A new heritable fragile site at 15q13 in a three-generation family

Zamani, Ayse Gul; Durakbasi-Dursun, Hatice Gul; Acar, Ahmet

doi:10.1159/000100408

Cited by 2 publications

(3 citation statements)

References 33 publications

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“…Our analysis establishes that in three cases out of four (BP2-BP3, BP3-BP5, and BP4-BP5), the inverted orientation is the ancestral state; these include the BP2-BP3 and BP4-BP5 regions, which are the only ones inverted in the human population and they are also hotspots of recurrent CNV associated with disease. While our study primarily focuses on the evolutionary analysis of structural variations in the 15q11-q13 region, it is worth noting that this region has indeed been recognized as a breakage-prone area, harboring fragile sites within the human genome [61][62][63]. Fragile sites are regions in the genome that are prone to breakage and instability, often resulting in structural variations and genomic rearrangements [64].…”

Section: Discussionmentioning

confidence: 99%

Structural Variation Evolution at the 15q11-q13 Disease-Associated Locus

Paparella,

L’Abbate,

Palmisano

et al. 2023

IJMS

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The impact of segmental duplications on human evolution and disease is only just starting to unfold, thanks to advancements in sequencing technologies that allow for their discovery and precise genotyping. The 15q11-q13 locus is a hotspot of recurrent copy number variation associated with Prader–Willi/Angelman syndromes, developmental delay, autism, and epilepsy and is mediated by complex segmental duplications, many of which arose recently during evolution. To gain insight into the instability of this region, we characterized its architecture in human and nonhuman primates, reconstructing the evolutionary history of five different inversions that rearranged the region in different species primarily by accumulation of segmental duplications. Comparative analysis of human and nonhuman primate duplication structures suggests a human-specific gain of directly oriented duplications in the regions flanking the GOLGA cores and HERC segmental duplications, representing potential genomic drivers for the human-specific expansions. The increasing complexity of segmental duplication organization over the course of evolution underlies its association with human susceptibility to recurrent disease-associated rearrangements.

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Section: Discussionmentioning

confidence: 99%

Structural Variation Evolution at the 15q11-q13 Disease-Associated Locus

Paparella,

L’Abbate,

Palmisano

et al. 2023

IJMS

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“…Spontaneous fragile sites occur without the need for induction at chromosomal locations distinct from either the common or rare fragile sites. These spontaneous sites can be expressed at unusually high levels, from 80 to 100% of the population, compared to the 4–30% for most fragile sites ( Dar et al, 1995 ; Karadeniz et al, 2003 ; Zamani et al, 2007 ). The nature of the molecular cause (sequence, epigenetic, or other) of most of these spontaneous fragile sites is not known and warrants further investigation.…”

Section: Introductionmentioning

confidence: 99%

“…The length of the chromosomal gaps or despiralized regions can vary widely between individuals, is considered to be hereditary, and due to the highly variable lengths of the satellite tracts ( Craig-Holmes and Shaw, 1971 ; Yunis and Yasmineh, 1971 ; Craig-Holmes et al, 1975 , 1973 ; McKenzie and Lubs, 1973 ; Podugolnikova and Korostelev, 1980 ). These spontaneous, heritable fragile sites often map to loci known to be prone to structural variations including microdeletions, microduplications, and copy number variations (CNVs) ( Zamani et al, 2007 ; Szafranski et al, 2010 ; Gillentine and Schaaf, 2015 ). Viral integration can also be a driving factor for these spontaneous sites ( O’Neill and Miles, 1969 ; Peat and Stanley, 1986 ) (reviewed in ( Fortunato and Spector, 2003 ).…”

Section: Introductionmentioning

confidence: 99%

Fragile sites, chromosomal lesions, tandem repeats, and disease

Mirceta

Shum²,

Schmidt³

et al. 2022

Front. Genet.

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Expanded tandem repeat DNAs are associated with various unusual chromosomal lesions, despiralizations, multi-branched inter-chromosomal associations, and fragile sites. Fragile sites cytogenetically manifest as localized gaps or discontinuities in chromosome structure and are an important genetic, biological, and health-related phenomena. Common fragile sites (∼230), present in most individuals, are induced by aphidicolin and can be associated with cancer; of the 27 molecularly-mapped common sites, none are associated with a particular DNA sequence motif. Rare fragile sites (≳ 40 known), ≤ 5% of the population (may be as few as a single individual), can be associated with neurodevelopmental disease. All 10 molecularly-mapped folate-sensitive fragile sites, the largest category of rare fragile sites, are caused by gene-specific CGG/CCG tandem repeat expansions that are aberrantly CpG methylated and include FRAXA, FRAXE, FRAXF, FRA2A, FRA7A, FRA10A, FRA11A, FRA11B, FRA12A, and FRA16A. The minisatellite-associated rare fragile sites, FRA10B, FRA16B, can be induced by AT-rich DNA-ligands or nucleotide analogs. Despiralized lesions and multi-branched inter-chromosomal associations at the heterochromatic satellite repeats of chromosomes 1, 9, 16 are inducible by de-methylating agents like 5-azadeoxycytidine and can spontaneously arise in patients with ICF syndrome (Immunodeficiency Centromeric instability and Facial anomalies) with mutations in genes regulating DNA methylation. ICF individuals have hypomethylated satellites I-III, alpha-satellites, and subtelomeric repeats. Ribosomal repeats and subtelomeric D4Z4 megasatellites/macrosatellites, are associated with chromosome location, fragility, and disease. Telomere repeats can also assume fragile sites. Dietary deficiencies of folate or vitamin B12, or drug insults are associated with megaloblastic and/or pernicious anemia, that display chromosomes with fragile sites. The recent discovery of many new tandem repeat expansion loci, with varied repeat motifs, where motif lengths can range from mono-nucleotides to megabase units, could be the molecular cause of new fragile sites, or other chromosomal lesions. This review focuses on repeat-associated fragility, covering their induction, cytogenetics, epigenetics, cell type specificity, genetic instability (repeat instability, micronuclei, deletions/rearrangements, and sister chromatid exchange), unusual heritability, disease association, and penetrance. Understanding tandem repeat-associated chromosomal fragile sites provides insight to chromosome structure, genome packaging, genetic instability, and disease.

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A new heritable fragile site at 15q13 in a three-generation family

Cited by 2 publications

References 33 publications

Structural Variation Evolution at the 15q11-q13 Disease-Associated Locus

Structural Variation Evolution at the 15q11-q13 Disease-Associated Locus

Fragile sites, chromosomal lesions, tandem repeats, and disease

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