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Human Molecular Genetics Advance Access originally published online on November 12, 2003
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Human Molecular Genetics, 2004, Vol. 13, No. 1 103-115
DOI: 10.1093/hmg/ddh004
© 2004 Oxford University Press

A palindrome-mediated mechanism distinguishes translocations involving LCR-B of chromosome 22q11.2

Anthony L. Gotter1, Tamim H. Shaikh1,2, Marcia L. Budarf1,2, C. Harker Rhodes3 and Beverly S. Emanuel1,2,*

1Division of Human Genetics and Molecular Biology, Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, ARC 1002, Philadelphia, PA 19104, USA, 2Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA and 3Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA

Received September 22, 2003; Accepted October 29, 2003

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.

* To whom correspondence should be addressed. Tel: +1 2155903856; Fax: +1 2155903764; Email: beverly{at}mail.med.upenn.edu


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