Break-induced replication underlies formation of inverted triplications and generates unexpected diversity in haplotype structures
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE250451 | GEO | 2023/12/18
REPOSITORIES: GEO
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Project description:Inverted repeats (IRs) can facilitate structural variation as crucibles of genomic rearrangement. Complex DUP-TRP/INV-DUP rearrangements that contain breakpoint junctions within IRs have been recently associated with both MECP2 duplication syndrome (MIM#300260) and Pelizaeus-Merzbacher disease (PMD, MIM#312080). We investigated 17 unrelated PMD subjects with copy number gains at the PLP1 locus including triplication and quadruplication of specific genomic intervals – 16/17 were found to have a DUP-TRP/INV-DUP rearrangement product. An IR distal to PLP1 facilitates DUP-TRP/INV-DUP formation as well as an inversion structural variation found frequently amongst normal individuals. We show that a homology—or homeology—driven replicative mechanism of DNA repair can apparently mediate template switches within stretches of microhomology. Moreover, we provide evidence that quadruplication, and potentially higher order amplification of a genomic interval, can occur in a manner consistent with rolling circle amplification as predicted by the microhomology mediated break induced replication (MMBIR) model.
2014-11-25 | GSE63594 | GEO
Project description:Inverted repeats (IRs) can facilitate structural variation as crucibles of genomic rearrangement. Complex DUP-TRP/INV-DUP rearrangements that contain breakpoint junctions within IRs have been recently associated with both MECP2 duplication syndrome (MIM#300260) and Pelizaeus-Merzbacher disease (PMD, MIM#312080). We investigated 17 unrelated PMD subjects with copy number gains at the PLP1 locus including triplication and quadruplication of specific genomic intervals M-bM-^@M-^S 16/17 were found to have a DUP-TRP/INV-DUP rearrangement product. An IR distal to PLP1 facilitates DUP-TRP/INV-DUP formation as well as an inversion structural variation found frequently amongst normal individuals. We show that a homologyM-bM-^@M-^Tor homeologyM-bM-^@M-^Tdriven replicative mechanism of DNA repair can apparently mediate template switches within stretches of microhomology. Moreover, we provide evidence that quadruplication, and potentially higher order amplification of a genomic interval, can occur in a manner consistent with rolling circle amplification as predicted by the microhomology mediated break induced replication (MMBIR) model. To determine size, genomic extent and gene content for each rearrangement, we used a customized tiling-path oligonucleotide microarray spanning the Xq22 chromosomal region to query the genomic DNA of 7 males with Pelizaeus-Merzbacher disease, and 5 unaffected or carrier/unaffected family members. A 4x44k Agilent Technologies (Santa Clara, CA) microarray was designed using the Agilent e-array website targeting the region of the genome encompassing the dosage-sensitive PLP1 gene.
2014-11-25 | E-GEOD-63594 | biostudies-arrayexpress
Project description:Many loci in the human genome harbor complex genomic structures that can result in susceptibility to genomic rearrangements leading to various genomic disorders. Nephronophthisis 1 (NPHP1, MIM# 256100) is an autosomal recessive disorder that can be caused by defects of NPHP1; the gene maps within the human 2q13 region where low copy repeats (LCRs) are abundant. Loss of function of NPHP1 is responsible for approximately 85% of the NPHP1 cases - about 80% of such individuals carry a large recurrent homozygous NPHP1 deletion that occurs via non-allelic homologous recombination (NAHR) between two flanking directly oriented ~45 kb LCRs. Published data revealed a non-pathogenic inversion polymorphism involving the NPHP1 gene flanked by two inverted ~358 kb LCRs. Using optical mapping and array-comparative genomic hybridization, we identified three potential novel structural variant (SV) haplotypes at the NPHP1 locus that may protect a haploid genome from genomic instability and NPHP1 deletion. Inter-species comparative genomic analyses among primate genomes revealed massive genomic changes during evolution. The aggregated data suggest that dynamic genomic rearrangements occurred historically within the NPHP1 locus and generated SV haplotypes observed in the human population today, which may have differential susceptibility to the NPHP1 deletion within a personal genome. Our study documents diverse SV haplotypes at a complex LCR-laden human genomic region. Comparative analyses provide a model for how this complex region arose during primate evolution, and studies among humans reflect the possibility that intra-species polymorphism may potentially modulate an individual’s susceptibility to acquiring disease-associated alleles.
