THE ENIGMA OF COMMON FRAGILE SITES

One hundred and fifty breakpoint sites were recorded during an analysi s of aphidicolin-ethanol inducible fragile sites (FS) in 56 blood samp les and 13 amniocyte cultures and were classified according to the cri teria formulated by the Chromosome Coordinating Meeting. The finding o f previously unlisted FS in this sample, the altered expression of FS in conditions not usually associated with chromosomal abnormalities an d the apparent lack of tissue specificity indicate the importance of o ne or more fundamental mechanisms operating to produce the diverse ass ociated clinical phenotypes, with the chromosomal fragility representi ng an intermediate phenotype. Several lines of evidence converge towar ds the conclusion that FS are a manifestation of an altered state of g enetic activity at areas associated with transcriptional regulation, b ecause of their concordance with CpG islands, nuclease sensitive sites , replication origins, zinc finger protein domains and viral integrati on sites. An investigation is required whether this phenomenon could c ontribute both to evolutionary diversity through increased recombinati on, the formation of unstable repeat sequences and variable methylatio n, and to the expression of multigene disease processes resulting in t he production of variable and complex phenotypes. even within families .