Is the Human Globin Α‐chain Locus Duplicated?

Wasi, P

doi:10.1111/j.1365-2141.1973.tb01651.x

Cited by 25 publications

(8 citation statements)

References 42 publications

(8 reference statements)

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“…The inheritance of a-thalassemia is determnined by two different types of a-thalassemia genes, the more severe of which is called the a-thalassemia-1 (a-thal-1)l gene and the milder of which is called the a-thalassemia-2 (a-thal-2) gene (8). Restriction endonuclease mapping has shown that the latter is composed of a single a-globin locus (9,10) and that the former consists of a chromosome devoid of a-globin genes (10), as contrasted with the two a-globin loci of the normal a-globin genotype (10,11).…”

Section: Dr Kain Is An Investigator Of the Hovard Huighes Medicalmentioning

confidence: 99%

Two different molecular organizations account for the single alpha-globin gene of the alpha-thalassemia-2 genotype.

Embury¹,

Miller²,

Dozy³

et al. 1980

J. Clin. Invest.

250

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A B S T R A C T The a-thalassemia-2 (a-thal-2) genotype or mild a-thalassemia gene consists of a single structural a-globin gene on the chromosome that normally bears two a-globin genes. We used blot hybridization to investigate variation in the molecular organization of this genotype and to determine the distributions of these variations in the world population. Two different patterns of gene organization responsible for the a-thal-2 genotype were found: the first was the result of a 4.2-kilobase pair deletion involving the normal 5' a-globin gene (leftward deletion a-thal-2 genotype), and the second probably the result of a crossover deletion of a DNA fragment bridging the two normal a-globin genes (rightward deletion a-thal-2-genotype). The rightward deletion was found in all 9 Black subjects, all 8 Mediterranean subjects, and 4 of 13 Chinese subjects. The leftward deletion was found in four and the nondeletion a-thalassemia lesion was found in five of the nine remaining Chinese subjects. It is likely that these deletions are related to specific DNA sequences that determine DNA recombinational events.

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Section: Dr Kain Is An Investigator Of the Hovard Huighes Medicalmentioning

confidence: 99%

Two different molecular organizations account for the single alpha-globin gene of the alpha-thalassemia-2 genotype.

Embury¹,

Miller²,

Dozy³

et al. 1980

J. Clin. Invest.

250

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“…On this basis it appears that the aminoterminal segment (residues 1-118, inclusive) of the elongated Hba gene originates from the Hba locus of one chromosome and the carboxyl-terminal segment (residues 116-141 with the duplication of residues 116-118) from the Hba locus of the other. If the chromosome carries two tandemly repeated loci, as some have suggested (24)(25)(26), and these are in direct tandem (27,28). Other residues in the vicinity are also participating in the af#, contact.…”

Section: Discussionmentioning

confidence: 99%

Hemoglobin Grady: The First Example of a Variant with Elongated Chains Due to an Insertion of Residues

Huisman

Wilson

Gravely

et al. 1974

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

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A black 25-year-old woman and her father have a fast-moving a chain variant in an amount of 8% (the father) and 18% (the daughter). Structural data indicate that this chain has been elongated by the addition of three amino-acid residues to give the sequence: -Pro-(114)-Ala(115)-Glu(116)-Phe(117)-Thr(118)-Glu-Phe-ThrPro(119)-Ala(120)-. The underlying genetic alteration responsible for hemoglobin Grady appears, therefore, to be a tandem duplication of nine base pairs which may have arisen by a process of mismatched intragenic crossing over. Functional and physicochemical properties of the variant are not greatly altered, and hematological data are normal.Comparative phylogenetic studies of sequences of many proteins suggest that intragenic duplications have played an important role in the evolution of structural genes and proteins. The evidence for such duplications has been reviewed elsewhere (1). We report here the first case of tandem repetition of a short sequence of amino-acid residues occurring in the a chain of a human hemoglobin (Hb). The variant, termed Hb-Grady, was observed in a 25-year-old black woman and her father. It has an increased electrophoretic mobility at alkaline pH, and subsequent structural analyses showed that its a chains were elongated with three amino-acid residues because the sequence Glu-Phe-Thr in positions 116-118 was repeated. Since this variant has been detected thus far in only two members of one family, it may be assumed that the tandem intragenic duplication is of recent origin. The nature of the duplication is such as to suggest that it may have arisen by unequal crossing-over. EXPERIMENTALSource of Blood. Samples from the propositus and from five relatives were collected in EDTA and analyzed in Atlanta or shipped by air to Augusta, Ga.Identification Procedures. Solutions of Hb were prepared by mixing one volume of washed erythrocytes with one volume of distilled water and 0.5 volume of carbontetrachloride. Debris was removed by centrifugation. Initial identification of the Hb types was made by cellulose acetate electrophoresis in Tris-EDTA-borate buffer (pH 8.4) (2), and by starch gel electrophoresis with the Tris-EDTA-borate discontinuous buffer system, pH 9.0 (3). Alkali-resistant Hb was measured by the method of Betke et al. (4). Chromatographic analyses made use of columns of DEAE-Sephadex (5, 6) or DEAEcellulose (7).Isolation of Hb Variant and Abnormal Chain. The variant was isolated bv chromatography on DEAE-Sephadex (5, 6). Hb-Grady was contaminated with the normally occurring minor Hb-A1, but was used without further purification because the abnormal a chain of Hb-Grady was readily separated from the the normal a chain of Hb-A1 on 1.7 X 15-cm columns of carboxymethylcellulose (8).Digestion of the a Chain. The chain was digested with trypsin for 4 hr at room temperature in a pH stat at pH 9.0 with addition of enzyme at zero and at 1 hr in an enzyme: protein ratio of 1: 100. The pH was lowered to 6.5, and the insoluble core was isolated by centrifugation. The pH...

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“…The unstable mutant hemoglobins synthesize only 20-27% of their hemoglobin as Hasharon, have a greater tendency t o dissociate into subunits, and this which demonstrated that decreased synthesis determines the proportion of Hasharon in heterozygotes. The genetics of the a chain are unclear at present (30). It may be that there are two loci for the a chain; this could account for the presence of 20-25% a chain mutants instead of the 50% which might be expected if there were only a single locus.…”

Section: Change In Rate Of Synthesis Of Variant Chainmentioning

confidence: 99%

“…The propositus was a 965-g female born in September 1971 identical with that of her mother and the variant hemoglobin at 30 weeks' gestation to a 29-year-old gravida 4 mother.…”

Section: Case Reportmentioning

confidence: 99%