First reported duplication of the entire beta globin gene cluster causing an unusual sickle cell trait phenotype

2014 ◽  
Vol 170 (1) ◽  
pp. 128-131 ◽  
Author(s):  
Claire Shooter ◽  
Tania Senior McKenzie ◽  
Matthew Oakley ◽  
Tracey Jacques ◽  
Barnaby Clark ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Sickle Cell ◽  
Sickle Cell Trait ◽  
Globin Gene ◽  
Beta Globin ◽  
Beta Globin Gene ◽  
Globin Gene Cluster

scholarly journals Production of F cells in sickle cell anemia: regulation by a genetic locus or loci separate from the beta-globin gene cluster

Blood ◽  
1984 ◽  
Vol 64 (5) ◽  
pp. 1053-1058 ◽  
Author(s):  
SH Boyer ◽  
GJ Dover ◽  
GR Serjeant ◽  
KD Smith ◽  
SE Antonarakis ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Sickle Cell ◽  
Genetic Locus ◽  
Globin Gene ◽  
The United States ◽  
Beta Globin ◽  
Cell Production ◽  
Beta Globin Gene ◽  
Globin Gene Cluster ◽  
Sib Pairs

Abstract Levels of fetal hemoglobin (HbF) bearing reticulocytes (F reticulocytes) range from 2% to 50% in patients with sickle cell (SS) anemia. To learn whether any portion of such variation in F cell production is regulated by loci genetically separable from the beta- globin gene cluster, percentages of F reticulocytes were compared in 59 sib pairs composed solely of SS members, including 40 pairs from Jamaica and 19 from the United States. We reasoned that differences in F reticulocyte levels might arise (1) from any of several kinds of artifact, (2) via half-sib status, or (3) because one or more genes regulating F cell production segregate separately from beta S. We minimized the role of artifact by assay of fresh samples from 84 SS individuals, including both members of 38 sib pairs. In 78 of the 84 subjects, serial values for percent F reticulocytes fell within 99.9% confidence limits or were alike by t test (P greater than or equal to .05). This left 32 sib pairs for which F reticulocyte levels in each member were reproducible. When sib-sib comparisons were limited to these 32 pairs, percentages of F reticulocytes were grossly dissimilar within 12 Jamaican and 3 American sibships. Within them, the probability that sibs were alike was always less than or equal to .005 and usually less than or equal to 10(-4). We next minimized the contribution of half-sibs among Jamaicans by a combination of paternity testing and sib-sib comparison of beta-globin region DNA restriction fragment length polymorphisms, especially among discordant pairs. We thereafter concluded that at least seven to eight Jamaican pairs were composed of reproducibly discordant full sibs. There is thus little doubt that there are genes regulating between-patient differences in F cell production that are separate from the beta-globin gene cluster. Still unanswered is (1) whether or not these genes are actually linked to beta S, (2) why F reticulocyte levels in Americans tend to be lower than in Jamaicans, and (3) whether or not differences in F cell production among SS patients are regulated by several major loci or by only one.

Beta-Globin Gene Cluster Haplotypes in Yemeni Children with Sickle Cell Disease

2010 ◽  
Vol 123 (3) ◽  
pp. 182-185 ◽  
Author(s):  
Abdul-Wahab M. Al-Saqladi ◽  
Bernard J. Brabin ◽  
Hassan A. Bin-Gadeem ◽  
Warsha A. Kanhai ◽  
Marion Phylipsen ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Gene Cluster ◽  
Sickle Cell ◽  
Globin Gene ◽  
Beta Globin ◽  
Cell Disease ◽  
Beta Globin Gene ◽  
Globin Gene Cluster

scholarly journals Beta-globin gene cluster haplotypes in Venezuelan sickle cell patients from the State of Aragua

