Molecular rearrangements of the human alpha-globin gene cluster.
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Chromosome Deletion↗
Biomedical subjects
J B Clegg
Publications and source records attributed to J B Clegg.
Genetic and molecular analysis of mild forms of homozygous beta-thalassemia.
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Adult↗
Prenatal diagnosis of the common haemoglobin disorders.
New techniques of DNA analysis have been applied to the prenatal diagnosis of the common haemoglobin disorders. Currently, it is possible to provide a comprehensive programme for the prevention of these conditions, although this entails the use of several different techniques including globin chain synthesis analysis, direct identification of mutations with restriction enzymes, linkage analysis of restriction fragment length polymorphisms, and the use of oligonucleotide probes. At present, the best combination of these approaches has to be worked out for individual populations, but as the techniques of chorion villus sampling and DNA analysis improve it should be possible to rationalise these prenatal diagnosis programmes and thus make them simpler and less expensive.
Anemia, Sickle Cell↗
The developmental genetics of human hemoglobin.
Clearly, it is impossible to combine the diverse information briefly outlined in this review to provide a coherent model of the regulation of globin gene expression during development. One of the great difficulties in this field is uncertainty as to whether the mutations which are associated with persistent gamma chain production or, for the matter, the experimental models which have been used to study the differential expression of the fetal and adult globin genes, have any real relevance to an understanding of the normal switching process. Probably they do, but only with respect to one aspect of what must be an extremely complex multi-step regulatory system. The consistent changes in chromatin and methylation state of the beta globin gene cluster which are associated with activation of the different gene loci at different stages of development provide an anatomical explanation for the activity of these loci but tell us nothing about their mode of regulation. However, the gene or chromosome transfer experiments suggest that there may be developmental-stage specific trans regulatory factors which may be involved in the regulation of these genes, presumably by interacting in some way with chromatin. This is a very promising lead. Equally interesting is the possibility that the upstream mutations which are being found in some of the forms of non-deletion HPFH could provide a clue as to the site of these interactions. Thus at least we have an indication of what might be the most productive area of investigation for trying to characterize the mechanisms of regulation at the chromosomal level. This may be as far as we can go in the immediate future. The central question remains, however. How is the differential expression of the globin genes during development actually timed? All we know at the moment is that it is related fairly closely to gestational age. The only experimental data relating to this question is derived from the sheep transplant model, and suggests that there might be some form of "developmental clock' built into the hemopoietic stem cell. Here we are in considerable difficulties because we don't have an obvious experimental model with which to analyze time-related events. None of the forms of HPFH is, strictly speaking, a heterochronic mutation.(ABSTRACT TRUNCATED AT 400 WORDS)
Adult↗
Alpha zero-thalassemia due to recombination between the alpha 1-globin gene and an AluI repeat.
A form of alpha zero-thalassemia found in subjects of Mediterranean origin has been analyzed by gene mapping and DNA sequencing. Homozygotes have the hemoglobin Bart's hydrops fetalis syndrome, while compound heterozygotes for this defect and alpha+-thalassemia have hemoglobin H disease. It results from a deletion that removes 20.5 kilobases of DNA from within the alpha-globin gene cluster. Sequence data from the regions adjacent to the breakpoint indicate that the recombination event that caused this deletion occurred between the alpha 1-gene and an unusual AluI sequence located between the embryonic zeta genes.
Chromosome Deletion↗
Melanesians and Polynesians share a unique alpha-thalassemia mutation.
Several genetic markers that provide information on population migrations and affinities have been detected by studies of proteins and cellular antigens in blood. Analysis of DNA polymorphisms promises to yield many further population markers, and we report here the distribution of a new alpha-globin gene deletion (-alpha 3.7 III) detected by a restriction enzyme mapping. This is found frequently in Melanesians and Polynesians but not in five other populations in which alpha-thalassemia is prevalent. We used restriction enzyme haplotype analysis to support a single origin for this mutation and propose that it is a useful population marker. Its geographical distribution supports a route through Island Melanesia for the colonizers of Polynesia.
Chromosome Deletion↗
Genetic disorders of human haemoglobin as models for analysing gene regulation.
