Study of the single nucleotide polymorphism (SNP) at the palindromic sequence of hypersensitive site (HS)4 of the human β‐globin locus control region (LCR) in Indian population

Kukreti, Ritushree; B-Rao, Chandrika; Das, Swapan K.; De, Madhusnata; Talukder, Geeta; Vaz, F. E. E.; Verma, Ishwar C.; Brahmachari, Samir K.

doi:10.1002/ajh.10026

Cited by 20 publications

(8 citation statements)

References 6 publications

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“…Taken together, these findings imply that the genetic basis of inter-individual differences in GH1 gene expression is likely to be extremely complex. In this regard, our results are also reminiscent of the b-globin LCR in which SNPs have been previously reported in the HS2 and HS4 regions [Perichon et al, 1993;Kukreti et al, 2002], with different alleles of the HS2 SNP conferring different levels of enhancement upon the expression of a gglobin promoter-linked reporter gene [Ofori-Acquah et al, 2001].…”

Section: Discussionsupporting

confidence: 73%

Human growth hormone 1 (GH1) gene expression: Complex haplotype-dependent influence of polymorphic variation in the proximal promoter and locus control region

et al. 2003

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The proximal promoter region of the human pituitary expressed growth hormone (GH1) gene is highly polymorphic, containing at least 15 single nucleotide polymorphisms (SNPs). This variation is manifest in 40 different haplotypes, the high diversity being explicable in terms of gene conversion, recurrent mutation, and selection. Functional analysis showed that 12 haplotypes were associated with a significantly reduced level of reporter gene expression whereas 10 haplotypes were associated with a significantly increased level. The former tend to be more prevalent in the general population than the latter (p<0.01), possibly as a consequence of selection. Although individual SNPs contributed to promoter strength in a highly interactive and non-additive fashion, haplotype partitioning was successful in identifying six SNPs as major determinants of GH1 gene expression. The prediction and functional testing of hitherto unobserved super-maximal and sub-minimal promoter haplotypes was then used to test the efficacy of the haplotype partitioning approach. Electrophoretic mobility shift assays demonstrated that five SNP sites exhibit allele-specific protein binding. An association was noted between adult height and the mean in vitro expression value corresponding to an individual's GH1 promoter haplotype combination (p=0.028) although only 3.3% of the variance of adult height was found to be explicable by reference to this parameter. Three additional SNPs, identified within sites I and II of the upstream locus control region (LCR), were ascribed to three distinct LCR haplotypes. A series of LCR-GH1 proximal promoter constructs were used to demonstrate that 1) the LCR enhanced proximal promoter activity by up to 2.8-fold depending upon proximal promoter haplotype, and that 2) the activity of a given proximal promoter haplotype was also differentially enhanced by different LCR haplotypes. The genetic basis of inter-individual differences in GH1 gene expression thus appears to be extremely complex.

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Section: Discussionsupporting

confidence: 73%

Human growth hormone 1 (GH1) gene expression: Complex haplotype-dependent influence of polymorphic variation in the proximal promoter and locus control region

et al. 2003

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“…The observed variations led to allelic variability, both in base composition and in the length of the repeat, and they add an element to the genetically variable environment of the ␤-thalassemia chromosome. Sequence analysis of the 462-bp HS2 fragment, including the highly polymorphic (AT) x N y (AT) z motif of the ␤-LCR, showed polymorphisms identical to those described previously [16,17] and occurred in three different sequence configurations of the (AT) x N y (AT) z motif: (AT) 1 0 N 1 2 (AT) 1 1 , (AT) 9 N 12 (AT) 11 , (AT) 9 N 12 (AT) 10 specific to the genotype of the SNP at the palindromic region of HS4 of the ␤-LCR. It was observed that the G allele of ␤-LCR HS4 is associated with only one distinct polymorphic pattern of AT-rich segments, (AT) 9 N 12 (AT) 10 of the LCR HS2 region [17] (Table IV), indicating these mutational events were probably rare and arose from a common founder.…”

Section: Polymorphic Sites In ␤-Lcr Hs1 ␤-Lcr Hs2 ␤-Lcr Hs3 and ␤-supporting

confidence: 74%

“…We observed from automated genotyping and direct sequence analysis that the G allele in the palindromic sequence of the HS4 locus is a s s o c i a t e d w i t h o n l y o n e d i s t i n c t p a t t e r n , (AT) 9 N 12 (AT) 10 , of HS2 of the ␤-LCR. There appears to be linkage disequilibrium at the two loci with the pre- ponderance of occurrence of the G allele at HS4 along with the (AT) 9 N 12 (AT) 10 allele at the HS2 locus of ␤-LCR, suggesting that the G allele could be an evolutionarily new mutation in the study population [17]. There are reports that sequence variations in the HS2 region of ␤-LCR are associated with altered levels of fetal hemoglobin [16] in the thalassemia intermediate patients.…”

