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J B Clegg

Publications and source records attributed to J B Clegg.

At least 91 records · Page 5Linked to original sources
PubMed1987

Gene conversions in the horse alpha-globin gene complex.

The sequences of the linked alpha 2- and alpha 1-globin genes of the equine BI and BII haplotypes are greater than 99% identical within a 1.2-kb region extending from approximately 75 bp upstream of the putative cap site to a point approximately 150 bp 3' to the poly A addition signal. Differences between the alpha 2 and alpha 1 genes that are common to both haplotypes indicate that a major gene conversion occurred approximately 12 Myr ago and that this has been followed by shorter, more localized, conversions. Interhaplotype (allelic) comparisons at the alpha loci suggest that the BI and BII haplotypes have probably existed independently greater than or equal to 0.5 Myr and that the alpha 1 genes may have undergone a recent interchromosomal gene conversion.

Animals↗
PubMed1987

Non-deletion haemoglobin H disease in Papua New Guinea.

Analysis of DNA from members of a Melanesian family from Papua New Guinea with haemoglobin (Hb) H disease revealed that all four alpha globin genes are intact in affected subjects. Study of restriction enzyme site and length polymorphisms and the use of oligonucleotide probes indicated that the molecular basis of this Papuan form of non-deletion Hb H disease differs from the previously described Middle Eastern and Mediterranean types.

Female↗
PubMed1987

High frequency of beta thalassaemia in a small island population in Melanesia.

A study of the causes of anaemia in the south west Pacific archipelago of Vanuatu has identified one island, Maewo, where the carrier rate for beta thalassaemia exceeds 20%, one of the highest recorded incidences in the world. Homozygous beta thalassaemia is a major cause of infant mortality and a serious drain on health resources on this island. Interactions of beta thalassaemia with various forms of alpha + thalassaemia were common in this population. Coexistent alpha + thalassaemia leads to better haemoglobinised and larger red cells than are seen in simple beta thalassaemia heterozygotes and screening for the latter can only be reliably carried out by Hb A2 estimation.

Female↗
PubMed1987

Alpha-thalassaemia and the malaria hypothesis.

Recent population genetic studies of the distribution of alpha+-thalassaemia in Melanesia using DNA analysis have provided strong support for the hypothesis that high frequencies of this genetic disorder are the result of natural selection by malaria.

Age Factors↗
PubMed1987

Different hematologic phenotypes are associated with the leftward (-alpha 4.2) and rightward (-alpha 3.7) alpha+-thalassemia deletions.

We have compared the phenotypes of the two common deletion forms of alpha+-thalassemia by analysis of umbilical cord blood samples from Melanesia. Homozygotes for the leftward, 4.2-kilobase, deletion (-alpha 4.2) had significantly higher levels of Hb Bart's at birth than homozygotes for the rightward, 3.7-kilobase, deletion (-alpha 3.7). Compound heterozygotes for each deletion had intermediate values. Although deletion forms of alpha 0 thalassemia were not found in this survey, nondeletion alpha-thalassemia was present at low frequency. Since the predominant rightward deletion in this population, -alpha 3.7III, entirely removes the alpha 1-gene and the 4.2-kilobase deletion deletes the alpha 2-gene, these data indicate that the alpha 2-globin gene has a higher output than the alpha 1-gene, on single alpha-gene chromosomes.

Chromosome Deletion↗
PubMed1987

Polynesian origins and affinities: globin gene variants in eastern Polynesia.

Analysis of copy number variants of the duplicated alpha-, zeta-, and gamma-globin genes in eastern Polynesians revealed a high frequency of both triplicated-zeta-gene chromosomes and a specific alpha thalassemia deletion. This deletion and a novel restriction-enzyme-site polymorphism associated with a zeta zeta zeta chromosome are found only in Melanesians and Polynesians. Analysis of alpha-globin restriction-enzyme haplotypes indicated further similarities to Melanesians but suggested an additional non-Melanesian genetic component in eastern Polynesia. Several globin gene alleles showed evidence of marked frequency fluctuations due to genetic drift.

Alleles↗
PubMed1987

Heterogeneity and origins of the alpha-thalassemias.

