Recombination and amplification of pyrimidine‐rich sequences may be responsible for initiation and progression of the Xq27 fragile site: An hypothesis

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Abstract
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 mechanisms. When a simple PRS is present on both homologous X chromosomes during oogenesis, PRS may undergo amplification through non‐homologous crossing‐over ot produced 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.

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