Abstract
Several recurrent common chromosomal deletion and duplication breakpoints have been localized to large, highly homologous, low-copy repeats (LCRs). The mechanism responsible for these rearrangements, viz., non-allelic homologous recombination between LCR copies, has been well established. However, fewer studies have examined the mechanisms responsible for non-recurrent rearrangements with non-homologous breakpoint regions. Here, we have analyzed four uncommon deletions of 17p11.2, involving the Smith–Magenis syndrome region. Using somatic cell hybrid lines created from patient lymphoblasts, we have utilized a strategy based on the polymerase chain reaction to refine the deletion breakpoints and to obtain sequence data at the deletion junction. Our analyses have revealed that two of the four deletions are a product of Alu/Alu recombination, whereas the remaining two deletions result from a non-homologous end-joining mechanism. Of the breakpoints studied, three of eight are located in LCRs, and five of eight are within repetitive elements, including Alu and MER5B sequences. These findings suggest that higher-order genomic architecture, such as LCRs, and smaller repetitive sequences, such as Alu elements, can mediate chromosomal deletions via homologous and non-homologous mechanisms. These data further implicate homologous recombination as the predominant mechanism of deletion formation in this genomic interval.
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Acknowledgements
We thank the patients and their parents for participation. We are also grateful to Dr. K. Inoue and Dr. P. Stankiewicz for critical reviews, and Marjorie Withers for technical assistance. This work was supported in part by grants from the National Institute of Child Health and Human Development (PO1 HD39420) and the Mental Retardation Research Center (HD24064).
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Shaw, C.J., Lupski, J.R. Non-recurrent 17p11.2 deletions are generated by homologous and non-homologous mechanisms. Hum Genet 116, 1–7 (2005). https://doi.org/10.1007/s00439-004-1204-9
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DOI: https://doi.org/10.1007/s00439-004-1204-9