High-resolution mapping of the 8p23.1 beta-defensin cluster reveals strictly concordant copy number variation of all genes

Groth, Marco; Szafranski, Karol; Taudien, Stefan; Huse, Klaus; Mueller, Oliver; Rosenstiel, Philip; Nygren, Anders O.H.; Schreiber, Stefan; Birkenmeier, Gerd; Platzer, Matthias

doi:10.1002/humu.20751

Cited by 52 publications

(83 citation statements)

References 30 publications

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“…Consistent with previous data (18)(19)(20)(21), copy number among the parents of these 26 families varied between 2 and 7, with a modal copy number of 4 and a mean of 4.58. We observed that at least 24 offspring inherited recombinant haplotypes in which parental copies of the ␤-defensin repeat had been reassorted.…”

Section: Resultssupporting

confidence: 91%

“…Although the copy-variable ␤-defensins have generally been treated as outside the inverted segment (28,29), it is evident that at least at the distal locus they are located between complex nested series of repeat sequences (REPD) (17,26,29,30), of which different elements may sponsor a variety of exchanges, including recombination between inverted repeats at REPP to mediate a change in inversion status. Despite the dynamic nature of the defensin repeats, it is clear that there are few if any repeats of variant gene composition; measurements of copy number within the defensin CNV have shown that the copy numbers of all genes in the repeat vary coordinately (18,21).…”

Section: Discussionmentioning

confidence: 99%

“…For most of these genes there is little detailed information about function and expression (14), and the ␤-defensin CNV forms part of a complex spectrum of population and evolutionary dynamics in this region of the genome (17). Nearly all individuals have between 2 and 7 copies of this cluster per diploid genome (18)(19)(20)(21), but some individuals can have up to 12 copies, with the highest-copy-number haplotypes forming the basis of the cytogenetic 8p23.1 euchromatic variant (18,22). In the more frequent copy number range, low ␤-defensin copy number has been reported to be associated with Crohn's disease of the colon (23) and high copy number with predisposition to psoriasis (20).…”

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confidence: 99%

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Allelic recombination between distinct genomic locations generates copy number diversity in human β-defensins

Bakar

Hollox

Armour

2009

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

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␤-Defensins are small secreted antimicrobial and signaling peptides involved in the innate immune response of vertebrates. In humans, a cluster of at least 7 of these genes shows extensive copy number variation, with a diploid copy number commonly ranging between 2 and 7. Using a genetic mapping approach, we show that this cluster is at not 1 but 2 distinct genomic loci Ϸ5 Mb apart on chromosome band 8p23.1, contradicting the most recent genome assembly. We also demonstrate that the predominant mechanism of change in ␤-defensin copy number is simple allelic recombination occurring in the interval between the 2 distinct genomic loci for these genes. In 416 meiotic transmissions, we observe 3 events creating a haplotype copy number not found in the parent, equivalent to a germ-line rate of copy number change of Ϸ0.7% per gamete. This places it among the fastest-changing copy number variants currently known.

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Allelic recombination between distinct genomic locations generates copy number diversity in human β-defensins

Bakar

Hollox

Armour

2009

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

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“…Within DEFA, the CNV unit of 19 kb encompasses DEFA1A3 and the pseudogene DEFTP. [10][11][12][13][14] However, the 200 kb DEFB varies en bloc in its copy number (CN). 11 Individuals carrying 2-12 copies per diploid genome were found.…”

Section: Introductionmentioning

confidence: 99%

Both copy number and sequence variations affect expression of human DEFB4

et al. 2010

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Copy number variations (CNVs) were found to contribute massively to the variability of genomes. One of the best studied CNV region is the b-defensin cluster (DEFB) on 8p23.1. Individual DEFFB copy numbers (CNs) between 2 and 12 were found, whereas low CNs predispose for Crohn's disease. A further level of complexity is represented by sequence variations between copies (multisite variations, MSVs). To address the relation of DEFB CN and MSV to the expression of b-defensin genes, we analyzed DEFB4 expression in B-lymphoblastoid cell lines (LCLs) and primary keratinocytes (normal human epidermal keratinocyte, NHEK) before and after stimulation with lipopolysaccharide, tumor necrosis factor-a (TNF-a) and interferon-g (IFN-g). Moreover, we quantified one DEFB4 MSV in DNA and mRNA as a marker for variant-specific expression (VSE) and resequenced a region of B2 kb upstream of DEFB4 in LCLs. We found a strong correlation of DEFB CN and DEFB4 expression in 16 LCLs, although several LCLs with very different CNs exhibit similar expression levels. Quantification of the MSV revealed VSE with consistently lower expression of one variant. Costimulation of NHEKs with TNF-a/IFN-g leads to a synergistic increase in total DEFB4 expression and suppresses VSE. Analysis of the DEFB4 promoter region showed remarkably high density of sequence variabilities (B1 MSV/41 bp).

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“…6 The human b-defensin genes (DEFB) are clustered on chromosome 8p23.1 and show considerable variations in copy number except for DEFB1, which has only two copies per diploid genome. 7 This makes DEFB1 accessible to straightforward association analysis of potential genetic susceptibility variants. Consistent with all human epithelial tissues tested to date, including intestinal mucosa, 8 the urogenital tract, 9 and airway epithelia, 10 DEFB1 is constitutively expressed in the gingival epithelial tissues.…”

Section: Introductionmentioning

confidence: 99%

A 3′ UTR transition within DEFB1 is associated with chronic and aggressive periodontitis

Schäefer¹,

Richter²,

Nothnagel³

et al. 2009

Genes Immun

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Periodontal diseases are complex inflammatory diseases and affect up to 20% of the worldwide population. An unbalanced reaction of the immune system toward microbial pathogens is considered as the key factor in the development of periodontitis. Defensins have a strong antimicrobial function and are important contributors of the immune system toward maintaining health. Here, we present the first systematic association study of DEFB1. Using a haplotype-tagging single nucleotide polymorphism (SNP) approach, including described promoter SNPs of DEFB1, we investigated the associations of the selected variants in a large population (N ¼ 1337 cases and 2887 ethnically matched controls). The 3 0 untranslated region SNP, rs1047031, showed the most significant association signal for homozygous carriers of the rare A allele (P ¼ 0.002) with an increased genetic risk of 1.3 (95% confidence interval: 1.11-1.57). The association was consistent with the specific periodontitis forms: chronic periodontitis (odds ratio ¼ 2.2 (95% confidence interval: 1.16-4.35), P ¼ 0.02), and aggressive periodontitis (odds ratio ¼ 1.3 (95% confidence interval 1.04-1.68), P ¼ 0.02). Sequencing of regulatory and exonic regions of DEFB1 identified no other associated variant, pointing toward rs1047031 as likely being the causative variant. Prediction of microRNA targets identified a potential microRNA-binding site at the position of rs1047031.

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High-resolution mapping of the 8p23.1 beta-defensin cluster reveals strictly concordant copy number variation of all genes

Cited by 52 publications

References 30 publications

Allelic recombination between distinct genomic locations generates copy number diversity in human β-defensins

Allelic recombination between distinct genomic locations generates copy number diversity in human β-defensins

Both copy number and sequence variations affect expression of human DEFB4

A 3′ UTR transition within DEFB1 is associated with chronic and aggressive periodontitis

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