Characterization of the past and current duplication activities in the human 22q11.2 region

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.

Unmasking of a Recessive SCARF2 Mutation by a 22q11.12 de novo Deletion in a Patient with Van den Ende-Gupta Syndrome

“…Thus the deletion corresponds to the common DiGeorge/ VCFS '3-Mb' deletion between low copy repeats LCR-A (LCR22-2) and LCR-D (LCR22-4) [Rauch et al, 2005;Guo et al, 2011]. To confirm the array data, a second array-CGH experiment was performed in the patient and parents.…”

22q11.2 Microduplication syndrome and epilepsy with continuous spikes and waves during sleep (CSWS). A case report and review of the literature

“…The mechanisms by which such chromosomal rearrangement leads to epilepsy remain, however, unsettled. Low copy repeats on 22q11.2 (LCRs22) and Alu elements [33] serve as substrates for meiotic NAHR events resulting in clinically significant genomic disorders, such as DiGeorge/ Velo-cardio-facial or 22q11.2 microduplication syndromes. Patients having 22q11.2 microduplication syndrome and epilepsy frequently harbor duplications between LCRs 22E and 22G, leading to the hypothesis that one or more epileptogenic genes are present in that duplicated region [13].…”

Modeling a model: Mouse genetics, 22q11.2 Deletion Syndrome, and disorders of cortical circuit development

“…Instead of crossovers occurring between homologous regions of chromosome pairs, non-homologous regions align (often along non-allelic, homologous SDs) and recombine, resulting in inappropriate splicing of chromosomal DNA. Deletion or duplication of segments of genes result from these NAHR-related recombination events, including the deletions and rare duplications associated with 22q11DS (Guo et al, 2011c). In 22q11DS, the typically deleted region contains four major SDs, referred to as LCR A-D.…”