Fragile sites

There are two kinds of fragile sites: common and rare fragile sites. Rare fragile sites are found in less than 5% of the population and are composed of tri- or dinucleotide repeats that may cause spontaneous breaks during replication, frequently affecting neighboring genes. One such example is FRAXA, the fragile site implicated in the "fragile X syndrome", a common cause of hereditary mental retardation. The affected gene is FMR1 and is found on chromosome Xq27.3. The number of repeats in a rare fragile site may increase from generation to generation, giving rise to a phenomenon known as anticipation, where offspring are more severely affected than their parents. Rare fragile sites are of little importance in cancer studies.

Common fragile sites are considered a normal part of the human genome and are not prone to spontaneous breaks under normal conditions. The majority of common fragile sites only show breaks when DNA replication is partially inhibited by addition of a chemical agent known as aphidicolin. Some common fragile sites are known to be vulnerable to other stress-inducing chemicals, such as BrdU or 5-azacytidine but are generally less well studied. The sequence properties of common fragile sites are much more complicated and have not yet been fully elucidated, although some authors have speculated that DNA flexibility, local adenine-thymine content and the presence of repetitive DNA elements (such as LINE-1 or Alu) may be responsible.

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 studied extensively.