Recombination and amplification of pyrimidine-rich sequences may be responsible for initiation and progression of the Xq27 fragile site: an hypothesis.

A pyrimidine-rich sequence (PRS) of DNA is present as a normal sequence in the q27 band of the human X chromosome. Under conditions of pyrimidine nucleotide triphosphate deprivation during S phase, deoxyuridine monophosphate is misincorporated and has to be excised during G2 by DNA repair mechanisms. When a simple PRS is present on both homologous X chromosomes during oogenesis, PRS may undergo amplification through non-homologous crossing-over to produce the initial lesion of the fragile (X). Carriers of such initial lesions will be unaffected transmitting females or males. When an X chromosome bearing such an initial lesion is itself paired with a homologous X carrying a simple PRS during oogenesis, a much higher rate of non-homologous crossing-over may occur resulting in progression to an even longer stretch of pyrimidine rich DNA in this region; the increased length of PRS through amplification makes the region too long to be repaired during G2 and allows it to be seen as a fragile site in metaphase chromosome preparations. Furthermore, this amplified lesion may interfere with transcription of one or more genes in this region and produce the phenotype of the Martin-Bell syndrome.