A chromosomal fragile site is a specific heritable point on a chromosome that tends to form a gap or constriction and may tend to break when the cell is exposed to partial replication stress. Based on their frequency, fragile sites are classified as "common" or "rare". To date, more than 120 fragile sites have been identified in the human genome. Common fragile sites are considered part of normal chromosome structure and are present in all (or nearly all) individuals in a population. Under normal conditions, most common fragile sites are not prone to spontaneous breaks. Common fragile sites are of interest in cancer studies because they are frequently affected in cancer and they can be found in healthy individuals. Sites FRA3B (harboring the FHIT gene) and FRA16D (harboring the WWOX gene) are two well known examples and have been a major focus of research. Rare fragile sites are found in less than 5% of the population, and are often composed of two- or three-nucleotide repeats. They are often susceptible to spontaneous breakage during replication, frequently affecting neighboring genes. Clinically, the most important rare fragile site is FRAXA in the FMR1 gene, which is associated with the fragile X syndrome, the most common cause of hereditary intellectual disability. For detailed information regarding each characterized fragile site, please visit HumCFS: a database of fragile sites in human chromosomes, published in BMC Genomics. Rare fragile sites Classification Rare fragile sites (RFSs) are classified into two sub-groups based on the compounds that elicit breakage: folate-sensitive groups (for examples, see ), and nonfolate-sensitive groups, which are induced by bromodeoxyuridine (BrdU) or distamycin A, an antibiotic that preferentially binds to AT-pairs of DNA. The folate-sensitive group is characterized by an expansion of CGG repeats, while the nonfolate-sensitive group contains many AT-rich minisatellite repeats. Mechanisms of instability The CGG and AT-rich repeats characteristic of RFSs can form hairpins and other non-B DNA structures that block replication forks and can result in breakage. DNA polymerase has been shown to pause at CTG and CGG triplet repeat sequences, which can result in continual expansion via slippage. Common fragile sites Classification Unlike RFSs, common fragile sites (CFSs) are not the result of nucleotide repeat expansion mutations. They are a part of the normal human genome and are typically stable when not under replicative stress. The majority of breakages at CFSs are induced by low doses of the antibiotic aphidicolin .