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

Guo X, Freyer L, Morrow B, Zheng D - BMC Genomics (2011)

Bottom Line: 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.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.Our 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

ABSTRACT

Background: 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.

Results: To 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.

Conclusions: Our 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.

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Distribution of BAC and other genomic clones and CNVs derived from them. A total of 191 clones were mapped to the 22q11.2 region in the human reference genome, resulting 28 CNVs (blue for gain and red for loss). Only clones with CNVs are shown here to simplify the figure. Coordinates of these CNVs are available in Table 3.
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Figure 6: Distribution of BAC and other genomic clones and CNVs derived from them. A total of 191 clones were mapped to the 22q11.2 region in the human reference genome, resulting 28 CNVs (blue for gain and red for loss). Only clones with CNVs are shown here to simplify the figure. Coordinates of these CNVs are available in Table 3.

Mentions: In addition to publicly available CNV data, we have employed a BAC/PAC clone mapping approach to uncover CNVs on 22q11.2. We collected DNA sequence from 191 large insert clones, cosmids, PACs and BACs, from GenBank, and their alignment to the reference 22q11.2 sequence revealed 10 insertions and 18 deletions of sizes > 200 bp (Figure 6; Table 3). Four of these CNVs were more than 10 kb in size, one 11.9 kb insertion, and the other three were 25.9 kb, 37.1 kb and 54.3 kb deletions (Table 3). A total of 11 of the remaining CNVs were relatively small (< 1 kb), whereas 13 of them were intermediate in length (1 ~10 kb). Moreover, 19 and nine of these CNVs (p < 0.001) were in the duplicated and unique regions, respectively, providing additional line of evidence that SDs show significant genetic variation.


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

Guo X, Freyer L, Morrow B, Zheng D - BMC Genomics (2011)

Distribution of BAC and other genomic clones and CNVs derived from them. A total of 191 clones were mapped to the 22q11.2 region in the human reference genome, resulting 28 CNVs (blue for gain and red for loss). Only clones with CNVs are shown here to simplify the figure. Coordinates of these CNVs are available in Table 3.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3040729&req=5

Figure 6: Distribution of BAC and other genomic clones and CNVs derived from them. A total of 191 clones were mapped to the 22q11.2 region in the human reference genome, resulting 28 CNVs (blue for gain and red for loss). Only clones with CNVs are shown here to simplify the figure. Coordinates of these CNVs are available in Table 3.
Mentions: In addition to publicly available CNV data, we have employed a BAC/PAC clone mapping approach to uncover CNVs on 22q11.2. We collected DNA sequence from 191 large insert clones, cosmids, PACs and BACs, from GenBank, and their alignment to the reference 22q11.2 sequence revealed 10 insertions and 18 deletions of sizes > 200 bp (Figure 6; Table 3). Four of these CNVs were more than 10 kb in size, one 11.9 kb insertion, and the other three were 25.9 kb, 37.1 kb and 54.3 kb deletions (Table 3). A total of 11 of the remaining CNVs were relatively small (< 1 kb), whereas 13 of them were intermediate in length (1 ~10 kb). Moreover, 19 and nine of these CNVs (p < 0.001) were in the duplicated and unique regions, respectively, providing additional line of evidence that SDs show significant genetic variation.

Bottom Line: 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.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.Our 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

ABSTRACT

Background: 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.

Results: To 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.

Conclusions: Our 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.

Show MeSH
Related in: MedlinePlus