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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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The mosaic architecture of segmental duplications in the human 22q11.2 region. (A) Duplicated subunits, genes and pseudogenes. The 22q11.2 region is depicted as a grey line and colored boxes for unique and SD sequences, respectively. Eight duplicated blocks are labelled with red arrow lines for current boundary definition (Table 1) and blue arrow lines for the previous definition [14]. Paralogous subunits (i.e., in the same subunit family) are shown with same color. For simplification, both genes (green) and pseudogenes (purple) were drawn without names. (B) Hierarchy of non-overlapping duplicated loci. A total of 33 groups of duplication loci in 22q11.2 were identified and all loci were aligned to the largest locus of their corresponding groups (all subunits have the same color as in Figure 2A). Horizontal order shows relative chromosome locations with white spaces added to separate sequences in distinct duplication groups. Arrows point to paralogous subunits at the breakpoints of recurrent (> 5) duplications; numbers below them are the total subunits at breakpoints and subsets with Alu elements. A gap in LCR22-3a' was represented by a dash line with 'N'.
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Figure 2: The mosaic architecture of segmental duplications in the human 22q11.2 region. (A) Duplicated subunits, genes and pseudogenes. The 22q11.2 region is depicted as a grey line and colored boxes for unique and SD sequences, respectively. Eight duplicated blocks are labelled with red arrow lines for current boundary definition (Table 1) and blue arrow lines for the previous definition [14]. Paralogous subunits (i.e., in the same subunit family) are shown with same color. For simplification, both genes (green) and pseudogenes (purple) were drawn without names. (B) Hierarchy of non-overlapping duplicated loci. A total of 33 groups of duplication loci in 22q11.2 were identified and all loci were aligned to the largest locus of their corresponding groups (all subunits have the same color as in Figure 2A). Horizontal order shows relative chromosome locations with white spaces added to separate sequences in distinct duplication groups. Arrows point to paralogous subunits at the breakpoints of recurrent (> 5) duplications; numbers below them are the total subunits at breakpoints and subsets with Alu elements. A gap in LCR22-3a' was represented by a dash line with 'N'.

Mentions: It is well known that DNA duplications can lead to new copies of genes or create pseudogenes [17,18]; and both genes [1] and pseudogenes [19] are enriched within SDs. Using the most recent and comprehensive data from the ENCODE gene annotation group [20], we have surveyed the pseudogene and gene content on 22q11.2 (Figure 2A). Overall, the SD regions of 22q11.2 were enriched with about three times more pseudogenes than non-SD regions, as 6% and 2% of the base pairs in the two regions were annotated as pseudogenic, respectively (p < 0.001). The percentages of base pairs corresponding to coding exons, however, were more similar (6% in SD vs 8% in the unique regions). These numbers are higher than average for the human genome, which reflect the known enrichment of genes in 22q11.2.


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)

The mosaic architecture of segmental duplications in the human 22q11.2 region. (A) Duplicated subunits, genes and pseudogenes. The 22q11.2 region is depicted as a grey line and colored boxes for unique and SD sequences, respectively. Eight duplicated blocks are labelled with red arrow lines for current boundary definition (Table 1) and blue arrow lines for the previous definition [14]. Paralogous subunits (i.e., in the same subunit family) are shown with same color. For simplification, both genes (green) and pseudogenes (purple) were drawn without names. (B) Hierarchy of non-overlapping duplicated loci. A total of 33 groups of duplication loci in 22q11.2 were identified and all loci were aligned to the largest locus of their corresponding groups (all subunits have the same color as in Figure 2A). Horizontal order shows relative chromosome locations with white spaces added to separate sequences in distinct duplication groups. Arrows point to paralogous subunits at the breakpoints of recurrent (> 5) duplications; numbers below them are the total subunits at breakpoints and subsets with Alu elements. A gap in LCR22-3a' was represented by a dash line with 'N'.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: The mosaic architecture of segmental duplications in the human 22q11.2 region. (A) Duplicated subunits, genes and pseudogenes. The 22q11.2 region is depicted as a grey line and colored boxes for unique and SD sequences, respectively. Eight duplicated blocks are labelled with red arrow lines for current boundary definition (Table 1) and blue arrow lines for the previous definition [14]. Paralogous subunits (i.e., in the same subunit family) are shown with same color. For simplification, both genes (green) and pseudogenes (purple) were drawn without names. (B) Hierarchy of non-overlapping duplicated loci. A total of 33 groups of duplication loci in 22q11.2 were identified and all loci were aligned to the largest locus of their corresponding groups (all subunits have the same color as in Figure 2A). Horizontal order shows relative chromosome locations with white spaces added to separate sequences in distinct duplication groups. Arrows point to paralogous subunits at the breakpoints of recurrent (> 5) duplications; numbers below them are the total subunits at breakpoints and subsets with Alu elements. A gap in LCR22-3a' was represented by a dash line with 'N'.
Mentions: It is well known that DNA duplications can lead to new copies of genes or create pseudogenes [17,18]; and both genes [1] and pseudogenes [19] are enriched within SDs. Using the most recent and comprehensive data from the ENCODE gene annotation group [20], we have surveyed the pseudogene and gene content on 22q11.2 (Figure 2A). Overall, the SD regions of 22q11.2 were enriched with about three times more pseudogenes than non-SD regions, as 6% and 2% of the base pairs in the two regions were annotated as pseudogenic, respectively (p < 0.001). The percentages of base pairs corresponding to coding exons, however, were more similar (6% in SD vs 8% in the unique regions). These numbers are higher than average for the human genome, which reflect the known enrichment of genes in 22q11.2.

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