Complex low-copy repeats associated with a common polymorphic inversion at human chromosome 8p23

Sugawara, Hirotake; Harada, Naoki; Ida, Tomoko; Ishida, Takafumi; Ledbetter, David H.; Yoshiura, Ko–ichiro; Ohta, Tohru; Kishino, Tatsuya; Niikawa, Norio; Matsumoto, Naomichi

doi:10.1016/s0888-7543(03)00108-3

Cited by 77 publications

(105 citation statements)

References 24 publications

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“…Given the evidence for recurrent inversion between the proximal and distal ␤-defensin loci discussed above, 1 simple mechanism for the creation of diversity in the placement of ␤-defensin repeats would be for frequent flipping of this sequence between different inversion states to sometimes include, and sometimes exclude, ␤-defensin repeats at each location. 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%

“…REPP and REPD contain not only olfactory receptor gene repeats but also complex and polymorphic clusters of FAM90A genes (28). Approximately onequarter of Europeans and one-third of Japanese are heterozygous for this inversion; in these heterozygotes unequal recombination can lead to the formation of the pathological rearrangement inv dup(8p) or its reciprocal product, ϩder (8) (26,29).…”

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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: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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“…Mechanisms have been proposed as to how a pair of low-copy inverted repeats may mediate inversion events in the genome (Lupski 1998;Giglio et al 2001;Shaw and Lupski 2004). Pairs of inverted repeats have also been detected near the inversion breakpoints for several known inversion polymorphisms (Sugawara et al 2003;Feuk et al 2005). We checked for the presence of pairs of low-copy homologous repeats near the breakpoints of our predicted inversions.…”

Section: Sequence Analysis Of Inversion Breakpointsmentioning

confidence: 99%

Evidence for large inversion polymorphisms in the human genome from HapMap data

Bansal

Bashir²,

Bafna³

2006

Genome Res.

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Knowledge about structural variation in the human genome has grown tremendously in the past few years. However, inversions represent a class of structural variation that remains difficult to detect. We present a statistical method to identify large inversion polymorphisms using unusual Linkage Disequilibrium (LD) patterns from high-density SNP data. The method is designed to detect chromosomal segments that are inverted (in a majority of the chromosomes) in a population with respect to the reference human genome sequence. We demonstrate the power of this method to detect such inversion polymorphisms through simulations done using the HapMap data. Application of this method to the data from the first phase of the International HapMap project resulted in 176 candidate inversions ranging from 200 kb to several megabases in length. Our predicted inversions include an 800-kb polymorphic inversion at 7p22, a 1.1-Mb inversion at 16p12, and a novel 1.2-Mb inversion on chromosome 10 that is supported by the presence of two discordant fosmids. Analysis of the genomic sequence around inversion breakpoints showed that 11 predicted inversions are flanked by pairs of highly homologous repeats in the inverted orientation. In addition, for three candidate inversions, the inverted orientation is represented in the Celera genome assembly. Although the power of our method to detect inversions is restricted because of inherently noisy LD patterns in population data, inversions predicted by our method represent strong candidates for experimental validation and analysis.

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“…1A), constituted by complex repeats containing olfactory receptor gene clusters lying at 8 and 12 Mb on the short arm of chromosome 8 and flanking a single copy region (6,9). The rearrangement was the result of non-allelic homologous recombination (NAHR) leading to the formation of a dicentric (qter->p23.1::p23.…”

Section: History Of a Recurrent Rearrangementmentioning

confidence: 99%

Inverted duplications deletions: underdiagnosed rearrangements??

et al. 2009

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Molecular techniques led to the discovery that several chromosome rearrangements interpreted as terminal duplications were in fact inverted duplications contiguous to terminal deletions. Inv dup del rearrangements originate through a symmetric dicentric chromosome that, after asymmetric breakage, generates an inv dup del and a deleted chromosome. In recurrent inverted duplications the dicentric chromosome is formed at meiosis through non‐allelic homologous recombination. In non‐recurrent inv dup del cases, dicentric intermediates are formed by non‐homologous end joining or intrastrand annealing. Some authors hypothesized that in these cases the dicentric may have been formed directly in the zygote. Healing of the broken dicentric chromosomes can occur not only in a telomerase‐dependent way but also through telomere capture and circularization thus creating translocated or ring inv dup del chromosomes. In all the cases reported up to now, the duplicated region was always longer than the deleted one, but we can safely assume that there is another group of rearrangements where the deleted region is longer than the duplicated portion. In general, in these cases, the cytogeneticist will suspect the presence of a deletion and confirm it by FISH with a subtelomeric probe, but he/she will almost certainly miss the duplication. It is likely that the conventional analysis techniques used until now have led to a substantial underestimate of the frequency of inv dup del rearrangements and that the widespread use of array‐CGH in routine analysis will allow a more realistic estimate. Obviously, the concomitant presence of deletion and duplication has important consequences in genotype/phenotype correlations.

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Complex low-copy repeats associated with a common polymorphic inversion at human chromosome 8p23

Cited by 77 publications

References 24 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

Evidence for large inversion polymorphisms in the human genome from HapMap data

Inverted duplications deletions: underdiagnosed rearrangements??

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