IMPLICATIONS OF FRA16A STRUCTURE FOR THE MECHANISM OF CHROMOSOMAL FRAGILE SITE GENESIS

Fragile sites are chemically induced nonstaining gaps in chromosomes. Different fragile sites vary in frequency in the population and in the chemistry of their induction. DNA sequences encompassing and includin g the rare, autosomal, folate-sensitive fragile site, FRA16A, were iso lated by positional cloning. The molecular basis of FRA16A was found t o be expansion of a normally polymorphic p(CCG), repeat. This repeat w as adjacent to a CpG island that was methylated in fragile site-expres sing individuals. The FRA16A locus in individuals who do not express t he fragile site is not a site of DNA methylation (imprinting), which s uggests that the methylation associated with fragile sites may be a co nsequence and not a cause of their genesis.