23 results on '"Boehm C"'
Search Results
2. Single-tube multiplex-PCR screen for common deletional determinants of alpha-thalassemia.
- Author
-
Chong SS, Boehm CD, Higgs DR, and Cutting GR
- Subjects
- Base Sequence, DNA Primers, Heterozygote, Homozygote, Humans, Multigene Family, DNA blood, Genetic Testing methods, Globins genetics, Polymerase Chain Reaction methods, Sequence Deletion, alpha-Thalassemia genetics
- Abstract
Alpha-thalassemia is very common throughout all tropical and subtropical regions of the world. In Southeast Asia and the Mediterranean regions, compound heterozygotes and homozygotes may have anemia that is mild to severe (hemoglobin [Hb] H disease) or lethal (Hb Bart's hydrops fetalis). We have developed a reliable, single-tube multiplex-polymerase chain reaction (PCR) assay for the 6 most frequently observed determinants of alpha-thalassemia. The assay allows simple, high throughput genetic screening for these common hematological disorders. (Blood. 2000;95:360-362)
- Published
- 2000
3. Two novel beta-thalassemia alleles: poly A signal (AATAAA-->AAAA) and -92 C-->T.
- Author
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Kimberland ML, Boehm CD, and Kazazian HH Jr
- Subjects
- Female, Humans, Male, Polymerase Chain Reaction, Sequence Analysis, DNA, Alleles, Globins genetics, Mutation, beta-Thalassemia genetics
- Published
- 1995
- Full Text
- View/download PDF
4. Phylogeny of human beta-globin haplotypes and its implications for recent human evolution.
- Author
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Long JC, Chakravarti A, Boehm CD, Antonarakis S, and Kazazian HH
- Subjects
- Africa, China, Cluster Analysis, Crossing Over, Genetic, Gene Conversion, Genetic Variation, Greece, Hominidae genetics, Humans, India, Italy, Mutation, Polymorphism, Restriction Fragment Length, Recombination, Genetic, Restriction Mapping, Thailand, Biological Evolution, Globins genetics, Haplotypes, Multigene Family, Phylogeny
- Abstract
The evolutionary histories and relationships among African, Eurasian, and Pacific Island populations are investigated by using observations on five polymorphic restriction sites in the beta-globin gene cluster. We present new data on 222 chromosomes from a global sample and combine these with previously published observations on 591 chromosomes. It is shown that the data are rich in rare haplotypes and that rare variants are not helpful for standard methods of population structure analysis. Consequently, a new approach is developed. We first consider the phylogeny of beta-globin haplotypes. The roles of mutation, gene conversion, and recombination in the generation of haplotype diversity are specifically focused upon. The relationships among human populations are then inferred from the phylogenetic relationships among the haplotypes, their presence or absence, and frequencies within populations. Questions regarding whether or not a phyletic process can account for relationships among the major geographical populations and whether or not an extant human population exhibits the qualities that would be expected of an ancestral group are addressed. The results of this analysis support an African origin for modern Homo sapiens and a phyletic structuring of the major geographical regions. However, it is shown that divergence times for the various populations cannot be determined from these data.
- Published
- 1990
- Full Text
- View/download PDF
5. Gene defects in beta-thalassemia and their prenatal diagnosis.
- Author
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Kazazian HH Jr, Dowling CE, Boehm CD, Warren TC, Economou EP, Katz J, and Antonarakis SE
- Subjects
- Base Sequence, Female, Genetic Counseling, Humans, Molecular Sequence Data, Pregnancy, RNA genetics, Thalassemia diagnosis, Thalassemia embryology, Globins genetics, Mutation, Prenatal Diagnosis, Thalassemia genetics
