The enigma of common fragile sites

Abstract

One hundred and fifty breakpoint sites were recorded during an analysis of aphidicolin-ethanol inducible fragile sites (FS) in 56 blood samples and 13 amniocyte cultures and were classified according to the criteria formulated by the Chromosome Coordinating Meeting. The finding of previously unlisted FS in this sample, the altered expression of FS in conditions not usually associated with chromosomal abnormalities and the apparent lack of tissue specificity indicate the importance of one or more fundamental mechanisms operating to produce the diverse associated clinical phenotypes, with the chromosomal fragility representing an intermediate phenotype. Several lines of evidence converge towards the conclusion that FS are a manifestation of an altered state of genetic activity at areas associated with transcriptional regulation, because of their concordance with CpG islands, nuclease sensitive sites, replication origins, zinc finger protein domains and viral integration sites. An investigation is required whether this phenomenon could contribute both to evolutionary diversity through increased recombination, the formation of unstable repeat sequences and variable methylation, and to the expression of multigene disease processes resulting in the production of variable and complex phenotypes, even within families.