Molecular evidences of single mutational events followed by recurrent crossing-overs in the common δ-globin alleles in the Mediterranean area

Lacerra, Giuseppina; Musollino, Gennaro; Scarano, Clelia; Lagona, Laura F.; Caruso, Daniela; Testa, R.; Prezioso, Romeo; Noce, Francesca Di; Medulla, Emilia; Friscia, Maria G.; Mastrullo, Lucia; Caldora, Mercedes; Nota, Lucia; Gaudiano, Carlo; Magnano, Carmelo; Ciaccio, C.; Romeo, M A; Carestia, Clementina

doi:10.1016/j.gene.2007.12.004

Cited by 8 publications

(8 citation statements)

References 26 publications

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“…One possible explanation for this apparent inconsistency could be that genetic variation has been more exhaustively assessed for HBB than for HBD . Even though the β-globin cluster is among the most extensively studied regions in the human genome, current genetic diversity estimates for the HBD and HBB genes across human populations are likely to be biased, because the genetic analysis of HBD and HBB has been performed mainly for diagnostic purposes and often based on a set of pre-ascertained single nucleotide polymorphisms (SNPs) (Morgado et al 2007; Lacerra et al 2008; Liu et al 2009; Phylipsen et al 2011). …”

Section: Introductionmentioning

confidence: 99%

Evolutionary Constraints in the β-Globin Cluster: The Signature of Purifying Selection at the δ-Globin (HBD) Locus and Its Role in Developmental Gene Regulation

Moleirinho

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et al. 2013

Genome Biology and Evolution

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Human hemoglobins, the oxygen carriers in the blood, are composed by two α-like and two β-like globin monomers. The β-globin gene cluster located at 11p15.5 comprises one pseudogene and five genes whose expression undergoes two critical switches: the embryonic-to-fetal and fetal-to-adult transition. HBD encodes the δ-globin chain of the minor adult hemoglobin (HbA2), which is assumed to be physiologically irrelevant. Paradoxically, reduced diversity levels have been reported for this gene. In this study, we sought a detailed portrait of the genetic variation within the β-globin cluster in a large human population panel from different geographic backgrounds. We resequenced the coding and noncoding regions of the two adult β-globin genes (HBD and HBB) in European and African populations, and analyzed the data from the β-globin cluster (HBE, HBG2, HBG1, HBBP1, HBD, and HBB) in 1,092 individuals representing 14 populations sequenced as part of the 1000 Genomes Project. Additionally, we assessed the diversity levels in nonhuman primates using chimpanzee sequence data provided by the PanMap Project. Comprehensive analyses, based on classic neutrality tests, empirical and haplotype-based studies, revealed that HBD and its neighbor pseudogene HBBP1 have mainly evolved under purifying selection, suggesting that their roles are essential and nonredundant. Moreover, in the light of recent studies on the chromatin conformation of the β-globin cluster, we present evidence sustaining that the strong functional constraints underlying the decreased contemporary diversity at these two regions were not driven by protein function but instead are likely due to a regulatory role in ontogenic switches of gene expression.

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Section: Introductionmentioning

confidence: 99%

Evolutionary Constraints in the β-Globin Cluster: The Signature of Purifying Selection at the δ-Globin (HBD) Locus and Its Role in Developmental Gene Regulation

Moleirinho

Seixas

Bento

et al. 2013

Genome Biology and Evolution

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“…Alleles of the δ-, β-, and α-globin genes The δand β-globin alleles were analyzed with the ARMS method or gap-polymerase chain reaction (gap-PCR) or DNA sequencing [1,10]. The α-thalassemia deletions "−α3.7", "−(α)20.5," and "--Med" were tested with gap-PCR [11]; point mutations were analyzed with multiplex ARMS or DNA sequencing [12,13].…”

Section: Hematological Data and Hb Analysesmentioning

confidence: 99%

“…The analysis of the RFLPs present along the β-like globin gene cluster was carried out on PCR-amplified DNA fragments [1,[14][15][16]. RFLP haplotypes associated with mutated δ-globin alleles were determined with family segregation study; when parents or relatives of the probands were not available and carriers were not homozygous, the haplotypes were assembled-if possible-according to those already reported for each allele [17,18].…”

Section: Rflp Haplotypes Of the β-Like Globin Gene Clustermentioning

confidence: 99%

“…The human hemoglobin A2 (HbA2) is a minor hemoglobin, made of two α-globin and two δ-globin chains (α2δ2); its range is 2.1-3.3% of the total hemoglobin in the postnatal life [1]. The gene for the δ-globin chain is located on the cluster of the β-like globin genes at 7,373 bp 5′ of the βglobin gene on chromosome 11 [2].…”

