Fragile Sites

Abstract

According to Sutherland and Hecht (Giraud et al., Hum Genet 34:125–136, 1976), fragility at specific sites on chromosomes were first described by Dekeban (1965) and by Lejeune (1968). Magenis et al. (1970) (Harvey et al., J Med Genet 20:280–285, 1977) used a heritable fragile site on chromosome 16 to map α-haptoglobin. The term “fragile site”, however, is attributed to Frederick Hecht who, in referring to this site on chromosome 16, “wanted to convey the concept of transmissible points of chromosome fragility in the human genome” (Giraud et al., Hum Genet 34:125–136, 1976). The clinically significant fragile site at Xq27.3 was initially reported by Lubs (Lubs, Am J Hum Genet 21:231–244, 1969) as a familial marker X chromosome in four mentally retarded males and their normal mother. This marker was shown to be more than sporadically associated with a common form of X-linked male mental retardation in 1976–77 (Sutherland, Science 197:265–266, 1977; Sutherland, Am J Hum Genet 31:125–135, 1979). However, it was not until Sutherland (Hecht and Sutherland, Fragile Sites on Human Chromosomes, 1985) showed that expression of the fragile X required culture in medium that was deficient in folic acid and thymidine that the fragile X in particular was accepted as a reproducible marker of the disease, and that other fragile sites became of interest as possible markers of disease. It was soon apparent that numerous other sites were sensitive to a variety of culture conditions (Giraud et al., Hum Genet 34:125–136, 1976). These included: (1) folate-sensitive sites; (2) distamycin A-inducible sites; (3) BrdU–requiring sites; (4) common fragile sites (most strongly induced by aphidicolin, but weakly induced by conditions in the first three groups).