The fragile site at Xq27 (FRAXA) is associated with a common form of X-linked mental retardation (Martin-Bell syndrome). It is induced in culture by conditions of thymidylate stress and is generally considered a rare fragile site found only in association with an X-linked form of mental retardation. Using a somatic cell hybrid system, we previously demonstrated that fragile-X expression can be induced by thymidylate stress in normal X chromosomes at low levels (4%-5%). In the present report, significantly higher levels of fragile-X expression (6%-28%) have been induced in lymphocytes or lymphoblasts of all seven control males using high doses of aphidicolin (1.5 microM). Similar high levels of expression (10%-12%) were observed in both of two normal male chimpanzees (Pan troglodytes). These data demonstrate that Xq27 contains a common fragile site (FRAXD) that is ancestral to the divergence of man and the chimpanzee. Presence of a common and a rare fragile site in the same metaphase chromosome band does not prove that they are identical and may, in fact, represent two unrelated fragile sites. However, the possibility exists that the common fragile site at Xq27 may be the substrate for unequal recombination events that produces the rare fragile site associated with Martin-Bell syndrome. In addition, presence of a common fragile site at Xq27 may explain the occasional observation of low-frequency fragile-X expression in normal control individuals. Caution is therefore warranted in the interpretation of low-level fragile-X expression in diagnostic and prenatal diagnostic settings.