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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.

The presence of a small supernumerary marker chromosome (SMC) in a karyotype creates a diagnostic dilemma, because the resulting duplications/triplications may cause abnormal development, depending on the location and size of the extra material. The most common SMC is the inv dup(15), the effect of which varies with size of triplication as well as the parent of origin. inv dup(22) is associated with the highly variable cat eye syndrome. Both are thought to be caused by U-type recombination between neighboring low-copy repeats (LCRs), resulting in both symmetric and asymmetric bisatellited dicentric supernumerary chromosomes. Studies are underway to associate the abnormal features of each syndrome with specific genes in the duplicated regions.

Neoplastic disorders are characterized by recurrent somatically acquired chromosomal aberrations that alter the structure and/or expression of a large number of genes. Most “cancer genes” discovered to date in human neoplasms have been identified through isolation of genes at the breakpoints of balanced chromosomal translocations. Although functional studies of such cancer-causing genes have demonstrated their causal role in tumorigenesis, the mechanisms underlying the formation of recurrent chromosomal changes in cancer remain enigmatic. Low-copy repeats (LCRs) are important mediators of erroneous meiotic recombination, resulting in constitutional chromosomal rearrangements. Recently, LCRs have been implicated in the formation of the frequent and characteristic neoplasia-associated chromosomal aberrations t(9;22)(q34;q1 1) and i(17q), suggesting that similar genome architecture features may play an important role in generating also other somatic chromosomal rearrangements.

Rearrangement breakpoints resulting from nonallelic homologous recombination (NAHR) are typically clustered within small, well-defined portions of the segmental duplications that promote the rearrangement. These NAHR “hotspots” have been identified in every NAHR-promoted rearrangement in which breakpoint junctions have been sequenced in sufficient numbers. Enhancement of recombinatorial activity in NAHR hotspots varies from 3 to 237 times more than in the surrounding “cold” duplicated sequence. NAHR hotspots share many features in common with allelic homologous recombination (AHR) hotspots. Both AHR and NAHR hotspots appear to be relatively small (<2 kb) and are initiated by double-strand breaks. Gene conversion events as well as crossovers are enhanced at NAHR hotspots. Recent work has improved our understanding of the origins of NAHR and AHR hotspots, with both appearing to be relatively short-lived phenomena. Our present understanding of NAHR hotspots comes from a limited number of locus-specific studies. In the future, we can expect genome-wide analyses to provide many further insights.

Position effects describe the observed alteration in protein-coding gene expression that may accompany a change in genomic position of a given gene. A position effect may result from chromosomal translocation or other genomic rearrangements. Recent advances in chromatin studies in several different species including yeast, Drosophila, and mouse have contributed significantly to better understanding of human diseases resulting from abnormal epigenetic effects. Molecular models attempting to explain position effects in humans have been proposed; however, none of them adequately addresses a variety of mechanisms. According to the noncontact models, the cis- or trans-regulatory elements, or locus control regions, are physically separated from the target gene and act either at the RNA level, by protein interactions, or by mediation of boundary elements, termed insulators. On the contrary, the contact models invoke spatial-temporal modifications of chromatin structure (e.g., active chromatin hub). In both models, the conserved nongenic sequences (CNGs) may play an important role in genomic regulation of gene expression. The recent introduction of new techniques including tagging and recovery of associated proteins (RNA-TRAP) and capturing chromatin conformation (CCC or 3C), has provided powerful tools to investigate position effects in humans.

Chromosome rearrangements cause genomic disorders and cancer in human. Region-specific low-copy repeats (LCRs) can mediate nonallelic homologous recombination (NAHR) that results in chromosome rearrangements. Using the Cre-loxP site-specific recombination system, chromosome rearrangements that cause genomic disorders and cancer can be recapitulated in the mouse. Technology advancements in mouse genetics, such as recombineering, will undoubtedly facilitate modeling genetic changes associated with genomic disorders in the mouse.

Rapid, high-resolution analysis of genomic rearrangements has become possible using array-comparative genomic hybridization (aCGH), a combination of CGH with DNA microarray technology. Using aCGH, genome copy number changes and rearrangement breakpoints can now be mapped and analyzed at resolutions down to a few kilobases or even less in a single hybridization. This technology is enabling us to identify previously hidden rearrangements in patients with suspected genomic disorders for which no karyotype aberrations could be identified using conventional cytogenetic analysis. Furthermore, the development of array painting has revealed a surprising level of rearrangement complexity in patients with apparently balanced translocations.