The genetic and acquired disorders of human haemoglobin provide a diverse group of naturally occurring models for analysing the regulation of protein synthesis. They include structural haemoglobin variants, thalassaemias, which are conditions in which there is a reduced rate of globin chain production, and hereditary persistence of foetal haemoglobin (HPFH) in which there is an inherited abnormality in the switch from foetal to adult haemoglobin synthesis. The thalassaemias result from a diverse series of cis acting lesions of the globin genes which include deletions, insertions, frame shift mutations, and point mutations involving transcription, messenger RNA processing, initiation, termination, poly A addition and globin chain stability. Many forms of HPFH are due to deletions of the beta-like gene cluster; it has been suggested that they may involve regions of the cluster which are involved in the regulation of the foetal to adult globin chain switch. So far, however, no regions of this type have been identified with certainty. The varieties of HPFH not associated with major gene deletions, or those caused by genetic determinants that are not linked to the globin gene clusters, and some of the acquired forms of alpha thalassaemia associated with mental retardation or leukaemia, may be more useful models for studying the regulation of the globin genes, particularly their developmental control.
Base Sequence↗
Genetic organization of the polymorphic equine alpha globin locus and sequence of the BII alpha 1 gene.
The equine alpha globin gene complex comprises two functional alpha genes and an alpha-like pseudogene arranged in the order 5'-alpha 2-(5kb)-alpha 1-(3kb)-psi alpha-3'. A single (embryonic) zeta-like sequence lies within a 12 kb region 5' to the alpha 2 gene. We have determined the sequence of the alpha 1 gene of the BII haplotype, one of two most common haplotypes (the other being BI) which encode alpha globins with either Tyr (BI) or Phe (BII) at codon 24 in both linked alpha genes. In BI and BII the non-allelic alpha 2 and alpha 1 genes respectively code for Gln or Lys at codon 60, thus accounting for the 4 alpha globin types seen in BI/BII heterozygotes. Genomic restriction enzyme maps of the BII alpha complex (24Phe/60Lys,Gln) and the allelic BI (24Tyr/60Lys,Gln) are identical to each other, and to those of a rarer normal haplotype, A, which encodes only alpha 24Tyr/60Gln globin, and a low expression mutant of BII which encodes only 24Phe/60Lys globin. These two latter haplotypes must therefore have a linked pair of alpha genes, as in BI and BII, but with identical coding properties, and it is suggested that this has arisen by gene conversion.
Alleles↗
Independent recombination events between the duplicated human alpha globin genes; implications for their concerted evolution.
We have examined the molecular structure of the human alpha globin gene complex from individuals with a common form of alpha thalassaemia in which one of the duplicated pair of alpha genes (alpha alpha) has been deleted (-alpha 3-7). Restriction mapping and DNA sequence analysis of the mutants indicate that different -alpha 3.7 chromosomes are the result of at least three independent events. In each case the genetic crossover has occurred within a region of complete homology between the alpha 1 and alpha 2 genes. Since the -alpha chromosomes may reflect the processes of crossover fixation and gene conversion between the two genes, their structures may provide some insight into the mechanism by which the concerted evolution of the human alpha globin genes occurs.
Base Sequence↗
The molecular basis of alpha-thalassaemia in Thailand.
The molecular basis of alpha-thalassaemia has been established in 48 Thai subjects with Hb H disease and 15 with the Hb Bart's hydrops fetalis syndrome. This study has shown that in this population there are at least 18 different types of chromosome carrying seven independent alpha-thalassaemia mutations one of which is a novel deletion removing the entire alpha-globin gene complex. Although there are a limited number of alpha-thalassaemia determinants in the Thai population, there is a remarkable degree of variation in the genetic markers which flank them. These markers may be of value in establishing the evolutionary history of the alpha-thalassaemias.
Chromosome Deletion↗
(A gamma delta beta) thalassaemia: similarity of phenotype in four different molecular defects, including one newly described.
Globin gene mapping of DNA from families with (A gamma delta beta) thalassaemia has revealed a previously unreported gene deletion responsible for this condition. The deletion removes the A gamma, delta and beta genes and while its 5' end is in a similar position to that described in a previous deletion of this type, the 3' ends of the two deletions are quite different. In addition we have observed further examples of two other previously described deletions which result in this disorder. Phenotypic comparisons of families with (A gamma delta beta) thalassaemia, in which the molecular basis has been defined, show a remarkable similarity among the four different deletion defects, with important implications with regard to the mechanism by which deletions allow the continued expression of gamma genes.