- Published
- 1990
- Full Text
- View/download PDF
6. Nonuniform recombination within the human beta-globin gene cluster.
- Author
-
Chakravarti A, Buetow KH, Antonarakis SE, Waber PG, Boehm CD, and Kazazian HH
- Subjects
- Animals, Black People, DNA Restriction Enzymes metabolism, Genes, Genetics, Population, Haploidy, Humans, Mice, Polymorphism, Genetic, Racial Groups, White People, Globins genetics, Recombination, Genetic
- Abstract
Population genetic analysis of 15 restriction site polymorphisms demonstrates nonuniform recombination within the human beta-globin gene cluster. These DNA polymorphisms show two clusters of high nonrandom associations, one 5' and another 3' to the beta-globin structural gene, with no significant linkage disequilibrium between the two clusters. The 5'- and 3'-association clusters are 34.6 kilobases (kb) and 19.4 kb long, respectively, and are separated by 9.1 kb of DNA immediately 5' to the beta-globin gene. For each of these three DNA regions, we have observed a relationship between nonrandom associations and physical distance between the polymorphisms. However, this relationship differed for each of these regions. On the assumption that the effective population size (Ne) is 5,000-50,000, we estimate the total recombination rate to be 0.0017%-0.0002% in the 5' cluster, 0.0931%-0.0093% in the 3' cluster, and 0.2912%-0.0219% in the 9.1-kb region between them. The beta cluster thus shows nonuniformity in recombination. Moreover, the recombination rate in the 9.1-kb DNA segment is 3-30 times greater than expected and is thus a hot spot for meiotic recombination.
- Published
- 1984
7. Linkage of beta-thalassaemia mutations and beta-globin gene polymorphisms with DNA polymorphisms in human beta-globin gene cluster.
- Author
-
Orkin SH, Kazazian HH Jr, Antonarakis SE, Goff SC, Boehm CD, Sexton JP, Waber PG, and Giardina PJ
- Subjects
- Cloning, Molecular, DNA Restriction Enzymes, Genetic Linkage, Humans, Mutation, Polymorphism, Genetic, Transcription, Genetic, Genes, Globins genetics, Thalassemia genetics
- Published
- 1982
- Full Text
- View/download PDF
8. beta-Thalassemia due to a deletion of the nucleotide which is substituted in the beta S-globin gene.
- Author
-
Kazazian HH Jr, Orkin SH, Boehm CD, Sexton JP, and Antonarakis SE
- Subjects
- Base Sequence, Codon, DNA analysis, DNA Restriction Enzymes, Humans, Mutation, Chromosome Deletion, Genes, Regulator, Globins genetics, Thalassemia genetics
- Abstract
Sickle-cell anemia results from an A leads to T transversion in the second nucleotide of codon 6 of the beta-globin gene. We now report an uncommon beta-thalassemia gene that contains a deletion of this nucleotide. Thus, one mutation (GAG leads to GTG) produces sickle-cell anemia, while the other (GAG leads to GG) eliminates beta-globin production. These data establish that different alterations affecting one specific nucleotide can produce either an abnormal hemoglobin or beta-thalassemia. Moreover, the nucleotide sequence comprising codons 6-8 of the beta-globin gene appears to be particularly susceptible to mutations affecting nucleotide number.
- Published
- 1983
9. Comparison of deficiency alleles of the beta-globin and factor VIII:C genes: new lessons from a giant gene.
- Author
-
Kazazian HH Jr, Antonarakis SE, Youssoufian H, Dowling CE, Phillips DG, Wong C, and Boehm CD
- Subjects
- Codon, Female, Globins deficiency, Humans, Male, Mutation, Pedigree, Protein Biosynthesis, RNA Splicing, Alleles, Factor VIII genetics, Genes, Globins genetics, Hemophilia A genetics, Thalassemia genetics
- Published
- 1986
- Full Text
- View/download PDF
10. Molecular characterization of seven beta-thalassemia mutations in Asian Indians.
- Author
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Kazazian HH Jr, Orkin SH, Antonarakis SE, Sexton JP, Boehm CD, Goff SC, and Waber PG
- Subjects
- Gene Frequency, Genetic Linkage, Humans, India ethnology, Mutation, Globins genetics, Thalassemia genetics
- Abstract
To characterize systematically the mutations which produce beta-thalassemia in Asian Indians, we first determined the DNA polymorphism haplotype in the beta-globin gene cluster of 44 beta-thalassemia chromosomes in the ethnic group. Nine different haplotypes were observed. Upon molecular cloning and partial DNA sequencing of one beta-gene from each of eight haplotypes and two from the ninth, seven different mutations were found. None of these have been identified in Mediterranean patients, even among the five haplotypes which appeared identical in the two groups. Asian Indian mutations included one nonsense and three frameshift mutations, one deletion affecting an acceptor splice site, and two mutations affecting a donor splice site. The correlation of a specific mutation with a specific haplotype was high but not invariant. Two mutations were associated with more than one haplotype but, in each instance, the mutation spread to a new haplotype could be explained most simply by recombination 5' to the beta-globin gene. In addition, four mutations, one reported here and three others previously reported, have been observed on two chromosome backgrounds that are identical except for the status of a polymorphic HinfI site 5' to the beta gene. This HinfI site does not show significant linkage disequilibrium with markers both 5' and 3' to it, suggesting that it lies within a region of relative sequence randomization.
