Structural Chromosome Rearrangments

Autosomal reciprocal translocations

Robertsonian Translocations

X-autosome translocations

Y-autosome translocations

X-Y translocations

3-way exchange

Inversions

Deletions

Duplications

Inversion Duplications

Isochromosomes

Ring chromosomes

Marker Chromosomes

Insertions

Epidemiology and Etiology:

· 75% of de novo structural chromosome rearrangements are paternally derived

· May be due to number of mitotic divisions

· May be male gametogenesis is more sensitive to mutagens than oogenesis

· Exceptions to this rule:

· De novo nonhomologous Robertsonian translocations (90% maternal)

· Terminal chromosome 1 short arm deletions (80% maternal)

· Several supernumerary isochromosomes

· Inverted duplicated chromosomes

· Interstitial microdeletions associated with NAHR (no parental bias)

· Rarely seen in mosaic form:

· Exceptions are rings and dicentric chromosomes (mitotically unstable)

· Regions of the genome that are more susceptible to breakage and rearrangement:

· DNA sequences that are repeated elsewhere in the genome

· Fragile sites

· Tandem repeat sequences

· Note: usually no repeat expansion found

· Does not explain all fragile sites

· May be due to delayed +/- incomplete DNA replication

· Particular secondary DNA structures

· Mechanisms:

· Homologous recombination (HR) is predominant pathway underlying recurrent rearrangements in our genome

· Non-allelic homologous recombination (NAHR):

· Paralogous DNA sequences misaligning during meiosis

· High copy number repeats:

· Alu

· Satellite DNA

· Low-copy repeats (segmental duplications)

· In mice, requires a minimal amount of 132 to 232 bp of perfectly shared sequence

· “hotspots” of HR are seen in both non-allelic and allelic HR

· Clustering within small (< 1 kb) genomic regions

· Coincidence with apparent gene conversion events

· No obvious sequence similarities between hotspots (as opposed to prokaryotes)

· Occurring between homologs or sister chromatids

· Results in reciprocally imbalanced recombinant products

· Intrachromosomal recombination (occurring within the same chromosome)

· Results in a deletion with no reciprocally duplicated partner

· (the other product is an acentric ring)

· About equal proportions from mothers and fathers

· Male heterozygotes for Bloom syndrome have a high frequency of (sperm) chromosome breaks

· Types of recurring structural rearrangements:

· Duplications (direct orientation on same chromosome)

· Deletions (direct orientation on same chromosome)

· Inversions (inverted orientation on same chromosome) (ex. pericentric inversion 9)

· Translocations (any orientation on different chromosome) (ex. t(4;8)(p16;p23))

· Robertsonian translocations

· Isochromosomes

· Marker chromosomes

· May be:

· Involving a single gene (ex. DMD, hemophilia A)

· Involving multiple genes (microdeletion and microduplication syndromes)

· Non-homologous end-joining (NHEJ):

· Likely mechanism for non-recurrent genomic rearrangements

· Two broken ends are simply pieced together

· Sometimes after limited processing of ends

· Quick, but error-prone, repair

· Ku complex:

· Initially recognizes DNA break

· DNA end binding

· protein kinase DNA-PKcs

· signals presence of the break

· activates repair proteins

· DNA-end processing enzymes

· XRCC4–Ligase IV complex

· re-ligates the broken DNA ends

· Note that breakpoints often map to LCRs, but the two breakpoints may be different LCRs

· Homologous repair (HR):

· More accurate

· Information is copied from an intact homologous DNA duplex

· Requirement of specific cell cycle phases (S/G2)

· Fragile sites:

· Likely minimal involvement in most chromosomal rearrangements

· Paucity of data suggesting their role

· secondary DNA structures:

· hairpin-shaped secondary structures predicted to be formed by AT-rich palindromic sequences

· DNA sequences that contain two inverted regions complementary to each other

· Susceptible to nucleases that produce double-stranded breaks

· Implicated in recurring t(11;22), and one other translocation, a t(17;22) in a family with NF type I

· DNA double-stranded breaks (DSB):

· Intrinsic sources:

· Products of cellular metabolism

· Reactive oxygen species (ROS)

· Programmed DSBs:

· V(D)J recombination in B cells

· Replication fork passes through a template with a nick

· Estimated 10-100 DSBs per nucleus per day

· Extrinsic sources:

· X-rays / gamma-rays

· Chemotherapeutic drugs

· Repair process may be error-prone

· DNA repair process:

· Cell cycle arrest

· Apoptosis maybe

· Homologous repair:

· Only during S/G2 phases of cell cycle (sister chromatid present)

· NHEJ:

· Any phase in the cell cycle

· Predominant repair pathway in mammalian cells

Common sites:

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Gross features:

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Histologic features:

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Immunophenotype:

Marker:

Sensitivity:

Specificity:

Molecular features:

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Other features:

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References:

· Gersen SL, Keagle MB. The Principles of Clinical Cytogenetics. 2nd ed. Humana Press; 2004:616.

· Lupski JR, Stankiewicz P. Genomic disorders: molecular mechanisms for rearrangements and conveyed phenotypes. PLoS Genet. 2005;1(6):e49.