Monosomy 1p36 As a Model for the Molecular Basis of Terminal Deletions

Abstract

Deletion of the most distal, telomeric band of human chromosomes can result in a variety of mental retardation and multiple congenital anomaly syndromes. These terminal deletions are some of the most commonly observed structural chromosome abnormalities detected by routine cytogenetic analysis. Terminal deletions of 1p36 occur in approx 1 in 5000 live births, making it the most frequently observed terminal deletion and one of the most commonly observed mental retardation syndromes in humans. Molecular characterization of subjects with monosomy 1p36 indicates that, like other terminal deletions, 1p36 deletions have breakpoints occurring in multiple locations over several megabases and are comprised of terminal truncations, interstitial deletions, complex rearrangements, and derivative chromosomes. In addition, cryptic interrupted inverted duplications have been observed at the end of terminally deleted chromosomes, suggesting premeiotic breakage-fusion-bridge (BFB) cycles can be intermediate steps in the process of generating and stabilizing terminal deletions of 1p36. Overall, these observations are identical to those made in yeast and other model systems in which a double-strand break (DSB) near a telomere can be repaired by a variety of mechanisms to stabilize the end of a broken chromosome. Furthermore, sequence analysis and fluorescent in situ hybridization (FISH) mapping of the terminal 10.5 Mb of 1p36 including a variety of terminal deletion breakpoint junctions indicate that segmental duplications, low-copy repeats (LCRs), and short repetitive DNA sequence elements may mediate the generation and stabilization of terminal deletions of 1p36. We hypothesize that nonallelic homologous recombination (NAHR) between palindromic or inverted LCRs in the subtelomeric region of 1p36 could generate a dicentric chromosome that is broken at a random location during the subsequent anaphase as the centromeres move to opposite poles. This model suggests that the molecular basis of terminal deletions may be directly linked to genomic architectural features in the subtelomeric regions that generate the initial, variable-sized terminally deleted chromo-some, and that stabilization of the broken chromosome occurs by one of a variety of competing DSB repair pathways.