Limits...
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.

Show MeSH

Related in: MedlinePlus

Distribution of previously annotated CNVs in the 22q11.2 region. The gain and loss CNVs collected from previous publications are shown with blue and red, respectively. The bottom row illustrates SD subunits. The figure was prepared using the UCSC browser.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3040729&req=5

Figure 5: Distribution of previously annotated CNVs in the 22q11.2 region. The gain and loss CNVs collected from previous publications are shown with blue and red, respectively. The bottom row illustrates SD subunits. The figure was prepared using the UCSC browser.

Mentions: SDs are a major source of genome instability and they have been suggested to play an important role in the etiology of copy number variations (CNVs), but the extent and features of CNVs in 22q11.2 have not been characterized to date. To explore this, we obtained all previously annotated human CNVs and overlaid them on our map of 22q11.2 SD subunits. Due to the high sequence identity of 22q11.2 SDs, which may cause cross-hybridization signals, we only considered genome-wide CNVs detected using relatively high-resolution technology (either using microarray with short probes or based on direct sequencing). We collected 452 CNVs from previous studies (69 gains and 72 losses > 460 bp [31]; 133 gains and 178 losses > 1 kb [32]; and other CNVs obtained from the Database of Genome Variants based on either paired-end fosmid clone mapping or individual personal genomes) (Figure 5). Respectively, these CNVs were enriched in SDs by two-fold vs non-SD region of 22q11.2. Further examination found that the two breakpoints for 13 of these CNVs (mean length 65 kb) were located to the same duplication subunit family (i.e., paralogous subunits), providing direct evidence that some pairs of paralogous subunits could indeed mediate CNV formation by NAHR (Table 2). Interestingly, 12 of these 13 CNVs were deletions. More surprisingly, except one in LCR22-2', all SD-overlapping CNVs were located to either LCR22-5' or LCR22-7' regions (Figure 5), where paralogous subunits frequently exist in tandem.


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 previously annotated CNVs in the 22q11.2 region. The gain and loss CNVs collected from previous publications are shown with blue and red, respectively. The bottom row illustrates SD subunits. The figure was prepared using the UCSC browser.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Distribution of previously annotated CNVs in the 22q11.2 region. The gain and loss CNVs collected from previous publications are shown with blue and red, respectively. The bottom row illustrates SD subunits. The figure was prepared using the UCSC browser.
Mentions: SDs are a major source of genome instability and they have been suggested to play an important role in the etiology of copy number variations (CNVs), but the extent and features of CNVs in 22q11.2 have not been characterized to date. To explore this, we obtained all previously annotated human CNVs and overlaid them on our map of 22q11.2 SD subunits. Due to the high sequence identity of 22q11.2 SDs, which may cause cross-hybridization signals, we only considered genome-wide CNVs detected using relatively high-resolution technology (either using microarray with short probes or based on direct sequencing). We collected 452 CNVs from previous studies (69 gains and 72 losses > 460 bp [31]; 133 gains and 178 losses > 1 kb [32]; and other CNVs obtained from the Database of Genome Variants based on either paired-end fosmid clone mapping or individual personal genomes) (Figure 5). Respectively, these CNVs were enriched in SDs by two-fold vs non-SD region of 22q11.2. Further examination found that the two breakpoints for 13 of these CNVs (mean length 65 kb) were located to the same duplication subunit family (i.e., paralogous subunits), providing direct evidence that some pairs of paralogous subunits could indeed mediate CNV formation by NAHR (Table 2). Interestingly, 12 of these 13 CNVs were deletions. More surprisingly, except one in LCR22-2', all SD-overlapping CNVs were located to either LCR22-5' or LCR22-7' regions (Figure 5), where paralogous subunits frequently exist in tandem.

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