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A palindrome-driven complex rearrangement of 22q11.2 and 8q24.1 elucidated using novel technologies.

ABSTRACT: Constitutional translocations at the same 22q11.21 low copy repeat B (LCR-B) breakpoint involved in the recurrent t(11;22) are relatively abundant. A novel 46,XY,t(8;22)(q24.13;q11.21) rearrangement was investigated to determine whether the recurrent LCR-B breakpoint is involved. Investigations demonstrated an inversion of the 3Mb region typically deleted in patients with the 22q11.2 deletion syndrome. The 22q11.21 inversion appears to be mediated by low copy repeats, and is presumed to have taken place prior to translocation with 8q24.13. Despite predictions based on inversions observed in other chromosomes harboring low copy repeats, this 22q11.2 inversion has not been observed previously. The current studies utilize novel laser microdissection and MLPA (multiplex ligation-dependent probe amplification) approaches, as adjuncts to FISH, to map the breakpoints of the complex rearrangements of 22q11.21 and 8q24.21. The t(8;22) occurs between the recurrent site on 22q11.21 and an AT-rich site at 8q24.13, making it the fifth different chromosomal locus characterized at the nucleotide level engaged in a translocation with the unstable recurrent breakpoint at 22q11.21. Like the others, this breakpoint occurs at the center of a palindromic sequence. This sequence appears capable of forming a perfect 145 bp stem-loop. Remarkably, this site appears to have been involved in a previously reported t(3;8) occurring between 8q24.13 and FRA3B on 3p14.2. Further, the fragile site-like nature of all of the breakpoint sites involved in translocations with the recurrent site on 22q11.21, suggests a mechanism based on delay of DNA replication in the initiation of these chromosomal rearrangements.

SUBMITTER: Gotter AL

PROVIDER: S-EPMC1832094 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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A palindrome-driven complex rearrangement of 22q11.2 and 8q24.1 elucidated using novel technologies.

Gotter Anthony L AL Nimmakayalu Manjunath A MA Jalali G Reza GR Hacker April M AM Vorstman Jacob J Conforto Duffy Danielle D Medne Livija L Emanuel Beverly S BS

Genome research 20070309 4

Constitutional translocations at the same 22q11.21 low copy repeat B (LCR-B) breakpoint involved in the recurrent t(11;22) are relatively abundant. A novel 46,XY,t(8;22)(q24.13;q11.21) rearrangement was investigated to determine whether the recurrent LCR-B breakpoint is involved. Investigations demonstrated an inversion of the 3Mb region typically deleted in patients with the 22q11.2 deletion syndrome. The 22q11.21 inversion appears to be mediated by low copy repeats, and is presumed to have tak ...[more]

PMID: 17351131

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Project description:Two known recurrent constitutional translocations, t(11;22) and t(17;22), as well as a non-recurrent t(4;22), display derivative chromosomes that have joined to a common site within the low copy repeat B (LCR-B) region of 22q11.2. This breakpoint is located between two AT-rich inverted repeats that form a nearly perfect palindrome. Breakpoints within the 11q23, 17q11 and 4q35 partner chromosomes also fall near the center of palindromic sequences. In the present work the breakpoints of a fourth translocation involving LCR-B, a balanced ependymoma-associated t(1;22), were characterized not only to localize this junction relative to known genes, but also to further understand the mechanism underlying these rearrangements. FISH mapping was used to localize the 22q11.2 breakpoint to LCR-B and the 1p21 breakpoint to single BAC clones. STS mapping narrowed the 1p21.2 breakpoint to a 1990 bp AT-rich region, and junction fragments were amplified by nested PCR. Junction fragment-derived sequence indicates that the 1p21.2 breakpoint splits a 278 nt palindrome capable of forming stem-loop secondary structure. In contrast, the 1p21.2 reference genomic sequence from clones in the database does not exhibit this configuration, suggesting a predisposition for regional genomic instability perhaps etiologic for this rearrangement. Given its similarity to known chromosomal fragile site (FRA) sequences, this polymorphic 1p21.2 sequence may represent one of the FRA1 loci. Comparative analysis of the secondary structure of sequences surrounding translocation breakpoints that involve LCR-B with those not involving this region indicate a unique ability of the former to form stem-loop structures. The relative likelihood of forming these configurations appears to be related to the rate of translocation occurrence. Further analysis suggests that constitutional translocations in general occur between sequences of similar melting temperature and propensity for secondary structure.

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Dataset Information

A palindrome-driven complex rearrangement of 22q11.2 and 8q24.1 elucidated using novel technologies.

Publications

A palindrome-driven complex rearrangement of 22q11.2 and 8q24.1 elucidated using novel technologies.

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