The alpha-globin gene cluster is far from static. It shows remarkable diversity within and among populations, both in gene number and in the pattern of polymorphisms involving the hypervariable regions. The deletions that have given rise to alpha(0)-thalassemia appear to have resulted from rare genetic events, and the affected chromosomes have been distributed among localized populations by selection. On the other hand, the deletions that have given rise to at least one of the alpha(+)-thalassemias seem to have occurred on multiple occasions in different populations. The genesis of this condition, the most common single gene disorder, may reflect the concerted evolution of the alpha-globin genes, and the alpha(+)-thalassemias may have arisen as a by-product of this evolutionary process. The existence of such a polymorphic gene family and the fact that its mutations are the most common single gene disorders in man provide us with a remarkable, natural model for studying population genetics at the molecular level. Further analysis of this cluster may provide valuable information about the timing of racial diversions, population movements, and the molecular events that have helped to maintain such high gene frequencies for some of the mutations of these loci.

Biological Evolution↗
PubMed1986

A silent deletion in the beta-globin gene cluster.

A survey of the gamma-globin gene region of over 1000 normal individuals revealed a novel 2.5 kb deletion which removes the 5' end of the A gamma-globin gene. Unusually, this deletion in the beta-globin gene cluster is not associated with increased fetal haemoglobin production. Sequence analysis of the deletion endpoints revealed no significant homology at the breakpoint and failed to support a role for a proposed recombination hotspot in IVS-2 in the generation of this illegitimate recombination event. The existence of small "silent" deletions in the beta-globin gene cluster emphasizes the importance of deletion size in altering expression of the fetal globin genes.

Base Sequence↗
PubMed1986

Molecular characterisation of a hypervariable region downstream of the human alpha-globin gene cluster.

We have characterised an unusual, highly polymorphic region of DNA located 8-kb downstream of the human alpha-globin gene complex. This hypervariable region (alpha-globin 3' HVR) is composed of an array of 17-bp tandem repeats, the number of which differs considerably (70-450) from one allele to another. The sequence of the 17-bp repeats is highly conserved within and between alleles. Furthermore, this sequence identifies a core oligonucleotide [5'-GNGGGG(N)ACAG-3'] that is common to three previously characterised hypervariable regions. At reduced stringency, a probe to the 3' HVR detects a new family of multiallelic loci that will be of value in the study of human genetics.

Alleles↗
PubMed1986

Interaction of five globin gene abnormalities in a Cambodian family.

Members of a Cambodian family with an undiagnosed hypochromic, microcytic anaemia were found by haemoglobin and DNA analysis to have five interacting globin gene abnormalities. One child has Hb E and typical Hb H disease, while his mother has the form of Hb H disease associated with Hb Constant Spring interacting with Hb E. Quantitation of Hbs E and A2 by globin chain separation and triton/urea gel electrophoresis support the concept that Hb H/Constant Spring disease is a more severe form of alpha thalassaemia than Hb H disease. This family illustrates how the remarkably high prevalence of globin gene abnormalities in Southeast Asians can give rise to a series of atypical thalassaemic phenotypes, and how they can be defined by direct globin gene analysis.

Adolescent↗
PubMed1986

Chromosomes with one, two, three, and four fetal globin genes: molecular and hematologic analysis.

Analysis of DNA from 852 Island Melanesians has revealed a high frequency of single- and triple-gamma-globin genes in this population. Homozygotes for triple- and single-gamma genes have normal hematologic findings, normal hemoglobin F (HbF) levels, and when there is coexisting alpha thalassemia, appropriate levels of Bart's Hb (gamma 4) at birth. In addition, we have identified an individual with a quadruple-gamma gene chromosome who also has a normal HbF level. All single-gamma genes were A gamma, all triple-gamma genes G gamma G gamma A gamma, and the quadruple-gamma gene G gamma G gamma G gamma A gamma. Analysis of G gamma:A gamma ratios in cord bloods and HbF levels in adults showed that these additional gamma genes are expressed and are down regulated appropriately by the fetal to adult Hb switch. Analysis of the restriction enzyme haplotypes of these various chromosomes indicates that intrachromosomal cross-overs are more likely to have produced these variants than interchromosomal recombination events.

Adult↗
PubMed1986

A population genetic survey of the haptoglobin polymorphism in Melanesians by DNA analysis.

We have determined the haptoglobin (Hp) genotypes of 831 Melanesians from Vanuatu, Papua New Guinea, and New Caledonia by Southern blot analysis of DNA extracted from umbilical cord and peripheral blood samples. There was complete agreement between these genotypes and the protein phenotype in cases where both were determined, and genotyping was possible in cases where no serum haptoglobins were measurable. Subtyping of Hp1 alleles using restriction enzymes showed that Melanesians, like Mongoloids and Australian Aboriginals, have only the Hp1S allele. Three cases of Hp Johnson were found in Vanuatu, and further restriction mapping supported a partial gene triplication model for the structure of this variant. We also report a new common BclI restriction enzyme polymorphism upstream of the Hp1 gene. The advantages of using DNA for haptoglobin typing are discussed.

