Shuffling of Genes Within Low-Copy Repeats on 22q11 (LCR22) by Alu-Mediated Recombination Events During Evolution

Abstract

Low-copy repeats, or segmental duplications, are highly dynamic regions in the genome. The low-copy repeats on chromosome 22q11.2 (LCR22) are a complex mosaic of genes and pseudogenes formed by duplication processes; they mediate chromosome rearrangements associated with velo-cardio-facial syndrome/DiGeorge syndrome, der (22) syndrome, and cat-eye syndrome. The ability to trace the substrates and products of recombination events provides a unique opportunity to identify the mechanisms responsible for shaping LCR22s. We examined the genomic sequence of known LCR22 genes and their duplicated derivatives. We found Alu (SINE) elements at the breakpoints in the substrates and at the junctions in the truncated products of recombination for USP18, GGT, and GGTLA, consistent with Alu-mediated unequal crossing-over events. In addition, we were able to trace a likely interchromosomal Alu-mediated fusion between IGSF3 on 1p13.1 and GGT on 22q11.2. Breakpoints occurred inside Alu elements as well as in the 5Ј or 3Ј ends of them. A possible stimulus for the 5Ј or 3Ј terminal rearrangements may be the high sequence similarities between different Alu elements, combined with a potential recombinogenic role of retrotransposon target-site duplications flanking the Alu element, containing potentially kinkable DNA sites. Such sites may represent focal points for recombination. Thus, genome shuffling by Alu-mediated rearrangements has contributed to genome architecture during primate evolution.

Molecular characterization of deletion breakpoints in adults with 22q11 deletion syndrome

“…The high density of LCRs and other repetitive sequences in 22q11.2 make this the region of the human genome most prone to rearrangements (Babcock et al 2003). Breakpoints outside of LCRs may be mediated by other repeat elements present in the 22q11.2 region, likely including Alu elements which are known to play a role in modulating genomic architecture (Babcock et al 2003;Shaw and Lupski 2005). Our results support the recurrence of breakpoints in specific regions of 22q11.2 but not necessarily in specific sites containing LCRs in 22q11.…”

“…However, for variant ~3 Mb deletions, such as that with a telomeric distal breakpoint flanked by HIC2 and UBE2L3, it is unclear whether LCRs or other repeat elements are involved. The high density of LCRs and other repetitive sequences in 22q11.2 make this the region of the human genome most prone to rearrangements (Babcock et al 2003). Breakpoints outside of LCRs may be mediated by other repeat elements present in the 22q11.2 region, likely including Alu elements which are known to play a role in modulating genomic architecture (Babcock et al 2003;Shaw and Lupski 2005).…”

FISH of supernumerary marker chromosomes (SMCs) identifies six diagnostically relevant intervals on chromosome 22q and a novel type of bisatellited SMC(22)

“…These data are in line with the molecular data placing the breakpoint at the LCR-A (between D22S427 and D22S36) 9,25 and correspond to the recently defined LCR22-3a (17.248 -17.433 Mb). 26 We detected only one larger (type II) CES chromosome (patient 6), a low rate not reported elsewhere. 8,9 Our data place the distal breakpoint of the type II CES chromosome between markers HCF2 (19.466 Mb) and BCR1 (21.847 Mb), matching the molecular positions of the LCR-D (between CRKL and D22S112) 9,25 and the LCR22-6 (20.347 -20.529 Mb).…”

Inviting instability: Transposable elements, double-strand breaks, and the maintenance of genome integrity

“…This allows for possible further cleavage of these target sites by subsequent endonuclease visits (Figure 4). This "revisitation" of target sites by L1 endonucleases, as well as its potential consequences for instability, was initially proposed in conjunction with Alu-mediated low-copy repeat shuffling on chromosome 22q11 [92]. Further support was provided through subsequent bioinformatic analyses, which indicated that in both the human and rodent lineages, SINE elements flanked by perfect (i.e.…”

“…Further support was provided through subsequent bioinformatic analyses, which indicated that in both the human and rodent lineages, SINE elements flanked by perfect (i.e. nonmutated) L1 endonuclease consensus sites were more rapidly lost from the genome [92]. Although it should be noted that a similar analysis for dog SINEs failed to show this effect; there are, however, indications that SINE/LINE dynamics in the dog differ significantly in key ways from those of humans and rodents [93].…”