locus for each of the six types of polpeptide chains identified in man-the a, p, y, 6, E, and 2 chains. The work of Huisman and Schroeder and their colleagues1 assures us that there are at least two and perhaps four loci for the y chains of fetal hemoglobin; one or more of these have glycine at residue 136 and one or more have alanine. They further propose the existence of major and minor loci for each of these types.z The possibility of two Hb, loci was first raised by Lehmann and Carrella who drew attention to the fact that heterozygotes for many a-chain variants possess approximately 20% of the abnormal component, whereas heterozygotes for mutants of the &chain structural locus possess 30 to 40% of the variant. The proportions of abnormal components present in published aand b-chain mutants are shown in TABLE 1. ' With some notable exceptions the proportion of abnormal a-chain variants vary between 15 and 35%. A few variants fall below this range; for instance, Hb Ann Arbor, comprising 2 to 4%: Hb tor in^,^ comprising 6 to lo%, and Hb Bibba,6 comprising 11 % of the total hemoglobin, are unstable and are probably denatured within the red cell. At the other extreme Hb G Philadelphia and Hb G Chinese comprise as much as 40 to 50% of the total hemoglobin. The majority of the @-chain variants vary between 25 and 40% of the total hemoglobin. Again, variants such as Hb Geneva? comprising 25%, Hb Zurich,Io comprising 20-36% Hb Sabine,\" comprising 8% and Hb Ko1n,I2 comprising 10-15% of the total hemoglobin, are unstable. However, in no less than sixteen a-chain variants, the proportion of abnormal hemoglobin is 50% or more of the total hemoglobin. Published data must be interpreted cautiously, however, because, aside from the variation imposed by instability, a wide variety of techniques were employed in the various studies. Moreover, since there is probably only a single Hbs locus, in all likelihood the wide range of values among jl-chain variants also reflects additional intrinsic differences in gene expression from one variant to the next. Taking all of these factors into account, however, the differences in the expression between a-chain and @-chain variants seems valid. One possible explanation for at least part of the variability is that a-chain mutants are more sensitive to amino acid substitution. That possibility has not been excluded. Nevertheless, in a number of mutants the qualitative abnormali-

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A.I. Goldberg

Papers

A variant present in unusually low concentration