Fragility Extraordinaire: Unsolved Mysteries of Chromosome Fragile Sites

Abstract

Chromosome fragile sites are a fascinating cytogenetic phenomenon now widely implicated in a slew of human diseases ranging from neurological disorders to cancer. Yet, the paths leading to these revelations were far from direct, and the number of fragile sites that have been molecularly cloned with known disease-associated genes remains modest. Moreover, as more fragile sites were being discovered, research interests in some of the earliest discovered fragile sites ebbed away, leaving a number of unsolved mysteries in chromosome biology. In this review we attempt to recount some of the early discoveries of fragile sites and highlight those phenomena that have eluded intense scrutiny but remain extremely relevant in our understanding of the mechanisms of chromosome fragility. We then survey the literature for disease association for a comprehensive list of fragile sites. We also review recent studies addressing the underlying cause of chromosome fragility while highlighting some ongoing debates. We report an observed enrichment for R-loop forming sequences in fragile site-associated genes than genomic average. Finally, we will leave the reader with some lingering questions to provoke discussion and inspire further scientific inquiries.

The FRA14B common fragile site maps to a region prone to somatic and germline rearrangements within the large GPHN gene

“…In total, 29 RLFS cluster at the FRA14B region, particularly within the first introns of GPHN and AL359232.1 (Figure E). In line with this observation, other rare fragile site‐associated or cFS‐associated genes have been shown to be significantly enriched in RLFS …”

“…Besides AT‐rich sequences with the potential to adopt secondary structures, transcription associated RNA:DNA hybrids (R‐loops) at cFSs have been suggested to contribute to instability of large actively transcribed cFS genes . Considering that FRA14B encompasses the genomic sequence of GPHN, a large gene (674 kb) ubiquitously expressed in all tissues, we used the R‐loop database to identify predicted RLFS.…”

“…Collision between replication and transcription has been proposed as crucial factor underlying instability at large cFS genes, a process mediated by R‐loop formation . RLFS clusters within the FRA14B core region may indicate involvement in GPHN instability, as significant enrichment has been associated with cFS genes …”

“…Replication stress often results in DNA damage and chromosomal instability that can lead to a wide spectrum of human diseases. Specific regions of the genome, known as common fragile sites (cFSs), are particularly prone to breakage under conditions of replication stress . They are considered to be present in all individuals, and represent intrinsic components of the normal chromosome structure.…”

Common fragile site instability in normal cells: Lessons and perspectives

“…Fragile sites are genomic regions characterized by gaps or breaks observed in metaphase chromosomes under conditions of mild replication stress . In addition, a historical excursus that comprehensively highlights the milestones of fragile site discovery and characterization has been published recently . The traditional classification of fragile sites is based on frequency of occurrence and genetic inheritance.…”