A functional neo-centromere formed through activation of a latent human centromere and consisting of non-alpha-satellite DNA

Sart, Desirée du; Cancilla, Michael R.; Earle, Elizabeth D.; Mao, Jen I.; Saffery, Richard; Tainton, Kellie M.; Kalitsis, Paul; Martyn, John R. C.; Barry, Alyssa E.; Choo, K.H. Andy

doi:10.1038/ng0697-144

Cited by 298 publications

(256 citation statements)

References 59 publications

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“…Due to their mitotic stability, it was proposed that these analphoid markers contained neocentromeres, a region of chromatin that may act as a functional centromere. 12 The mechanism of formation of the marker chromosome in our patient appears to be similar to that of two cases published by Depinet et al 13 The analphoid marker 12p is of paternal origin; reduction of paternal heterozygosity to homozygosity in all analysed STRs indicates a postzygotic mitotic error. Summarising the so far published data on the mechanism of formation of analphoid, inverted duplicated markers, postzygotic mitosis as cell stage of origin has been described three times, while maternal or paternal meiotic errors could each be delineated only once.…”

Section: Discussionsupporting

confidence: 63%

Partial tetrasomy 12pter-12p12.3 in a girl with Pallister-Killian syndrome: extraordinary finding of an analphoid, inverted duplicated marker

et al. 2001

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Cytogenetic analysis in a girl with multiple congenital anomalies indicating Pallister-Killian syndrome (PKS) showed a supernumerary marker chromosome in 1/76 lymphocytes and 34/75 fibroblast metaphases. GTGbanding pattern was consistent with the chromosomal region 12pter-12q11. While fluorescence-in-situ hybridisation (FISH) with a whole chromosome 12 painting probe confirmed the origin of the marker, a chromosome 12 specific a-satellite probe did not hybridise to it. FISH analysis with a specific subtelomeric probe 12p showed hybridisation to both ends of the marker chromosome. High-resolution multicolour-banding (MCB) studies revealed the marker to be a der(12)(pter?p12.3::p12.3?pter). Summarising the FISH information, we defined the marker as an inverted duplication of 12pter-12p12.3 leading to partial tetrasomy of chromosome 12p. In skin fibroblasts, cultured at the patient's age of 1 year and 9 years, the marker chromosome was found in similar frequencies, even after several culture passages. Therefore, we consider the marker to have a functional centromere although it lacks detectable centromeric a-satellite sequences. To the best of our knowledge, this is the first proven analphoid marker of chromosome 12. Molecular genetic studies indicated that this marker is of paternal origin. The finding of partial tetrasomy 12pter-12p12.3 in our PKS patient allows to narrow down the critical region for PKS. European Journal of Human Genetics (2001) 9, 572 ± 576.

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Section: Discussionsupporting

confidence: 63%

Partial tetrasomy 12pter-12p12.3 in a girl with Pallister-Killian syndrome: extraordinary finding of an analphoid, inverted duplicated marker

et al. 2001

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“…Independent of this sequence preference, specific deposition of the centromeric histone H3 variant CENP-A (Earnshaw and Rothfield, 1985) is thought to form the basis for an 'epigenetic' maintenance of centromere identity (Allshire and Karpen, 2008;Okamoto et al, 2007;Vafa and Sullivan, 1997;Warburton et al, 1997). The epigenetic control of centromere activity is strikingly illustrated by the inactivation of centromeres on dicentric chromosomes (Earnshaw and Migeon, 1985;Earnshaw et al, 1989;Merry et al, 1985;Sugata et al, 2000;Sullivan and Schwartz, 1995) and by rare neocentromeres that recruit CENP-A and assemble fully functional kinetochore structures on non-alphoid DNA (Alonso et al, 2007;Depinet et al, 1997;du Sart et al, 1997;Saffery et al, 2000;Warburton et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic engineering: histone H3K9 acetylation is compatible with kinetochore structure and function

Bergmann

Jakubsche

Martins

et al. 2012

Journal of Cell Science

103

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SummaryHuman kinetochores are transcriptionally active, producing very low levels of transcripts of the underlying alpha-satellite DNA. However, it is not known whether kinetochores can tolerate acetylated chromatin and the levels of transcription that are characteristic of housekeeping genes, or whether kinetochore-associated 'centrochromatin', despite being transcribed at a low level, is essentially a form of repressive chromatin. Here, we have engineered two types of acetylated chromatin within the centromere of a synthetic human artificial chromosome. Tethering a minimal NF-kB p65 activation domain within kinetochore-associated chromatin produced chromatin with high levels of histone H3 acetylated on lysine 9 (H3K9ac) and an ,10-fold elevation in transcript levels, but had no substantial effect on kinetochore assembly or function. By contrast, tethering the herpes virus VP16 activation domain produced similar modifications in the chromatin but resulted in an ,150-fold elevation in transcripts, approaching the level of transcription of an endogenous housekeeping gene. This rapidly inactivated kinetochores, causing a loss of assembled CENP-A and blocking further CENP-A assembly. Our data reveal that functional centromeres in vivo show a remarkable plasticity -kinetochores tolerate profound changes to their chromatin environment, but appear to be critically sensitive to the level of centromeric transcription.

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“…This hotspot of neocentromere emergence in 15q24-q26 has been attributed to the possible reactivation of an ancestral latent centromere in band 15q25.2 that was inactivated about 25 million years ago. 15,16 Chromosome 15q24-q26 is rich in segmental duplications and structural variation, which may promote chromosome rearrangements in this area. 17 These segmental duplications may be pathogenic, and rearrangements of them have been associated with susceptibility for panic and phobic disorders and joint laxity.…”

Section: Discussionmentioning

confidence: 99%

Tetrasomy 15q26: a distinct syndrome or Shprintzen-Goldberg syndrome phenocopy?

Levy

Tegay

Papenhausen

et al. 2012

Genetics in Medicine

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Original research articlePurpose: The aim of this study was to characterize the clinical phenotype of patients with tetrasomy of the distal 15q chromosome in the form of a neocentric marker chromosome and to evaluate whether the phenotype represents a new clinical syndrome or is a phenocopy of Shprintzen-Goldberg syndrome. methods:We carried out comprehensive clinical evaluation of four patients who were identified with a supernumerary marker chromosome. The marker chromosome was characterized by G-banding, fluorescence in situ hybridization, single nucleotide polymorphism oligonucleotide microarray analysis, and immunofluorescence with antibodies to centromere protein C. Results:The marker chromosomes were categorized as being neocentric with all showing tetrasomy for regions distal to 15q25 and the common region of overlap being 15q26→qter.conclusion: Tetrasomy of 15q26 likely results in a distinct syndrome as the patients with tetrasomy 15q26 share a strikingly more consistent phenotype than do the patients with Shprintzen-Goldberg syndrome, who show remarkable clinical variation.Genet Med 2012:14(9):811-818

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A functional neo-centromere formed through activation of a latent human centromere and consisting of non-alpha-satellite DNA

Cited by 298 publications

References 59 publications

Partial tetrasomy 12pter-12p12.3 in a girl with Pallister-Killian syndrome: extraordinary finding of an analphoid, inverted duplicated marker

Partial tetrasomy 12pter-12p12.3 in a girl with Pallister-Killian syndrome: extraordinary finding of an analphoid, inverted duplicated marker

Epigenetic engineering: histone H3K9 acetylation is compatible with kinetochore structure and function

Tetrasomy 15q26: a distinct syndrome or Shprintzen-Goldberg syndrome phenocopy?

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