Alleles↗
PubMed1986

The relationship between the common mutations of the alpha gene cluster and its evolutionary history.

The alpha globin gene cluster is far from static. It shows remarkable diversity within and among populations, both in gene number and the pattern of polymorphisms involving the HVRs. The deletions which have given rise to alpha o thalassemia appear to have resulted from rare genetic events and the affected chromosomes have been distributed among localized populations by selection. On the other hand, the deletions which have given rise to at least one of the alpha+ thalassemias seem to have occurred on multiple occasions in different populations. The genesis of this condition, the commonest single gene disorder, may reflect the concerted evolution of the alpha globin genes, and the alpha+ thalassemias may have arisen as a by-product of this evolutionary process. The existence of such a polymorphic gene family and the fact that its mutations are the commonest single gene disorders in man, provide us with a remarkable, natural model for studying population genetics at the molecular level. Further analysis of this cluster, and of the beta globin genes, may provide valuable information about the timing of racial diversions, population movements, and the molecular events which have helped to maintain such high gene frequencies for some of the mutations of these loci.

Biological Evolution↗
PubMed1985

Direct cloning of specific genomic DNA sequences in plasmid libraries following fragment enrichment.

We describe a simple method to directly clone any DNA fragment for which a flanking restriction enzyme map is known. Genomic DNA is digested with multiple enzymes cutting outside the fragment to be cloned, selected by electroelution from an agarose gel, and cloned directly into a plasmid vector. It is only necessary to screen 10-1000 colonies and recombinant DNA is ready for immediate molecular analysis without further subcloning. The use of this technique is demonstrated for the cloning of a sequence from within the human alpha-globin complex that was previously shown to be "unclonable" in bacteriophage and cosmid vectors and which is a multiallelic general genetic marker, as well as both beta-globin alleles from an individual with beta-thalassaemia.

Alleles↗
PubMed1985

Relative roles of genetic factors, dietary deficiency, and infection in anaemia in Vanuatu, South-West Pacific.

Hypochromic anaemia is very common among the island populations of Vanuatu in the South-West Pacific. Results of a large-scale survey show that, unexpectedly, this form of anaemia is seldom due to iron deficiency or coexistent parasitic disease. Rather, it results from a previously unsuspected high incidence of alpha-thalassaemia which has been identified only by application of DNA analysis to the populations studied. These findings suggest that hypochromic anaemia in tropical or subtropical populations should not necessarily be attributed to iron deficiency; detailed studies of iron status should be carried out before major dietary changes or fortification of food with iron are implemented.

Adolescent↗
PubMed1985

Alpha thalassaemia in British people.

Although alpha thalassaemia is rare in north Europeans, it has been identified in British people with no known foreign ancestry. Twelve such patients were studied, of whom eight shared a distinctive molecular defect, which was clearly different from defects seen in subjects of Mediterranean or South East Asian origin. A rare but specific form of alpha thalassaemia is therefore present in the British population. In addition, two patients from families of mixed racial origin were encountered who had a moderately severe form of thalassaemia (HbH disease) due to the inheritance of one form of alpha thalassaemia from the British parent and another type from the foreign parent. This shows the importance of careful genetic counselling of British patients with haematological findings of thalassaemia.

Chromosome Aberrations↗
PubMed1985

A mouse beta-globin mutant that is an exact model of hemoglobin Rainier in man.

A mutation induced by ethylnitrosourea in a spermatogonial stem cell of a 101/H mouse has resulted in a structurally altered beta-diffuse major globin in one of his offspring. The mutant hemoglobin is associated with polycythemia, rubor, increased oxygen affinity and decreased hem-hem interaction. The mutant haplotype has been designated Hbbd4, polycythemia. Amino acid analysis of the mutant globin has shown that a single substitution beta 145 Tyr----Cys has occurred, and it is proposed that ethylnitrosourea induced an A----G transition in the tyrosine codon (TAC----TGC). This murine polycythemia is homologous with hemoglobin Rainier in man, in which the amino acid substitution is also beta 145 Tyr----Cys and which is associated with similar physiological consequences.

Animals↗