Fragile sites, chromosomal lesions, tandem repeats, and disease

Abstract

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.

Discovery of Novel miRNAs in Colorectal Cancer: Potential Biological Roles and Clinical Utility

“…The validated miRNAs were mapped to chromosomes 2, 3, 9, 10, 11, 13, 15, 19, 20, and X, most of which were located in regions rich in known miRNAs. Three novel miRNAs (nov-miR-3345-5p, nov-miR-766-3p, and nov-miR-8861-5p) were detected in known genomic fragile sites, FRA2E, FRA11C, and FRA15A, all of which are classified as common fragile sites (CFS) because they are present in most of the human population [15]. Fragile sites are gaps, constrictions, or breaks in metaphase chromosomes that arise when cells are exposed to perturbation of the DNA replication process and are linked to regions of chromosomal rearrangement in cancer [16].…”

A Unifying Hypothesis for the Genome Dynamics Proposed to Underlie Neuropsychiatric Phenotypes

“…Clustered fragile sites and their chromosomal locations were cataloged by Mirceta et al in 2022 [58].…”

A Unifying Hypothesis for the Genome Dynamics Proposed to Underly Neuropsychiatric Phenotypes

“…Clustered fragile sites and their chromosomal locations were catalogued by Mirceta et al in 2022 [58].…”