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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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Related in: MedlinePlus

Subunit family spreading in multiple LCR22' blocks is often adjacent to Alu repeats. (A) The SD subunits were assigned to different layers of circles, whereas the numbers represent the total blocks in which a subunit family has one or more members. For example, a subunit family is given 3 if its members are found in 3 of the 8 blocks, and consequently all subunits of this family will be drawn in the circle labeled with "3". (B) Relationship between selected sequence features and block occupancy for SD subunits. The x-axis describes the number of blocks a subunit family occupies (A). The y-axis shows the percentage of subunit endpoints with a given sequence feature. No subunit family was found in and only in five blocks.
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Figure 4: Subunit family spreading in multiple LCR22' blocks is often adjacent to Alu repeats. (A) The SD subunits were assigned to different layers of circles, whereas the numbers represent the total blocks in which a subunit family has one or more members. For example, a subunit family is given 3 if its members are found in 3 of the 8 blocks, and consequently all subunits of this family will be drawn in the circle labeled with "3". (B) Relationship between selected sequence features and block occupancy for SD subunits. The x-axis describes the number of blocks a subunit family occupies (A). The y-axis shows the percentage of subunit endpoints with a given sequence feature. No subunit family was found in and only in five blocks.

Mentions: As shown in Figure 2, most duplication events involved in short sequences. We thus decided to investigate to what degree such small duplications have contributed to the mosaic duplication patterns of SDs in 22q11.2 and sequence shuffling between LCR22 blocks. The majority of subunit families (69%) had paralogs presence in two to four blocks, which seemed to be mostly a result of recent inter-block duplication among LCR22-2', LCR22-3' and LCR22-4' (Figure 4A). The subunit families in LCR22-2', -3', -4', -6' and -8' were quite active as more than 95% of their subunits had paralogs in other blocks. In contrast, 70% and 80% of the subunits in LCR22-5' and LCR22-7', respectively, existed as intra-block duplications (Figure 4A). Syntenic sequences to the tandem subunits of LCR22-7' were found in the genomes of chimpanzee and orangutan but not macaque (Figure 3), indicating the underlying duplication events occurred ~25 million years ago. Interestingly, 39 families occupied only in a single block, indicating their expansion was largely a result of local and potentially tandem duplications.


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)

Subunit family spreading in multiple LCR22' blocks is often adjacent to Alu repeats. (A) The SD subunits were assigned to different layers of circles, whereas the numbers represent the total blocks in which a subunit family has one or more members. For example, a subunit family is given 3 if its members are found in 3 of the 8 blocks, and consequently all subunits of this family will be drawn in the circle labeled with "3". (B) Relationship between selected sequence features and block occupancy for SD subunits. The x-axis describes the number of blocks a subunit family occupies (A). The y-axis shows the percentage of subunit endpoints with a given sequence feature. No subunit family was found in and only in five blocks.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Subunit family spreading in multiple LCR22' blocks is often adjacent to Alu repeats. (A) The SD subunits were assigned to different layers of circles, whereas the numbers represent the total blocks in which a subunit family has one or more members. For example, a subunit family is given 3 if its members are found in 3 of the 8 blocks, and consequently all subunits of this family will be drawn in the circle labeled with "3". (B) Relationship between selected sequence features and block occupancy for SD subunits. The x-axis describes the number of blocks a subunit family occupies (A). The y-axis shows the percentage of subunit endpoints with a given sequence feature. No subunit family was found in and only in five blocks.
Mentions: As shown in Figure 2, most duplication events involved in short sequences. We thus decided to investigate to what degree such small duplications have contributed to the mosaic duplication patterns of SDs in 22q11.2 and sequence shuffling between LCR22 blocks. The majority of subunit families (69%) had paralogs presence in two to four blocks, which seemed to be mostly a result of recent inter-block duplication among LCR22-2', LCR22-3' and LCR22-4' (Figure 4A). The subunit families in LCR22-2', -3', -4', -6' and -8' were quite active as more than 95% of their subunits had paralogs in other blocks. In contrast, 70% and 80% of the subunits in LCR22-5' and LCR22-7', respectively, existed as intra-block duplications (Figure 4A). Syntenic sequences to the tandem subunits of LCR22-7' were found in the genomes of chimpanzee and orangutan but not macaque (Figure 3), indicating the underlying duplication events occurred ~25 million years ago. Interestingly, 39 families occupied only in a single block, indicating their expansion was largely a result of local and potentially tandem duplications.

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