2002 ◽  
Vol 25 (1) ◽  
pp. 21-34 ◽  
Author(s):  
Nancy Moreno ◽  
José A. Martínez ◽  
Zorella Blanco ◽  
Leidys Osorio ◽  
Patrick Hackshaw
Keyword(s):  
Gene Cluster ◽  
Sickle Cell ◽  
Globin Gene ◽  
The State ◽  
Beta Globin ◽  
Beta Globin Gene ◽  
Globin Gene Cluster

scholarly journals Production of F cells in sickle cell anemia: regulation by a genetic locus or loci separate from the beta-globin gene cluster

Blood ◽  
1984 ◽  
Vol 64 (5) ◽  
pp. 1053-1058 ◽  
Author(s):  
SH Boyer ◽  
GJ Dover ◽  
GR Serjeant ◽  
KD Smith ◽  
SE Antonarakis ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Sickle Cell ◽  
Genetic Locus ◽  
Globin Gene ◽  
The United States ◽  
Beta Globin ◽  
Cell Production ◽  
Beta Globin Gene ◽  
Globin Gene Cluster ◽  
Sib Pairs

Levels of fetal hemoglobin (HbF) bearing reticulocytes (F reticulocytes) range from 2% to 50% in patients with sickle cell (SS) anemia. To learn whether any portion of such variation in F cell production is regulated by loci genetically separable from the beta- globin gene cluster, percentages of F reticulocytes were compared in 59 sib pairs composed solely of SS members, including 40 pairs from Jamaica and 19 from the United States. We reasoned that differences in F reticulocyte levels might arise (1) from any of several kinds of artifact, (2) via half-sib status, or (3) because one or more genes regulating F cell production segregate separately from beta S. We minimized the role of artifact by assay of fresh samples from 84 SS individuals, including both members of 38 sib pairs. In 78 of the 84 subjects, serial values for percent F reticulocytes fell within 99.9% confidence limits or were alike by t test (P greater than or equal to .05). This left 32 sib pairs for which F reticulocyte levels in each member were reproducible. When sib-sib comparisons were limited to these 32 pairs, percentages of F reticulocytes were grossly dissimilar within 12 Jamaican and 3 American sibships. Within them, the probability that sibs were alike was always less than or equal to .005 and usually less than or equal to 10(-4). We next minimized the contribution of half-sibs among Jamaicans by a combination of paternity testing and sib-sib comparison of beta-globin region DNA restriction fragment length polymorphisms, especially among discordant pairs. We thereafter concluded that at least seven to eight Jamaican pairs were composed of reproducibly discordant full sibs. There is thus little doubt that there are genes regulating between-patient differences in F cell production that are separate from the beta-globin gene cluster. Still unanswered is (1) whether or not these genes are actually linked to beta S, (2) why F reticulocyte levels in Americans tend to be lower than in Jamaicans, and (3) whether or not differences in F cell production among SS patients are regulated by several major loci or by only one.

scholarly journals Structural Variation within the Beta-Globin Gene Cluster Among HbS Haplotype Groups

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2365-2365
Author(s):  
Pamela Lurie ◽  
Bamidele Tayo ◽  
Richard S. Cooper ◽  
Guillame Lettre ◽  
Ambroise Wonkman ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Sickle Cell ◽  
Structural Variation ◽  
Globin Gene ◽  
Sub Saharan Africa ◽  
Beta Globin ◽  
Cis Acting ◽  
Beta Globin Gene ◽  
Globin Gene Cluster ◽  
Sub Saharan

