Genome Architecture Catalyzes Nonrecurrent Chromosomal Rearrangements

Abstract

To investigate the potential involvement of genome architecture in nonrecurrent chromosome rearrangements, we analyzed the breakpoints of eight translocations and 18 unusual-sized deletions involving human proximal 17p. Surprisingly, we found that many deletion breakpoints occurred in low-copy repeats (LCRs); 13 were associated with novel large LCR17p structures, and 2 mapped within an LCR sequence (middle SMS-REP) within the Smith-Magenis syndrome (SMS) common deletion. Three translocation breakpoints involving 17p11 were found to be located within the centromeric alpha-satellite sequence D17Z1, three within a pericentromeric segment, and one at the distal SMS-REP. Remarkably, our analysis reveals that LCRs constitute >23% of the analyzed genome sequence in proximal 17p--an experimental observation two- to fourfold higher than predictions based on virtual analysis of the genome. Our data demonstrate that higher-order genomic architecture involving LCRs plays a significant role not only in recurrent chromosome rearrangements but also in translocations and unusual-sized deletions involving 17p.

Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males

“…44,45 In a similar manner, nonrecurrent rearrangements may also have predisposing features in the local genome. 46,47 Segmental duplications or low-copy repeats (LCRs) have been implicated in the cause of chromosomal rearrangements that are associated with several genomic disorders. 24,48 Some of these repeats have the potential to form cruciform structures that are highly susceptible to doublestrand breaks, which could initiate recombination events leading to duplications within Xq28.…”

Characterisation of a non-recurrent familial translocation t(7;9)(q11.23;p24.3) points to a recurrent involvement of the Williams–Beuren syndrome region in chromosomal rearrangements

“…Besides known genes, predicted genes, repeats and GC%, low copy repeats (LCRs) have been added according to the Duplication in Human Genome browser (assembly July 2003; http://tcag.ca/index.php?pagename=tcagDatabases.php). The dotted lines in both a and b delimit the genomic intervals covering the breakpoint regions on chromosomes 7 and 9, respectively end of the distal SMS-REP on chromosome 17 (Stankiewicz et al 2003). The involvement of LCRs in the origin of common and uncommon deletions/duplications has been demonstrated for several regions and a role for LCRs in stimulating recurrent and non-recurrent translocation has been suggested (Stankiewicz et al 2003).…”

“…It is well known that recurrent deletions, duplications and inversions are caused mainly by non-allelic homologous recombination (NAHR), mediated by low copy repeats (LCRs) (Lupski 1998;Stankiewicz and Lupski 2002), while AT-rich repeats (Kurahashi et al 2003), fragile sites (Stankiewicz and Lupski 2002) and specific Alu repeats (Hill et al 2000) are often involved in recurrent translocations. Other than these features, the molecular mechanisms underlying non-recurrent chromosomal rearrangements are often unknown or are simply called ''mediated by random events'', even if some of them seem to reflect susceptibility to DNA rearrangements stimulated by genomic architecture (Inoue et al 2002;Stankiewicz et al 2003). Evidence for the involvement of LCR-rich regions in both recurrent segmental aneusomies and recurrent or non-recurrent translocations has been reported for chromosomal regions 17p11.2-p12, 22q11 and 7q11.23 (Stankiewicz et al 2003;Hill et al 2000;Morris et al 1993;von Dadelszen et al 2000;Duba et al 2002).…”

“…Other than these features, the molecular mechanisms underlying non-recurrent chromosomal rearrangements are often unknown or are simply called ''mediated by random events'', even if some of them seem to reflect susceptibility to DNA rearrangements stimulated by genomic architecture (Inoue et al 2002;Stankiewicz et al 2003). Evidence for the involvement of LCR-rich regions in both recurrent segmental aneusomies and recurrent or non-recurrent translocations has been reported for chromosomal regions 17p11.2-p12, 22q11 and 7q11.23 (Stankiewicz et al 2003;Hill et al 2000;Morris et al 1993;von Dadelszen et al 2000;Duba et al 2002). It is worth noting that 17p11.2-p12 LCRs are implicated in the deletion causing Smith-Magenis [SMS (MIM 182290)] and hereditary neuropathy with liability to pressure palsies [HNPP (MIM 162500)] (Chen et al 1997;Reiter et al 1996), and in the duplication of the same region causing Charcot-Marie-Tooth type 1A (CMT1A [MIM 118220]) and dup(17)(p11.2p11.2) syndrome (Chance et al 1994;Potocki et al 2000).…”

Interphase FISH screening for the LCR-mediated common rearrangement of isochromosome 17q in primary myelofibrosis

“…LCRs are not distributed evenly throughout the genome. In proximal 17p, for example, LCRs account for more than 23% of the genomic sequence, making this region a hotspot for NAHR [8]. Among the well-studied constitutional genomic disorders and rearrangements caused by LCRs in proximal 17p are the Charcot-Marie-Tooth disease type 1A duplication [9] and its reciprocal deletion, identified in patients with hereditary neuropathy with liability pressure palsies [10], and the SmithMagenis syndrome deletion and its reciprocal duplication, dup(17)(p11.2 p11.2) [11,12].…”