The haemoglobinopathies are the commonest single-gene disorders known, almost certainly because of the protection they provide against malaria, as attested by a number of observations. The geographical distributions of malaria and haemoglobinopathies largely overlap, and microepidemiological surveys confirm the close relationship between them. For two of the commonest disorders, haemoglobin S and alpha(+)-thalassaemia, there is also good clinical evidence for protection against malaria morbidity. However, not all the evidence appears to support this view. In some parts of the world malaria and haemoglobinopathies are not, and never have been, coexistent. It is also difficult to explain why the majority of haemoglobinopathies appear to be recent mutations and are regionally specific. Here we argue that these apparent inconsistencies in the malaria hypothesis are the result of processes such as genetic drift and migration and of demographic changes that have occurred during the past 10,000 years. When these factors are taken into account, selection by malaria remains the force responsible for the prevalence of the haemoglobinopathies.

The population genetics of the haemoglobinopathies.

A population genetic study of six VNTR loci in three ethnically defined populations.

We have analyzed the allele frequency distribution at the hypervariable locus 3' to the apolipoprotein B gene (ApoB 3' VNTR) in five well-defined human populations (Kacharis of northeast India, New Guinea Highlanders of Papua New Guinea, Dogrib Indians of Canada, Pehuenche Indians of Chile, and a relatively homogeneous Caucasian population of northern German extraction) by using the PCR technique. A total of 12 segregating alleles were detected in the pooled sample of 319 individuals. A fairly consistent bimodal pattern of allele frequency distribution, apparent in most of these geographically and genetically diverse populations, suggests that the ApoB 3' VNTR polymorphism predates the geographic dispersal of ancestral human populations. In spite of the observed high degree of polymorphism at this locus (expected heterozygosity levels 55%-78%), the genotype distributions in all populations (irrespective of their tribal or cosmopolitan nature) conform to their respective Hardy-Weinberg predictions. Furthermore, analysis of the congruence between expected heterozygosity and the observed number of alleles reveals that, in general, the allele frequency distributions at this locus are in agreement with the predictions of the classical mutation-drift models. The data also show that alleles that are shared by all populations have the highest average frequency within populations. These findings demonstrate the potential utility of highly informative hypervariable loci such as the ApoB 3' VNTR locus in population genetic research, as well as in forensic medicine and determination of biological relatedness of individuals.

Characteristics of polymorphism at a VNTR locus 3' to the apolipoprotein B gene in five human populations.

The distribution of the hemoglobin Constant Spring (Hb CS) gene in eight populations in Southeast Asia (including Assam) was determined using oligonucleotide hybridization. Hb CS was absent in two Assamese populations with a high prevalence of Hb E. The Hb CS gene frequency was 0.033 in northern Thailand and near 0.01 in central Thailand and Cambodia. High frequencies, between 0.05 and 0.06, were observed in northeastern Thailand. The present data and a similar study in Laotians suggest that the Lao-speaking populations of the Mekong River basin in northeastern Thailand and Laos have the highest frequencies of the Hb CS gene in Southeast Asia.

The distribution of the Hb constant spring gene in Southeast Asian populations.

Summary The thalassaemias are the most common genetic disorders of man, and over the last decade the molecular epidemiology of these defects has been studied in detail. After briefly reviewing the great diversity of mutations giving rise to these conditions, four global regions are discussed in more detail. The thalassaemias, of which haemoglobin E is one, are most frequent in Asia, where recent work has defined the molecular basis of the β thalassaemias and the frequencies of the various types of α + and α 0 thalassaemia. Oceanic populations have a range of globin gene variants remarkably different to those of south-east Asia. Most is known about the nature and frequencies of thalassaemia mutations in Mediterranean countries, where prenatal diagnosis programmes have been very successful in reducing the frequency of new cases of thalassaemia major. α + Thalassaemia is the most common haemoglobinopathy in sub-Saharan Africa, and molecular studies of American Blacks with β thalassaemia have elucidated the probable molecular basis of the mild form of this disorder in Africans. Although each geographical region has its own group of common β thalassaemia mutations, with little overlap, most of these appear to have had a single origin. The question of single or multiple origins for HbE in south-east Asia is unresolved. Recombination events producing α + thalassaemia deletions are frequent, whereas α 0 thalassaemia is produced by a variety of large deletions, each of which has had a single origin. The evidence favouring natural selection by P. falciparum malaria as the primary cause of high frequencies of the thalassaemias throughout the tropics and subtropics is reviewed. While the mechanism of protection remains unclear, epidemiological evidence supporting the hypothesis is strong, but more information is required from case-control studies on the amount of protection provided by the various thalassaemia genotypes.

Molecular epidemiology of the thalassaemias (including haemoglobin E).

DNA haplotypes and frameworks associated with the β-globin gene were determined in a Tibeto-Burman group, the Kachari, from Upper Assam, India, using restriction analysis at eight restriction sites. O

B. C. Gogoi

Papers

DNA haplotypes and frameworks associated with the beta-globin gene in the Kachari population of Assam (India).

Hemoglobinopathies in Northeast India

α-Thalassemia in the Kachari population of Assam (India)