Abstract BACKGROUND The severity of sickle cell anemia (SCA) has been associated with five specific haplotypes in the beta globin cluster, identifiable by distinct patterns of restriction fragment length polymorphism (RFLP). These RFLP-defined haplotypes, named according to the region where they were first discovered - Central Africa region (CAR), Benin, Senegal, Arabic-Indian, and Cameroon - suggested that the sickle cell mutation arose recently at least four independent times in Africa, each time on a different genetic background, and again in India - the Multi-centric Sickle Cell Model. The beta-globin locus, however, is prone to extensive structural rearrangements, and alongside observations of ancestral sequence haplotypes extending several hundreds of kilobases beyond the beta globin cluster, it has been suggested that there is more cis-variation in the beta-globin gene cluster than is evident from RFLP analyses, and current definitions of RFLP haplotypes may not accurately reflect the ancestral origin of the sickle mutation. This undescribed cis-variation is important to understanding inter-individual phenotype variation associated with the different haplotypes. To better define this variation, we have undertaken extended, long-range molecular haplotyping of the beta-globin cluster on differing RFLP haplotype backgrounds using real time single molecule sequencing (SMS). The SMS approach generates long, unbroken reads with uniform coverage, thereby allowing for detailed molecular phasing of RFLP haplotypes and identification of local structural variation that would otherwise be hidden within the complex repetitive elements of the beta-globin cluster. In so doing, we plan to evaluate the molecular evidence for a single origin for the sickle cell allele and identify potential cis-acting, disease-modifying, candidate variants within the beta globin cluster. METHODS DNA from 200 SCA patients from three countries in sub-Saharan Africa - Nigeria, Cameroon, and Kenya - were collected after informed consent. RFLP analysis revealed the majority of the patients to be homozygous for the Benin and CAR haplotypes, with a smaller sampling of Cameroon, Senegal, and Atypical haplotypes. From this group we selected 40 samples - representing the four main classical RFLP haplotypes in sub-Saharan Africa - were selected for SMS. PCR was used to tile barcoded amplicons across the cluster. SMS was performed on a Sequel machine (Pacific Biosciences). The resulting FASTQ sequences were de-multiplexed, read quality control filters were applied, and mapped to human reference genome Hg38, prior to annotation and calling of single nucleotide variants (SNV) and structural variants (SV). RESULTS Analyses have so far identified 227 insertions, 18 deletions, 7 duplications, 76 inversions and 13 translocations from long-read analyses of the initial 40 samples; the vast majority of these variants are not described in public variant databases. Atypical haplotypes demonstrated more translocation and duplication events than other haplotypes. Insertions ~48 kb upstream of the beta-globin locus control region and 1.3 kb upstream of gamma globin gene 2 (HBG2) were observed on 50% of Senegal and 45% of CAR haplotypes. Also, recurrent insertions ranging between 32bp and 1,184bp in length, 2.3 kb downstream of the beta globin gene (HBB), were seen on 50% of the Benin and 54% of the CAR haplotypes, but only once on Senegal haplotypes. CONCLUSIONS Our findings suggest there are more cis-SVs within the beta-globin gene cluster than previously described. Work to validate these SVs using orthogonal methods and complete similar analyses of SNVs is ongoing. Variation outside of the gene cluster will also be integrated with RFLP and within-cluster molecular haplotypes to investigate the ancestral origin of the mutation, and validated cis-acting variants will be used to identify markers associated with proxies of SCA disease modification. Disclosures No relevant conflicts of interest to declare.

Beta-Globin Gene Cluster Haplotypes of Amerindian Populations from the Brazilian Amazon Region

1994 ◽  
Vol 44 (3) ◽  
pp. 142-149 ◽  
Author(s):  
João Farias Guerreiro ◽  
Mauro Silvério Figueiredo ◽  
Marco Antonio Zago
Keyword(s):  
Gene Cluster ◽  
Globin Gene ◽  
Brazilian Amazon ◽  
Amazon Region ◽  
Beta Globin ◽  
Beta Globin Gene ◽  
Globin Gene Cluster ◽  
Brazilian Amazon Region

scholarly journals Z-DNA-forming sites within the human beta-globin gene cluster.

1996 ◽  
Vol 93 (2) ◽  
pp. 780-784 ◽  
Author(s):  
V. Muller ◽  
M. Takeya ◽  
S. Brendel ◽  
B. Wittig ◽  
A. Rich
Keyword(s):  
Gene Cluster ◽  
Globin Gene ◽  
Beta Globin ◽  
Beta Globin Gene ◽  
Globin Gene Cluster ◽  
Z Dna
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