Uncommon Deletions of the SMS Region Can Be Recurrent When Alternate LCRs Act as Homologous Recombination Substrates

LCR17ps predominate at breakpoints of uncommon nonrecurrent, or unusual sized chromosome deletions in proximal 17p. In fact, 64% of unusual sized SMS deletion breakpoints occur in LCRs (19,29,30). In some cases, the breakpoints of uncommon nonrecurrent deletions map to two different nonhomologous LCRs (e.g., SMS-REP and LCR17pA), indicating that they do not mediate the rearrangement by acting as homologous recombination substrates. However, genome architecture may stimulate rearrangements with nonrecurrent breakpoints, supporting the notion that chromosomal rearrangements are not random events but rather reflect structural features of the human genome.

A class of uncommon deletions were recurrent with breakpoints mapping to homologous LCRs. We identified a recombination hotspot within LCR17pA and LCR17pD, which serve as alternative substrates for NAHR that results in this recurrent large (approx 5 Mb) SMS deletion in 17p11.2 (29). Using polymerase chain reaction mapping of somatic cell hybrid lines, the breakpoints of six deletions within these LCRs were determined. Sequence analysis of the recombinant junctions revealed that all six strand exchanges occurred within a 524-bp interval, and four of them occurred within an AluSq/x element. This interval represents only 0.5% of the 124-kb stretch of 98.6% sequence identity between LCR17pA and LCR17pD. These findings indicate that alternative LCRs can mediate rearrangements, resulting in haploinsufficiency of the SMS critical region, and reimplicate homologous recombination as a major mechanism for genomic disorders (29).

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