- Published
- 1984
- Full Text
- View/download PDF
11. Prenatal diagnosis of sickle cell anemia by restriction and endonuclease analysis: HindIII polymorphisms in gamma-globin genes extend test applicability.
- Author
-
Phillips JA 3rd, Panny SR, Kazazian HH Jr, Boehm CD, Scott AF, and Smith KD
- Subjects
- Anemia, Sickle Cell genetics, Black People, DNA Restriction Enzymes, Genes, Genetic Linkage, Humans, Polymorphism, Genetic, Prenatal Diagnosis, United States, Black or African American, Anemia, Sickle Cell diagnosis, Globins genetics
- Abstract
Polymorphism for a Hpa I restriction endonuclease site associated with about 60% of beta S genes in American Blacks allows exact prenatal diagnosis of sickle cell anemia by amniocentesis in 36% of couples at risk. In three families in whom exact diagnosis by Hpa I sites was impossible, we found analysis for the presence of polymorphic HindIII sites in the G gamma and A gamma intervening sequences would allow an exact prenatal diagnosis of sickle cell status in all three. In one of these families, the presence of an A gamma HindIII site in amniocyte DNA confirmed the diagnosis (sickle cell trait) made by synthetic studies using fetal erythrocytes obtained at fetoscopy. Studies of other Black families and individuals provide evidence for linkage disequilibrium in the G gamma-A gamma-delta-beta gene complex involving the four sites, G gamma HindIII, A gamma HindIII, beta S, and Hpa I, which span 33 kilobases (kb). Ten of 14 chromosomes bearing a beta S gene in a 7.6-kb Hpa I fragment contained a G gamma but not an A gamma HindIII site, whereas 16 of 16 chromosomes bearing a beta S gene in a 13-kb Hpa I fragment lacked both the G gamma and A gamma HindIII sites. Two-thirds of beta A-bearing chromosomes lacked both G gamma and A gamma sites, whereas one-third contained either the G gamma or both G gamma and A gamma sites. These data demonstrate that combined analysis of both Hpa I and HindIII polymorphisms and verification of their linkage phase should increase the fraction of couples for whom amniocentesis can provide an exact diagnosis of sickle cell status from 36% to greater than 80%.
- Published
- 1980
- Full Text
- View/download PDF
12. Evidence for multiple origins of the beta E-globin gene in Southeast Asia.
- Author
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Antonarakis SE, Orkin SH, Kazazian HH Jr, Goff SC, Boehm CD, Waber PG, Sexton JP, Ostrer H, Fairbanks VF, and Chakravarti A
- Subjects
- DNA Restriction Enzymes, Genes, Humans, Polymorphism, Genetic, Asian People, Biological Evolution, Globins genetics
- Abstract
To investigate whether recurrent mutation has contributed to the high frequency of the beta E-globin gene in Southeast Asia, we used the haplotypes at three polymorphic restriction sites within and to the 3' side of the beta-globin gene to predict the framework of 23 beta E-globin genes. These haplotypes suggested that beta E-globin genes are present in two different beta-globin gene frameworks. DNA sequence determination of one gene representing each framework demonstrated that the same mutation (GAG leads to AAG at codon 26) was present in both frameworks. Moreover, the frameworks differed at three nucleotide positions known to be polymorphic in Mediterraneans. These polymorphic sites are located 70 nucleotides to the 5' side of the beta E mutation and 382 and 1032 nucleotides to the 3' side of it. The existence of the beta E mutation in these two beta-globin gene frameworks can be explained by (i) recurrent mutation giving rise to beta E-globin, (ii) a double crossing-over event, or (iii) two single crossing-over events. Mathematical analysis suggests that the first alternative, recurrent mutation of G leads to A at the first nucleotide of codon 26, is most likely.
