Summary

Combined, the data presented suggest that: (1) genomic architectural features may ultimately play a role in the generation of terminal deletions of 1p36 by generating the doublestrand DNA breaks near the telomere, and (2) a variety of DNA repair pathways are responsible for stabilizing the broken chromosomes. Furthermore, based on the variety of rearrangements and the various mechanisms that generate and stabilize broken chromosomes ends, these

Fig. 2. Model for nonallelic homologous recombination (NAHR) between palindromic low-copy repeats (LCRs) in the subtelomeric region of 1p36. Palindromic LCRs are shown as arrowheads. Telomeric repeat sequences are shown as filled circles at the ends of the chromosomes. Unique sequences, shown as solid, hatched, and open boxes, are included for illustrative purposes. (A) Palindromic LCRs can promote misalignment of homologous chromosomes. (B) NAHR between misaligned palindromic LCRs results in the formation of a dicentric chromosome. (C) In anaphase, when the centromeres move to opposite poles, the resulting dicentric chromosome forms a bridge that will eventually break at a random location. (D) Random breakage results in one chromosome with an inverted duplication and a distal deletion and a second chromosome (E) with a terminal deletion. This random breakage could account for the variability in deletion size observed in terminal deletions of 1p36. However, these broken chromosomes must acquire a telomeric cap to be stabilized.

Fig. 2. Model for nonallelic homologous recombination (NAHR) between palindromic low-copy repeats (LCRs) in the subtelomeric region of 1p36. Palindromic LCRs are shown as arrowheads. Telomeric repeat sequences are shown as filled circles at the ends of the chromosomes. Unique sequences, shown as solid, hatched, and open boxes, are included for illustrative purposes. (A) Palindromic LCRs can promote misalignment of homologous chromosomes. (B) NAHR between misaligned palindromic LCRs results in the formation of a dicentric chromosome. (C) In anaphase, when the centromeres move to opposite poles, the resulting dicentric chromosome forms a bridge that will eventually break at a random location. (D) Random breakage results in one chromosome with an inverted duplication and a distal deletion and a second chromosome (E) with a terminal deletion. This random breakage could account for the variability in deletion size observed in terminal deletions of 1p36. However, these broken chromosomes must acquire a telomeric cap to be stabilized.

studies indicate that monosomy 1p36 provides a fundamental model for the molecular basis of constitutional terminal deletions in humans. In the future, the delineation of the structure of terminal deletions for other chromosome ends will determine whether the monosomy 1p36 model is representative of the molecular basis of all terminal deletions.

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