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

Department of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
BMC Genomics (Impact Factor: 3.99). 01/2011; 12(1):71. DOI: 10.1186/1471-2164-12-71
Source: PubMed


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.
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.
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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Available from: Laina Freyer, Oct 28, 2015
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    • "However, only ~12% of all human duplications resulted from misalignment of two repeat elements [22], refuting the importance of repeat sequences in the production of duplications. Alu repeats are preferentially associated with actively duplicating clusters on human chromosome 22 [24], suggesting that repeats accelerate evolution by gene duplication and thereby cause expansion and/or contraction of gene families [25]. Alu repeats have also been found associated with gene clusters on human chromosome 7 [26] and Mirs, a type of SINE repeat, are associated with an OR gene cluster on human chromosome 17 [27]. "
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    ABSTRACT: Background Retrotransposons have been suggested to provide a substrate for non-allelic homologous recombination (NAHR) and thereby promote gene family expansion. Their precise role, however, is controversial. Here we ask whether retrotransposons contributed to the recent expansions of the Androgen-binding protein (Abp) gene families that occurred independently in the mouse and rat genomes. Results Using dot plot analysis, we found that the most recent duplication in the Abp region of the mouse genome is flanked by L1Md_T elements. Analysis of the sequence of these elements revealed breakpoints that are the relicts of the recombination that caused the duplication, confirming that the duplication arose as a result of NAHR using L1 elements as substrates. L1 and ERVII retrotransposons are considerably denser in the Abp regions than in one Mb flanking regions, while other repeat types are depleted in the Abp regions compared to flanking regions. L1 retrotransposons preferentially accumulated in the Abp gene regions after lineage separation and roughly followed the pattern of Abp gene expansion. By contrast, the proportion of shared vs. lineage-specific ERVII repeats in the Abp region resembles the rest of the genome. Conclusions We confirmed the role of L1 repeats in Abp gene duplication with the identification of recombinant L1Md_T elements at the edges of the most recent mouse Abp gene duplication. High densities of L1 and ERVII repeats were found in the Abp gene region with abrupt transitions at the region boundaries, suggesting that their higher densities are tightly associated with Abp gene duplication. We observed that the major accumulation of L1 elements occurred after the split of the mouse and rat lineages and that there is a striking overlap between the timing of L1 accumulation and expansion of the Abp gene family in the mouse genome. Establishing a link between the accumulation of L1 elements and the expansion of the Abp gene family and identification of an NAHR-related breakpoint in the most recent duplication are the main contributions of our study.
    Full-text · Article · May 2013 · BMC Evolutionary Biology
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    • "Low copy repeats on 22q11.2 (LCRs22) and Alu elements [33] serve as substrates for meiotic NAHR events resulting in clinically significant genomic disorders, such as DiGeorge/ Velo-cardio-facial or 22q11.2 microduplication syndromes. "
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    ABSTRACT: Chromosome 22q11.2 microduplication syndrome is characterized by a variable and usually mild phenotype and by incomplete penetrance. Neurological features of the syndrome may entail intellectual or learning disability, motor delay, and other neurodevelopmental disorders. However, seizures or abnormal EEG are reported in a few cases. We describe a 6-year-old girl with microduplication of chromosome 22q11.2 and epilepsy with continuous spikes and waves during sleep (CSWS). Her behavioral disorder, characterized by hyperactivity, impulsiveness, attention deficit, and aggressiveness, became progressively evident a few months after epilepsy onset, suggesting a link with the interictal epileptic activity characterizing CSWS. We hypothesize that, at least in some cases, the neurodevelopmental deficit seen in the 22q11.2 microduplication syndrome could be the consequence of a disorder of cerebral electrogenesis, suggesting the need for an EEG recording in affected individuals. Moreover, an array-CGH analysis should be performed in all individuals with cryptogenic epilepsy and CSWS.
    Full-text · Article · Nov 2012 · Epilepsy & Behavior
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    • "The development of next-generation sequencing techniques has been successfully used to analyze the CNV of the whole genome [13], as well as specific LCRs; this is the case of the LCR22 of the 22q11.2 region [14]. PCR-based techniques have also allowed the quantification of the number of repeats shaping specific LCRs (7q11.23; "
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    ABSTRACT: Low-copy repeats (LCRs) constitute 5% of the human genome. LCRs act as substrates for non-allelic homologous recombination (NAHR) leading to genomic structural variation. The aim of this study was to assess the potential of Fiber-FISH for LCRs direct visualization to support investigations of genome architecture within these challenging genomic regions. We describe a set of Fiber-FISH experiments designed for the study of the LCR22-2. This LCR is involved in recurrent reorganizations causing different genomic disorders. Four fosmid clones covering the entire length of the LCR22-2 and two single-copy BAC-clones, delimiting the LCR22-2 proximally and distally, were selected. The probes were hybridized in different multiple color combinations on DNA fibers from two karyotypically normal cell lines. We were able to identify three distinct structural haplotypes characterized by differences in copy-number and arrangement of the LCR22-2 genes and pseudogenes. Our results show that Multicolor Fiber-FISH is a viable methodological approach for the analysis of genome organization within complex LCR regions.
    Full-text · Article · Aug 2012 · Genomics
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