Abstract
BackgroundSegmental duplications (SDs) on 22q11.2 (LCR22), serve as substrates for meiotic non-allelic homologous recombination (NAHR) events resulting in several clinically significant genomic disorders.ResultsTo understand the duplication activity leading to the complicated SD structure of this region, we have applied the A-Bruijn graph algorithm to decompose the 22q11.2 SDs to 523 fundamental duplication sequences, termed subunits. Cross-species syntenic analysis of primate genomes demonstrates that many of these LCR22 subunits emerged very recently, especially those implicated in human genomic disorders. Some subunits have expanded more actively than others, and young Alu SINEs, are associated much more frequently with duplicated sequences that have undergone active expansion, confirming their role in mediating recombination events. Many copy number variations (CNVs) exist on 22q11.2, some flanked by SDs. Interestingly, two chromosome breakpoints for 13 CNVs (mean length 65 kb) are located in paralogous subunits, providing direct evidence that SD subunits could contribute to CNV formation. Sequence analysis of PACs or BACs identified extra CNVs, specifically, 10 insertions and 18 deletions within 22q11.2; four were more than 10 kb in size and most contained young AluYs at their breakpoints.ConclusionsOur study indicates that AluYs are implicated in the past and current duplication events, and moreover suggests that DNA rearrangements in 22q11.2 genomic disorders perhaps do not occur randomly but involve both actively expanded duplication subunits and Alu elements.
Highlights
Segmental duplications (SDs) on 22q11.2 (LCR22), serve as substrates for meiotic non-allelic homologous recombination (NAHR) events resulting in several clinically significant genomic disorders
We began by surveying the content and extent of duplications within the 22q11.2 region using SDs with sequence identity ≥ 90% and length ≥ 1 kb that have been annotated by Dr Eichler’s group through Whole Genome Assembly Comparison (WGAC) and Whole Genome Shotgun Sequences Detection (WSSD) [1,2]
We show that most of the breakpoints are at the ends, while a subset in the middle of Alu elements, suggesting that homology based alignment is essential for copy number variation (CNV) and SD formation, but likely there two distinct molecular mechanisms responsible, L1 endonuclease-mediated retrotransposition and NAHR events [14]. These results suggest that de novo and disease-implicated recombination events between LCR22-2 and LCR22-4 may not occur randomly but more frequently at Alu-embedding subsequences, an interesting hypothesis deserving of further investigation in the future
Summary
Segmental duplications (SDs) on 22q11.2 (LCR22), serve as substrates for meiotic non-allelic homologous recombination (NAHR) events resulting in several clinically significant genomic disorders. Characterization of the genomic sequence within and near LCR22s demonstrated that both Alu repeat elements and AT-rich repeats were enriched and likely involved in many of the past unequal crossover duplications that have shuffled DNAs among blocks and given rise to the current complex genomic architecture of LCR22s [14]. This is consistent with findings from genome-wide analyses of human SDs [15,16]
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