Adolescent↗
Hematologic and biosynthetic studies in homozygous hemoglobin Constant Spring.
The elongated alpha-globin chains of hemoglobin Constant Spring (alpha cs chain of HbCS ) are produced in low amounts such that the alpha cs-gene acts as a form of alpha-thalassemia; yet in the homozygous state the pathophysiological effects of this mutant are more severe than in the corresponding conditions that result from alpha-globin gene deletions. In studies designed to examine this discrepancy, we have demonstrated that a significant proportion of red cells produced in an HbCS homozygote has a much reduced red cell life span. Contrary to previous reports, we have been able to demonstrate the expected deficit in alpha-chain production in this condition and have shown that both the cessation of globin chain synthesis in vitro and the destruction of the excess beta-chains occur unusually rapidly. Comparison with various deletion forms of alpha-thalassemia suggests that, in terms of intracellular globin chain precipitates and free beta-chain pool, homozygous HbCS red cells more closely resemble those of HbH disease, with three of the four alpha-genes inactivated, than they do the more comparable alpha-thalassemia carriers with only two genes deleted.
Adult↗
Allelic variation and linkage properties of a highly polymorphic restriction fragment in humans.
The region between the human zeta-globin gene and the pseudo-zeta gene contains a stretch of tandemly reiterated 36 base-pair sequence elements. The structure of this locus offers the potential for unequal crossover events or slippage during replication to generate allelic variation in the length of restriction fragments spanning this region. The extent of allelic variation at this locus has been investigated in different populations at a high level of resolution. As many as ten discrete fragment lengths were observed whereas only three had been detected previously at a lower level of resolution. The linkage of alleles at this locus to closely flanking markers indicates that they are inherited as stable Mendelian traits over many generations, and therefore this and similar regions may provide highly polymorphic markers which will be of great value in genetic analysis of the human genome.
Alleles↗
Interaction of the alpha alpha alpha globin gene haplotype and sickle haemoglobin.
We have studied the interaction of the alpha alpha alpha/alpha alpha gene arrangement with various beta globin genotypes (AA, AS, AC, SS and SC). Whereas this interaction has no detectable clinical or haematological effects in subjects with AA, SS or SC genotypes it is associated with a significantly increased level of Hb S or Hb C in heterozygotes for these variants. These findings indicate that the additional alpha globin gene in the alpha alpha alpha gene arrangement is functional.
Adolescent↗
5-azacytidine for beta-thalassemia?
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Azacitidine↗
Molecular basis of length polymorphism in the human zeta-globin gene complex.
The length polymorphism between the human zeta-globin gene and its pseudogene is caused by an allele-specific variation in the copy number of a tandemly repeating 36-base-pair sequence. This sequence is related to a tandemly repeated 14-base-pair sequence in the 5' flanking region of the human insulin gene, which is known to cause length polymorphism, and to a repetitive sequence in intervening sequence (IVS) 1 of the pseudo-zeta-globin gene. Evidence is presented that the latter is also of variable length, probably because of differences in the copy number of the tandem repeat. The homology between the three length polymorphisms may be an indication of the presence of a more widespread group of related sequences in the human genome, which might be useful for generalized linkage studies.
Base Composition↗
Thalassaemia intermedia in Cyprus: the interaction of alpha and beta thalassaemia.
Restriction endonuclease analysis has been performed on the alpha and beta globin gene clusters of 57 Cypriots homozygous for beta thalassaemia, 30 with the transfusion dependent form of the condition (thalassaemia major) and 27 who are less severely affected (thalassaemia intermedia). There was a significant difference in the incidence of alpha thalassaemia between the two groups: 14/27 of the patients with thalassaemia intermedia also had deletion forms of alpha thalassaemia, while only 4/30 of the patients with thalassaemia major were similarly affected. Thus in Cypriot patients who are homozygous for beta thalassaemia the co-inheritance of alpha thalassaemia is an important factor in determining the clinical course.
Adolescent↗
Association of two DNA polymorphisms in the alpha-globin gene cluster: implications for genetic analysis.
A new polymorphic BgI II restriction endonuclease site in the alpha-globin gene complex has been found in Cypriot, Sardinian, and Greek populations. In all cases, this polymorphism is linked to a particular hypervariable region between the zeta 2 and zeta 1 genes. This suggests that these hypervariable regions are stable and will be useful for genetic analysis.
Chromosome Mapping↗