Fragile sites on human chromosomes
Fragile sites were seen intermittently in the early days of cytogenetics. They were regarded as normal variants and were seen in some laboratories only. The first rare autosomal fragile site was reported in 19651 and a fragile site on chromosome 2 was shown to be inherited in 19682. The fragile X was first recorded in 19693. It was not until 19774 that it was recognised that cytogenetic expression of most of the rare fragile sites was tissue culture medium dependent. They were seen only if the old culture medium TC199 was used and not if the more modern (at that time) RPMI 1640 or Ham’s F10 were used. The critical ingredients absent from TC199 that allowed for fragile site expression were folic acid and thymidine. In 1984 common fragile sites were described and a method for their induction published5. While a number of new types of fragile site were described, and fragile X syndrome became recognised as the most common form of familial intellectual disability, fragile sites remained an enigmatic phenomenon until 1991 when the fragile X was cloned6. The discovery that expansion of a naturally occurring polymorphic trinucleotide repeat (CCG) could produce premutations and full mutations that transcriptionally silenced the FMR1 gene provided a new mechanism of mutation in human genetics. The cloning of a few of the autosomal fragile sites allows the inference that all the rare folate sensitive fragile sites will be CCG expansions and the others more complex expansions of minisatellite repeats. The common fragile sites occur over megabase regions DNA and while this DNA has some common properties no satisfying molecular explanation of these fragile sites has emerged.
1 Dekaban 1965 J Nucl Med 6:740
2 Lejeune 1968 C R Acad Sci Paris 266:24
3 Lubs 1969 Am J Hum Genet 21:231
4 Sutherland 1977 Science 197:265
5 Glover et al 1984 Hum Genet 67:136
6 Yu et al 1991 Science 252:1179; Oberlé et al 1991 Science 252:1097; Verkerk et al 1991 Cell 65:905