Organization of the alpha-globin genes in the Chinese alpha-thalassemia syndromes.

Embury, Stephen H.; Lebo, Roger V.; Dozy, Andrée M.; Kan, YW

doi:10.1172/jci109426

Cited by 174 publications

(87 citation statements)

References 16 publications

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“…Chromosomes bearing these ␣-globin gene deletions are very common, particularly in Asia and Africa, where they can attain population frequencies as high as 90% (28,36,37), and are most likely maintained by malaria selection in favor of Ϫ␣ chromosomes (27,28). In contrast, nonmalarial populations show a much lower incidence of deletion chromosomes (Ϸ0.6% in northern Europeans; see Materials and Methods).…”

Section: Resultsmentioning

confidence: 99%

Processes of copy-number change in human DNA: The dynamics of α-globin gene deletion

Lam

Jeffreys²

2006

Proc. Natl. Acad. Sci. U.S.A.

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Ectopic recombination between locally repeated DNA sequences is of fundamental importance in the evolution of gene families, generating copy-number variation in human DNA and often leading to pathological rearrangements. Despite its importance, little is known about the dynamics and processes of these unequal crossovers and the degree to which meiotic recombination plays a role in instability. We address this issue by using as a highly informative system the duplicated ␣-globin genes in which ectopic recombination can lead to gene deletions, often very prevalent in populations affected by malaria, as well as reduplications. Here we show that spontaneous deletions can be accessed directly in genomic DNA by using single-DNA-molecule methods. These deletions proved to be remarkably common in both blood and sperm. Somatic deletions arise by a strictly intrachromosomal pathway of homologous exchange that also operates in the germ line and can generate mutational mosaicism, whereas sperm deletions frequently involve recombinational interactions between homologous chromosomes that most likely occur at meiosis. Ectopic recombination frequencies show surprisingly little requirement for long, identical homology blocks shared by paralogous sequences, and exchanges can occur even between short regions of sequence identity. Finally, direct knowledge of germ-line deletion rates can give insights into the fitness of individuals with these ␣-globin gene deletions, providing a new approach to investigating historical levels of selection operating in human populations.ectopic ͉ recombination ͉ selection ͉ mutation ͉ mosaicism

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Section: Resultsmentioning

confidence: 99%

Processes of copy-number change in human DNA: The dynamics of α-globin gene deletion

Lam

Jeffreys²

2006

Proc. Natl. Acad. Sci. U.S.A.

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“…Fig. 1 along with the map of the a-globin genes on a normal chromosome and on a chromosome with the rightward type aThal-2 deletion (5,24). Table I lists the genotype determined for each patient.…”

Section: Methodsmentioning

confidence: 99%

“…The a-globin cluster consists of five genes and pseudogenes organized over a 30-kilobase (kb)' distance in the order: 5't-i/'{-i/'a-a2-a 1 (3). The two adjacent a-globin genes, a 1 and a2, are located 3.7 kb apart and each is situated within a segment of duplicated DNA (3)(4)(5). During primate evolution the sequence composition of these duplicated segments encompassing the two a-globin genes has changed in parallel (6,7).…”

Section: Introductionmentioning

confidence: 99%

Compensatory increase in alpha 1-globin gene expression in individuals heterozygous for the alpha-thalassemia-2 deletion.

Liebhaber¹,

Cash²,

Main³

1985

J. Clin. Invest.

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a-Globin is encoded by the two adjacent genes, al and a2. Although it is clearly established that both a-globin genes are expressed, their relative contributions to a-globin messenger RNA (mRNA) and protein synthesis are not fully defined. Furthermore, changes that may occur in a-globin gene activity secondarily to the loss of function of one or more of these genes (a-thalassemia [Thall) have not been directly investigated. This study further defines the expression of the two human a-globin genes by determining the relative levels of al and a2 mRNA in the reticulocytes of normal individuals and in individuals heterozygous for the common 3.7-kilobase deletion within the a-globin gene cluster that removes the a2-globin gene (the rightward type aThal-2 deletion). To quantitate accurately the ratio of the two a-globin mRNAs, we have modified a previously reported S1 nuclease assay to include the use of 32P end-labeled probes isolated from al-and a2-globin complementary DNA recombinant plasmids. In individuals with a normal a-globin genotype (as determined by Southern blot analysis Iaa/aal), a2-globin mRNA is present at an average 2.8-fold excess to al. In individuals heterozygous for the rightward type a-Thal-2 deletion (-a/aa) the ct2/al mRNA ratio is 1:1. These results suggest that the loss of the a2-globin gene in the a-Thal-2 deletion is associated with a 1.8-fold compensatory increase al-globin gene expression.

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“…By use of the Southern blotting technique, progress was made toward the elucidation of the molecular basis of different forms of α thalassemia (20)(21)(22)(23). By then, it was clear that the normal α globin genes are duplicated, with the genotype αα/αα.…”

Section: Further Developments In Hemoglobin Genetics and The Evolutiomentioning

confidence: 99%

A Journey in Science: Early Lessons from the Hemoglobin Field

Weatherall

2014

Mol Med

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Real innovations in medicine and science are historic and singular; the stories behind each occurrence are precious. At Molecular Medicine we have established the Anthony Cerami Award in Translational Medicine to document and preserve these histories. The monographs recount the seminal events as told in the voice of the original investigators who provided the crucial early insight. These essays capture the essence of discovery, chronicling the birth of ideas that created new fields of research; and launched trajectories that persisted and ultimately influenced how disease is prevented, diagnosed, and treated. In this volume, the Cerami Award Monograph is by David J Weatherall, Founder, Weatherall Institute of Molecular Medicine, Oxford University, John Radcliffe Hospital. A visionary in the field of hemoglobin, this is the story of Professor Weatherall's scientific journey.

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Organization of the alpha-globin genes in the Chinese alpha-thalassemia syndromes.

Cited by 174 publications

References 16 publications

Processes of copy-number change in human DNA: The dynamics of α-globin gene deletion

Processes of copy-number change in human DNA: The dynamics of α-globin gene deletion

Compensatory increase in alpha 1-globin gene expression in individuals heterozygous for the alpha-thalassemia-2 deletion.

A Journey in Science: Early Lessons from the Hemoglobin Field

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