- Published
- 1982
- Full Text
- View/download PDF
13. Use of haplotype analysis in the beta-globin gene cluster to discover beta-thalassemia mutations.
- Author
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Kazazian HH Jr, Antonarakis SE, Cheng T, Boehm CD, and Waber PG
- Subjects
- Base Sequence, Genes, Genetic Linkage, Humans, Mutation, Polymorphism, Genetic, Globins genetics, Thalassemia genetics
- Abstract
DNA polymorphisms have been of great value in defining a small number of common sequences in the beta-globin gene cluster and a region within which recombination may be restricted. Moreover, they have led to a screening procedure that not only has been of great value for the molecular characterization of beta-thalassemia mutations but also has implications for the characterization of other single-gene disorders.
- Published
- 1983
14. On the origin and spread of beta-thalassemia: recurrent observation of four mutations in different ethnic groups.
- Author
-
Wong C, Antonarakis SE, Goff SC, Orkin SH, Boehm CD, and Kazazian HH Jr
- Subjects
- Black People, China ethnology, Ethnicity, Genetic Linkage, Humans, India ethnology, Iran ethnology, Laos ethnology, Mutation, Polymorphism, Genetic, Thalassemia epidemiology, Vietnam ethnology, Globins genetics, Thalassemia genetics
- Abstract
Seven beta-thalassemia genes were characterized after they were identified as candidates for previously undescribed mutations based upon the close association of DNA polymorphism haplotypes in the beta-globin gene cluster with specific ethnic mutations. The molecular defect in four of these genes was identical, a frameshift deletion of four nucleotides (-CTTT) within codons 41 and 42. This gene represents a common Southeast Asian mutation shared by a Laotian beta-thalassemia gene, [framework 1 (FR1)], a Vietnamese (FR1), and two Chinese patients (FR3 Asian and FR1). The deletion has been observed previously in Chinese (FR1) and Asian Indians (FR2) and is an example of independent origins of the same molecular defect, possible interallelic gene conversion (as it is seen on two different beta-globin gene frameworks in Chinese), and mutant gene migration in the Asian countries. A second example of mutant gene migration was identified in an Iranian patient with a nucleotide insertion (G) between codons 8 and 9, the same mutation previously found in an Asian Indian in the same chromosomal background. The last two genes examined represent further strong evidence for independent origins of mutation. A C-to-T substitution at position -88 in an Asian Indian has been identified previously in an American Black on a different beta-globin gene framework, and a G-to-A transition at nucleotide 1 of intervening sequence 2 found in an American Black has been observed previously on a different chromosome background in Mediterraneans. This study suggests that there are not many common beta-thalassemia mutations remaining to be discovered. It also suggests that certain sequences in the beta-globin gene are relatively mutation sensitive.
- Published
- 1986
- Full Text
- View/download PDF
15. Nonrandom association of polymorphic restriction sites in the beta-globin gene cluster.
- Author
-
Antonarakis SE, Boehm CD, Giardina PJ, and Kazazian HH Jr
- Subjects
- Anemia, Sickle Cell diagnosis, Anemia, Sickle Cell genetics, Base Sequence, DNA Restriction Enzymes, Ethnicity, Female, Gene Frequency, Genetic Linkage, Humans, Pregnancy, Prenatal Diagnosis, Thalassemia diagnosis, Thalassemia genetics, Genes, Globins genetics, Polymorphism, Genetic
- Abstract
By using probes for epsilon-, Psibeta(1)-, and beta-globin genes, we found four additional polymorphic restriction sites that have frequencies >0.1 in persons of Mediterranean area origin, Asian Indians, and American Blacks. Three of these (HincII sites) and the two previously described polymorphic HindIII sites [one in intervening sequence (IVS) II of each gamma-globin gene] are distributed over 32 kilobases (kb) of DNA located 5' to the delta-globin gene. This region of DNA comprises two-thirds of the beta-globin gene cluster. Since each of these five polymorphic sites can be present (+) or absent (-), in theory there exist 32 possible combinations of sites (haplotypes). However, in Italians, Greeks, Indians, and Turks, 3 of the 32 haplotypes, (+----), (-+-++), and (-++-+), account for 92% of 89 beta(A) chromosomes examined. The observed frequencies for these haplotypes are 0.64, 0.15, and 0.13 in the populations studied, in contrast to expected frequencies (based on the observed gene frequencies at each of the five sites) of 0.20, 0.006, and 0.005, respectively. In American Blacks, a fourth haplotype, (----+), which is rare in non-Black populations, has a frequency of 0.37 in contrast to its expected frequency of 0.05. These results suggest a nonrandom association of DNA sequences over 32 kb 5' to the delta-globin gene in all populations studied. Two other polymorphic sites 3' to the delta gene (the newly discovered Ava II site in IVS II of the beta-globin gene and the BamHI site 3' to it) are nonrandomly associated with each other but randomly distributed with respect to the above haplotypes. This suggests that randomization of sequences has occurred within 12 kb of DNA between these two nonrandomly associated sequence clusters. Nonrandom association of polymorphic restriction sites has practical consequences in that it limits the usefulness of these additional HincII sites for prenatal diagnosis of hemoglobinopathies by linkage analysis. These sites provide little additional information for detection of beta-thalassemia, while the polymorphic Ava II site, which lies outside the nonrandomly associated sequences 5' to the delta gene, improves the test applicability from 52% to 70% of couples at risk.
