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.
Nussbaum
R L
RL
Airhart
S D
SD
Ledbetter
D H
DH
D001483:Base Sequence; D043283:Chromosome Fragile Sites; D002873:Chromosome Fragility; D003434:Crossing Over, Genetic; D004247:DNA / Q000235:genetics; D005260:Female; D005600:Fragile X Syndrome / Q000235:genetics*; D005784:Gene Amplification; D008040:Genetic Linkage; D005819:Genetic Markers; D006801:Humans; D008297:Male; D008957:Models, Genetic; D011742:Pyrimidine Nucleotides / Q000235:genetics; D011995:Recombination, Genetic; D012306:Risk; D012729:Sex Chromosome Aberrations / Q000235:genetics*; D014960:X Chromosome
D005819:Genetic Markers; D011742:Pyrimidine Nucleotides; D004247:DNA