Section: Discussionmentioning

confidence: 95%

Spectrum of β‐thalassemia mutations and their association with allelic sequence polymorphisms at the β‐globin gene cluster in an eastern Indian population

et al. 2002

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In this report, the spectrum of ␤-thalassemia mutations and genotype-to-phenotype correlations were defined in large number of patients (␤-thalassemia carriers and major) with varying disease severity in an Eastern Indian population mainly from the state of West Bengal. The five most common ␤-thalassemia mutations were detected, which included IVS1-5 (G➝C), codon 15 (G➝A), codon 26 (G➝A), codon 30 (G➝C), and codon 41/42 (−TCTT). These accounted for 85% in 80 ␤-thalassemic alleles deciphered from 56 patients, including ␤-thalassemia major and carriers, and 15% of alleles remained uncharacterized in these patients. Expression of the human ␤-globin gene is regulated by an array of cis-acting DNA elements, including five DNase I hypersensitive sites (HSs) in the locus control region (LCR), promoters that incorporate certain silencer elements, and enhancers at 3 of the ␤-globin gene. For detailed studies and to understand the molecular basis of ␤-thalassemia, we studied two groups of subjects: a group of 12 patients from four families having ␤-thalassemia major and carrier phenotype and a control group of 26 healthy individuals. In these two groups, we examined portions of the ␤-globin gene locus control region HSs 1, 2, 3, and 4, which included the (CA) x (TA) y repeat motif, the (AT) x N y (AT) z repeat motif, the inverted repeat sequence TGGGGACCCCA, the promoter region of the G ␥-globin gene, an (AT) x (T) y repeat 5 of the silencer region, and the ␤-globin gene and its 3 flanking region. We investigated the allelic sequence polymorphisms in these regions and their association with the ␤-thalassemia mutations to know the possible genotype-phenotype relationship in ␤-thalassemia patients. An analysis of cisacting regulatory regions showed varied sequence haplotypes associated with some frequent ␤-thalassemia mutations in this Eastern Indian population. Am.

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“…Dyad symmetry sequences are present close to the four DNase I hypersensitive site (HS) in the β-globin LCR. More recent studies ( 24 ), on the spectrum of β-thalassemia mutation and their association with allelic sequence polymorphism at the human β-globin gene cluster have revealed a single nucleotide polymorphism (SNP) at the quasipalindromic sequence of HS4 of the LCR. The studies carried out on Indian population showed an A → G polymorphism in the sequence d-TGGGG(A/G)CCCCA ( 24 ).…”

Section: Introductionmentioning

confidence: 99%

Structural polymorphism exhibited by a quasipalindrome present in the locus control region (LCR) of the human -globin gene cluster

Kaushik

2006

Nucleic Acids Research

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Structural polymorphism of DNA is a widely accepted property. A simple addition to this perception has been our recent finding, where a single nucleotide polymorphism (SNP) site present in a quasipalindromic sequence of β-globin LCR exhibited a hairpin-duplex equilibrium. Our current studies explore that secondary structures adopted by individual complementary strands compete with formation of a perfect duplex. Using gel-electrophoresis, ultraviolet (UV)-thermal denaturation, circular dichroism (CD) techniques, we have demonstrated the structural transitions within a perfect duplex containing 11 bp quasipalindromic stretch (TGGGG(G/C)CCCCA), to hairpins and bulge duplex forms. The extended version of the 11 bp duplex, flanked by 5 bp on both sides also demonstrated conformational equilibrium between duplex and hairpin species. Gel-electrophoresis confirms that the duplex coexists with hairpin and bulge duplex/cruciform species. Further, in CD spectra of duplexes, presence of two overlapping positive peaks at 265 and 285 nm suggest the features of A- as well as B-type DNA conformation and show oligomer concentration dependence, manifested in A → B transition. This indicates the possibility of an architectural switching at quasipalindromic region between linear duplex to a cruciform structure. Such DNA structural variations are likely to be found in the mechanics of molecular recognition and manipulation by proteins.

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Study of the single nucleotide polymorphism (SNP) at the palindromic sequence of hypersensitive site (HS)4 of the human β‐globin locus control region (LCR) in Indian population

Cited by 20 publications

References 6 publications

Human growth hormone 1 (GH1) gene expression: Complex haplotype-dependent influence of polymorphic variation in the proximal promoter and locus control region

Human growth hormone 1 (GH1) gene expression: Complex haplotype-dependent influence of polymorphic variation in the proximal promoter and locus control region

Spectrum of β‐thalassemia mutations and their association with allelic sequence polymorphisms at the β‐globin gene cluster in an eastern Indian population

Structural polymorphism exhibited by a quasipalindrome present in the locus control region (LCR) of the human -globin gene cluster

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