- Published
- 1982
- Full Text
- View/download PDF
16. Characterization of a spontaneous mutation to a beta-thalassemia allele.
- Author
-
Kazazian HH Jr, Orkin SH, Boehm CD, Goff SC, Wong C, Dowling CE, Newburger PE, Knowlton RG, Brown V, and Donis-Keller H
- Subjects
- DNA Restriction Enzymes, Female, Genetic Markers, Humans, Male, Paternity, Pedigree, Polymorphism, Genetic, Alleles, Globins genetics, Mutation, Thalassemia genetics
- Abstract
We have studied a nuclear family containing a single child with severe beta-thalassemia intermedia, a Greek-Cypriot mother with hematological findings of beta-thalassemia trait, and a Polish father who is hematologically normal. Since both the child and her father were heterozygous for a DNA polymorphism within the beta-globin gene, it was possible to clone and sequence the beta-globin gene identical by descent from both the child and her father. A nonsense mutation in codon 121 (GAA----TAA) was found in the beta-globin gene of the child, while the same gene from her father lacked this mutation and was normal. This mutation has not been previously observed among over 200 beta-thalassemia genes characterized in Caucasians. Since the mutation eliminates an EcoRI site in the beta-globin gene, we could show that the mutation is not present in genomic DNA of the father. To rule out germinal mosaicism, sperm DNA of the father was also digested with EcoRI, and the mutant EcoRI fragment was not observed under conditions that would detect the mutation if it were present in at least 2% of sperm cells. Routine HLA and blood group testing supported stated paternity. In addition, studies with 17 DNA probes that detect multiple allele polymorphisms increased the probability of stated paternity to at least 10(8):1. These data provide evidence that the G----T change in codon 121 of the beta-globin gene in the child is the result of a spontaneous mutation that occurred during spermatogenesis in a paternal germ cell.
- Published
- 1986
17. Origin of the beta S-globin gene in blacks: the contribution of recurrent mutation or gene conversion or both.
- Author
-
Antonarakis SE, Boehm CD, Serjeant GR, Theisen CE, Dover GJ, and Kazazian HH Jr
- Subjects
- Homozygote, Humans, Jamaica ethnology, United States, Black or African American, Alleles, Anemia, Sickle Cell genetics, Black People, Gene Conversion, Genes, Globins genetics, Hemoglobin, Sickle genetics, Mutation, Polymorphism, Genetic
- Abstract
In order to investigate the origin(s) of the mutation(s) leading to the beta S-globin gene in North American populations of African ancestry, we analyzed DNA polymorphisms in the beta-globin gene cluster in a large number of both beta A- and beta S-globin gene-bearing chromosomes in U.S. and Jamaican Blacks. We found 16 different haplotypes of polymorphic sites associated with 170 beta S-globin gene-bearing chromosomes. The three most common beta S haplotypes, which account for 151/170 of the beta S-globin gene-bearing chromosomes, are only rarely seen in the chromosomes bearing the beta A-globin gene in these populations (6/47). Two observations suggest multiple origins or interallelic gene conversion, or both, of the beta S mutation. First, the mutation is present in all three beta-globin gene frameworks. Second, the beta S haplotypes can be divided into four groups, each of which cannot be derived from any other by less than two crossing-over events. In summary, our observation of the beta S mutation on 16 different haplotypes in African populations can be best explained by (i) a number of simple recombination events 5' to the beta-globin gene and (ii) up to four independent mutations and/or interallelic gene conversions.