Section: Introductionmentioning

confidence: 99%

“…Seventy point mutations or microdeletions causing decreased synthesis of the δ-chains (δ-thalassemia) or HbA2 variants have been reported [3]. In the Mediterranean area, the δ + thal cod 27 GCC>TCC or HbA2-Yialousa has the relative frequency of about 70%; several other alleles account for the remaining 30% [1]. The increase of the HbA2 over the normal range, associated with microcythemia, is an invaluable marker for the laboratory screening of β-thalassemia carriers [2].…”

Section: Introductionmentioning

confidence: 99%

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HbA2-Partinico or δ(A2)Pro→Thr, a new genetic variation in the δ-globin gene in cis to the β+ thal IVS-I-110 G>A, and the heterogeneity of δ-globin alleles in double heterozygotes for β- and δ-globin gene defects

et al. 2009

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The study of the alleles of the delta-globin gene is relevant to the prevention of beta-thalassemia homozygosis; in fact, the increase of the HbA2 is an invaluable hematological marker of the beta-thalassemia heterozygosis and the double heterozygosis for alleles of delta- and beta-globin genes can cause the decrease of the HbA2 up to normal or borderline values. We carried out the characterization of alleles of the delta- and beta-globin genes, restriction fragment length polymorphism (RFLP) haplotype background, and hematologic phenotype in 23 double heterozygotes belonging to 18 unrelated families. A wide heterogeneity of the delta-globin alleles was detected; seven known alleles in trans to the beta-globin gene defects were revealed in 17 out of 18 families, while a new allele in cis to a beta-thalassemia allele was detected in one family. Moreover, the relative frequency of the delta-mutants was quite different from that found among heterozygotes. The new allele delta-cod 5 CCT>ACT, in cis to the allele beta(+) thal IVS-I-110 G>A, was found in five carriers of a Sicilian family. The new variant delta5(A2)Pro-->Thr, named HbA2-Partinico upon the origin of the family, was detected with high-performance liquid chromatography; it overlapped the HbA2 peak which was partially split. The double in cis heterozygotes had increased percentage of normal and variant HbA2 of comparable size. The variant originated most likely from a new mutational event because it was associated with RFLP haplotype I, commonly found with the beta(+) thal IVS-I-110 G>A, even if crossing over or gene conversion cannot be excluded.

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The Mechanism by which TATA-Box Polymorphisms Associated with Human Hereditary Diseases Influence Interactions with the TATA-Binding Protein

et al. 2014

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SNPs in ТАТА boxes are the cause of monogenic diseases, contribute to a large number of complex diseases, and have implications for human sensitivity to external and internal environmental signals. The aim of this work was to explore the kinetic characteristics of the formation of human ТВР complexes with ТАТА boxes, in which the SNPs are associated with β-thalassemias of diverse severity, immunosuppression, neurological disorders, and so on. It has for the first time been demonstrated, using an electrophoretic mobility shift assay, that TBP interacts with SNP-containing ТАТА boxes with a significant (8-36-fold) decrease in TBP/ТАТА association rate constant (ka ) as compared with that in healthy people, a smaller decrease in dissociation rate constant (kd ) and changes in the half-lives of TBP/ТАТА complexes. Carriers of the -24G allele (rs 1800202T>G) in the TATA box of the triosephosphate isomerase gene promoter, associated with neurological and muscular disorders, were observed to have a 36-fold decrease in TBP/TATA association rate constant that are consistent with TPI deficiency shown for patients who carry this defective allele. The kinetic characteristics of TBP/ТАТА complexes obtained suggest that, at a molecular level, hereditary diseases are largely caused by changes in TBP/ТАТА association rates and these changes have a bearing on disease severity.

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Molecular evidences of single mutational events followed by recurrent crossing-overs in the common δ-globin alleles in the Mediterranean area

Cited by 8 publications

References 26 publications

Evolutionary Constraints in the β-Globin Cluster: The Signature of Purifying Selection at the δ-Globin (HBD) Locus and Its Role in Developmental Gene Regulation

Evolutionary Constraints in the β-Globin Cluster: The Signature of Purifying Selection at the δ-Globin (HBD) Locus and Its Role in Developmental Gene Regulation

HbA2-Partinico or δ(A2)Pro→Thr, a new genetic variation in the δ-globin gene in cis to the β+ thal IVS-I-110 G>A, and the heterogeneity of δ-globin alleles in double heterozygotes for β- and δ-globin gene defects

The Mechanism by which TATA-Box Polymorphisms Associated with Human Hereditary Diseases Influence Interactions with the TATA-Binding Protein

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