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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

A schematic cartoon for the decomposition of segmental duplications into duplication subunits and the construction of map for putative duplication events. (A) Five hypothetical duplication loci (a-e) are depicted with their duplication history shown below. Note that in real cases the historical duplication directions can only be inferred as duplications occurred in the past and are actually invisible. (B) The segmental duplication data for these five loci are represented by seven pairs of duplicons (boxes connected by dash lines). A total of 202 such pairs exist for 22q11.2 based on sequence comparison. (C) Fifteen duplication subunits (forming six paralogous families) decomposed from the pair-wise alignment information in B. (D) The five duplication loci are grouped and all loci are then aligned to the "a" locus, which is the largest one. Note that the entire locus "a" has to be derived from the merge of left duplicons in SD1 and SD2. 33 such duplication groups were defined for 22q11.2, containing 174 duplication loci (see Figure 2B).
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Figure 1: A schematic cartoon for the decomposition of segmental duplications into duplication subunits and the construction of map for putative duplication events. (A) Five hypothetical duplication loci (a-e) are depicted with their duplication history shown below. Note that in real cases the historical duplication directions can only be inferred as duplications occurred in the past and are actually invisible. (B) The segmental duplication data for these five loci are represented by seven pairs of duplicons (boxes connected by dash lines). A total of 202 such pairs exist for 22q11.2 based on sequence comparison. (C) Fifteen duplication subunits (forming six paralogous families) decomposed from the pair-wise alignment information in B. (D) The five duplication loci are grouped and all loci are then aligned to the "a" locus, which is the largest one. Note that the entire locus "a" has to be derived from the merge of left duplicons in SD1 and SD2. 33 such duplication groups were defined for 22q11.2, containing 174 duplication loci (see Figure 2B).

Mentions: To understand the duplication architecture of LCR22 and more importantly to gain insight to the molecular mechanism behind high incidence of pathogenic LCR22 rearrangements causing human congenital malformation syndromes, we have applied A-Bruijn graph algorithm to decompose the LCR22 architecture to fundamental duplication subunits at nucleotide-level resolution, without any bias to either genes or pseudogenes as was in the case of previous studies focused on LCR22s that are mentioned above (Figure 1). Our study moreover found unexpectedly high genetic variation between and within SDs, indicating them as highly dynamic in the genome. This is supported by the fact that many subunit copies emerged recently, at either the human or the African great ape lineage, through both small and large-scale duplications. Highly active subunits were found with significant enrichment of AluY, a young short interspersed nuclear element (SINE), at their ends or short adjacent sequences. This repeat and some subunits associated with it, continue to actively mediate CNV generation in human LCR22 region. These CNVs could alter risk to genomic disorders on 22q11.2 by making them better or worse substrates for meiotic recombination.


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)

A schematic cartoon for the decomposition of segmental duplications into duplication subunits and the construction of map for putative duplication events. (A) Five hypothetical duplication loci (a-e) are depicted with their duplication history shown below. Note that in real cases the historical duplication directions can only be inferred as duplications occurred in the past and are actually invisible. (B) The segmental duplication data for these five loci are represented by seven pairs of duplicons (boxes connected by dash lines). A total of 202 such pairs exist for 22q11.2 based on sequence comparison. (C) Fifteen duplication subunits (forming six paralogous families) decomposed from the pair-wise alignment information in B. (D) The five duplication loci are grouped and all loci are then aligned to the "a" locus, which is the largest one. Note that the entire locus "a" has to be derived from the merge of left duplicons in SD1 and SD2. 33 such duplication groups were defined for 22q11.2, containing 174 duplication loci (see Figure 2B).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: A schematic cartoon for the decomposition of segmental duplications into duplication subunits and the construction of map for putative duplication events. (A) Five hypothetical duplication loci (a-e) are depicted with their duplication history shown below. Note that in real cases the historical duplication directions can only be inferred as duplications occurred in the past and are actually invisible. (B) The segmental duplication data for these five loci are represented by seven pairs of duplicons (boxes connected by dash lines). A total of 202 such pairs exist for 22q11.2 based on sequence comparison. (C) Fifteen duplication subunits (forming six paralogous families) decomposed from the pair-wise alignment information in B. (D) The five duplication loci are grouped and all loci are then aligned to the "a" locus, which is the largest one. Note that the entire locus "a" has to be derived from the merge of left duplicons in SD1 and SD2. 33 such duplication groups were defined for 22q11.2, containing 174 duplication loci (see Figure 2B).
Mentions: To understand the duplication architecture of LCR22 and more importantly to gain insight to the molecular mechanism behind high incidence of pathogenic LCR22 rearrangements causing human congenital malformation syndromes, we have applied A-Bruijn graph algorithm to decompose the LCR22 architecture to fundamental duplication subunits at nucleotide-level resolution, without any bias to either genes or pseudogenes as was in the case of previous studies focused on LCR22s that are mentioned above (Figure 1). Our study moreover found unexpectedly high genetic variation between and within SDs, indicating them as highly dynamic in the genome. This is supported by the fact that many subunit copies emerged recently, at either the human or the African great ape lineage, through both small and large-scale duplications. Highly active subunits were found with significant enrichment of AluY, a young short interspersed nuclear element (SINE), at their ends or short adjacent sequences. This repeat and some subunits associated with it, continue to actively mediate CNV generation in human LCR22 region. These CNVs could alter risk to genomic disorders on 22q11.2 by making them better or worse substrates for meiotic recombination.

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