- Published
- 1984
- Full Text
- View/download PDF
18. Evidence supporting a single origin of the beta(C)-globin gene in blacks.
- Author
-
Boehm CD, Dowling CE, Antonarakis SE, Honig GR, and Kazazian HH Jr
- Subjects
- Haplotypes, Humans, Multigene Family, Mutation, Polymorphism, Restriction Fragment Length, Black or African American, Black People genetics, Globins genetics
- Abstract
In order to characterize the origin(s) of the beta C-globin gene in blacks, 25 chromosomes bearing this gene were characterized at eight polymorphic restriction sites within the beta-globin gene cluster. Twenty-two of the 25 chromosomes were identical at all sites and possessed a haplotype seen only infrequently among beta A-bearing chromosomes in black Americans. Two different haplotypes were observed among the three exceptional chromosomes. These haplotypes were identical to the most common beta C allele in the 3' end of the beta-globin gene cluster, but differed in the 5' region. Partial haplotype analysis on an additional 14 beta C alleles demonstrated complete association with the typical beta C-associated polymorphisms in the 3' region of the cluster. These data can be most easily explained by a single origin of the mutation followed by spread of the mutation to other haplotypes through meiotic recombination 5' to the beta-globin gene.
- Published
- 1985
19. Diagnosis of sickle cell anemia and beta-thalassemia with enzymatically amplified DNA and nonradioactive allele-specific oligonucleotide probes.
- Author
-
Saiki RK, Chang CA, Levenson CH, Warren TC, Boehm CD, Kazazian HH Jr, and Erlich HA
- Subjects
- Alleles, Colorimetry, DNA-Directed DNA Polymerase pharmacology, Female, Horseradish Peroxidase, Humans, Nucleic Acid Hybridization, Pregnancy, Retrospective Studies, Anemia, Sickle Cell diagnosis, DNA analysis, Fetal Diseases diagnosis, Gene Amplification, Globins genetics, Oligonucleotides, Prenatal Diagnosis methods, Thalassemia diagnosis
- Abstract
We have developed a simple and rapid nonradioactive method for detecting genetic variation and have applied it to the diagnosis of sickle cell anemia and beta-thalassemia. The procedure involves the selective amplification of a segment of the human beta-globin gene with oligonucleotide primers and a thermostable DNA polymerase, followed by hybridization of the amplified DNA with allele-specific oligonucleotide probes covalently labeled with horseradish peroxidase. The hybridized probes were detected with a simple colorimetric assay. We demonstrated the usefulness of this method in a retrospective analysis of two pregnancies at risk for beta-thalassemia and one at risk for sickle cell anemia, as well as in an analysis of nine DNA samples simulating three family sets.
- Published
- 1988
- Full Text
- View/download PDF
20. Molecular characterization of a beta zero-thalassemia resulting from a 1.4 kilobase deletion.
- Author
-
Anand R, Boehm CD, Kazazian HH Jr, and Vanin EF
- Subjects
- Base Sequence, Chromosome Mapping, DNA analysis, Fetal Hemoglobin analysis, Hemoglobin A2 analysis, Humans, Molecular Sequence Data, Chromosome Deletion, Globins genetics, Thalassemia genetics
- Abstract
We report the characterization of a beta zero-thalassemia in an American Black with unusually high HbA2 and HbF levels. Genomic southern analysis indicated that the individual was heterozygous for a deletion that began within the second intervening sequence of the beta-globin gene and extended approximately 1.4 kb in the 5' direction. A clone spanning the breakpoint on the abnormal chromosome was isolated and further mapped, and the deletion joint was sequenced. Comparison of the normal beta-globin gene and its 5' flanking region with the deletion joint sequence indicated that the 5' breakpoint for this deletion was 484 base pairs (bp) 5' to the transcriptional start site for the beta-globin gene and the 3' breakpoint was 908 bp into the beta-globin gene; the deletion removed a total of 1,393 bp. Comparison of the normal 5' and 3' breakpoint sequences indicated that this deletion was the result of a "clean" nonhomologous breakage and reunion event; ie, no spurious bases were added during the recombinational event. Analysis of the breakpoints of this deletion together with the breakpoints of two other small deletions involving the beta-globin gene suggests that the breakpoints may occur at DNA polymerase alpha pause sites.
- Published
- 1988
21. Characterization of a spontaneous mutation to a beta-thalassemia allele
- Author
-
Kazazian, H H, Orkin, S H, Boehm, C D, Goff, S C, Wong, C, Dowling, C E, Newburger, P E, Knowlton, R G, Brown, V, and Donis-Keller, H
- Subjects
Genetic Markers ,Male ,Polymorphism, Genetic ,Paternity ,DNA Restriction Enzymes ,Globins ,Pedigree ,hemic and lymphatic diseases ,Mutation ,Humans ,Thalassemia ,Female ,Alleles ,Research Article - Abstract
We have studied a nuclear family containing a single child with severe beta-thalassemia intermedia, a Greek-Cypriot mother with hematological findings of beta-thalassemia trait, and a Polish father who is hematologically normal. Since both the child and her father were heterozygous for a DNA polymorphism within the beta-globin gene, it was possible to clone and sequence the beta-globin gene identical by descent from both the child and her father. A nonsense mutation in codon 121 (GAA----TAA) was found in the beta-globin gene of the child, while the same gene from her father lacked this mutation and was normal. This mutation has not been previously observed among over 200 beta-thalassemia genes characterized in Caucasians. Since the mutation eliminates an EcoRI site in the beta-globin gene, we could show that the mutation is not present in genomic DNA of the father. To rule out germinal mosaicism, sperm DNA of the father was also digested with EcoRI, and the mutant EcoRI fragment was not observed under conditions that would detect the mutation if it were present in at least 2% of sperm cells. Routine HLA and blood group testing supported stated paternity. In addition, studies with 17 DNA probes that detect multiple allele polymorphisms increased the probability of stated paternity to at least 10(8):1. These data provide evidence that the G----T change in codon 121 of the beta-globin gene in the child is the result of a spontaneous mutation that occurred during spermatogenesis in a paternal germ cell.
- Published
- 1986
22. beta-Thalassemia due to a deletion of the nucleotide which is substituted in the beta S-globin gene
- Author
-
Kazazian, H H, Orkin, S H, Boehm, C D, Sexton, J P, and Antonarakis, S E
- Subjects
Base Sequence ,hemic and lymphatic diseases ,Genes, Regulator ,Mutation ,Humans ,Thalassemia ,DNA ,DNA Restriction Enzymes ,Chromosome Deletion ,Codon ,Research Article ,Globins - Abstract
Sickle-cell anemia results from an A leads to T transversion in the second nucleotide of codon 6 of the beta-globin gene. We now report an uncommon beta-thalassemia gene that contains a deletion of this nucleotide. Thus, one mutation (GAG leads to GTG) produces sickle-cell anemia, while the other (GAG leads to GG) eliminates beta-globin production. These data establish that different alterations affecting one specific nucleotide can produce either an abnormal hemoglobin or beta-thalassemia. Moreover, the nucleotide sequence comprising codons 6-8 of the beta-globin gene appears to be particularly susceptible to mutations affecting nucleotide number.
- Published
- 1983
23. Evidence supporting a single origin of the beta(C)-globin gene in blacks
- Author
-
Boehm, C D, Dowling, C E, Antonarakis, S E, Honig, G R, and Kazazian, H H
- Subjects
Haplotypes ,Multigene Family ,Mutation ,Black People ,Humans ,Polymorphism, Restriction Fragment Length ,Research Article ,Globins - Abstract
In order to characterize the origin(s) of the beta C-globin gene in blacks, 25 chromosomes bearing this gene were characterized at eight polymorphic restriction sites within the beta-globin gene cluster. Twenty-two of the 25 chromosomes were identical at all sites and possessed a haplotype seen only infrequently among beta A-bearing chromosomes in black Americans. Two different haplotypes were observed among the three exceptional chromosomes. These haplotypes were identical to the most common beta C allele in the 3' end of the beta-globin gene cluster, but differed in the 5' region. Partial haplotype analysis on an additional 14 beta C alleles demonstrated complete association with the typical beta C-associated polymorphisms in the 3' region of the cluster. These data can be most easily explained by a single origin of the mutation followed by spread of the mutation to other haplotypes through meiotic recombination 5' to the beta-globin gene.
- Published
- 1985
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