2015-11-30 | GSE73962 | GEO
Project description:Angelman syndrome (AS) and interstitial duplication 15q autism (int dup(15)) are reciprocal genomic disorders caused by maternal deletion or duplication of the 15q11.2-q13 region. While AS is caused by maternal loss of 15q and maternal duplications of 15q can cause autism implicating the maternally expressed UBE3A gene in these phenotypes. We investigated chromatin and gene expression changes in blood and cell lines from three int dup(15) and three reciprocal AS deletion subjects to identify global genomic and gene expression changes that may influence both the AS and autism phenotypes. Using formaldehyde-assisted isolation of regulatory elements (FAIRE) we identified 1104 regions of differential open chromatin in AS deletion and 2344 regions int dup(15) indicating changes in chromatin could influence gene expression in these regions. Microarray analysis revealed 1225 genes that were elevated in AS deletion vs int dup(15) and 976 genes that were elevated in int dup(15) vs AS deletion PBMC (pvalue<0.05). Significant differences in expression were found for genes at the 15q locus like UBE3A, ATP10A and HERC2. A larger set of genes involved in chromatin remodeling, DNA repair and neurogenesis were found, at FAIRE peaks in AS deletion samples but had increased transcription in int dup(15) samples. There was a significant enhancement for genes with FOXP1 binding sites in the int dup(15) gene set and elevated FOXP1 protein could be detected in the nucleus of int dup(15) as compared to AS deletion cell lines. This analysis provides the first insights into transcriptional changes which may unveil new sets of genes and pathways contributing to both AS and autism pathogenesis.
2014-10-09 | GSE32563 | GEO
Project description:Angelman syndrome (AS) and interstitial duplication 15q autism (int dup(15)) are reciprocal genomic disorders caused by maternal deletion or duplication of the 15q11.2-q13 region. While AS is caused by maternal loss of 15q and maternal duplications of 15q can cause autism implicating the maternally expressed UBE3A gene in these phenotypes. We investigated chromatin and gene expression changes in blood and cell lines from three int dup(15) and three reciprocal AS deletion subjects to identify global genomic and gene expression changes that may influence both the AS and autism phenotypes. Using formaldehyde-assisted isolation of regulatory elements (FAIRE) we identified 1104 regions of differential open chromatin in AS deletion and 2344 regions int dup(15) indicating changes in chromatin could influence gene expression in these regions. Microarray analysis revealed 1225 genes that were elevated in AS deletion vs int dup(15) and 976 genes that were elevated in int dup(15) vs AS deletion PBMC (pvalue<0.05). Significant differences in expression were found for genes at the 15q locus like UBE3A, ATP10A and HERC2. A larger set of genes involved in chromatin remodeling, DNA repair and neurogenesis were found, at FAIRE peaks in AS deletion samples but had increased transcription in int dup(15) samples. There was a significant enhancement for genes with FOXP1 binding sites in the int dup(15) gene set and elevated FOXP1 protein could be detected in the nucleus of int dup(15) as compared to AS deletion cell lines. This analysis provides the first insights into transcriptional changes which may unveil new sets of genes and pathways contributing to both AS and autism pathogenesis. Gene expression was performed using 100ng of total RNA from each subject as starting material for amplification and cRNA synthesis in accordance Affymetrix protocols (http://tinyurl.com/3j7dcp6). Hybridizations were performed to the Affy HumanGene_st_v1 chip and the signal data normalized using internal chip controls. Normalized expression data was then exported to a text file for subsequent expression analysis using the EXPANDER software analysis suite.
2014-10-09 | E-GEOD-32563 | biostudies-arrayexpress
Project description:gene expression profiles of lymphoblastoid cells from individuals with autism and duplication of 15q11-13 Keywords: autism with dup(15q)
2007-06-01 | GSE7315 | GEO
Project description:Mantle cell lymphoma (MCL) is a lymphoma characterized by aberrant activation of CCND1/cyclin D1 followed by sequential genetic abnormalities. Genomic abnormalities in MCL have been extensively examined by classical cytogenetics and microarray-based comparative genomic hybridization techniques, pointing out a number of alterations in genomic regions that correlate with the neoplastic phenotype and survival. Recently, single nucleotide polymorphism genomic microarrays (SNP-chip) have been developed and used for analysis of cancer genomics. This technique allows detection of genomic changes with higher resolution, including loss of heterozygosity without changes of gene dosage, so-called acquired uniparental disomy (aUPD). As a result of the analysis, known alterations were confirmed by SNP arrays, including deletion of INK4A/ARF, duplication/amplification of MYC, deletion of ATM, and deletion of TP53. We also identified a duplication/amplification that occurred at 13q involving oncogenic microRNA, miR17-92. We found other genomic abnormalities, including duplication/amplification of cyclin D1, del(1p), del(6q), dup(3q) and dup(18q). Our SNP-chip analysis detected these abnormalities at high resolution, allowing us to narrow the size of the commonly deleted regions, including 1p and 6q. Our SNP-chip analysis detected a number of aUPD sites, including whole chromosome 9 aUPD and 9p aUPD. We also found an MCL case with 19p, leading to homozygous deletion of TNFSF genes. keyword: SNP-chip; Kawmata_MCL
2009-11-13 | GSE18820 | GEO
Project description:The 16p11.2 deletion and duplication syndromes have been associated with developmental delay and autism spectrum disorders, and a reciprocal effect on body mass index. Here we explored these links with new engineered mouse models carrying a deletion (Del/+) and duplication (Dup/+) of the whole 16p11.2 homologous Sult1a1-Spn region. On a pure genetic background, compared to wild-types, Del/+ mice carrying the deletion showed weight and adipogenesis deficits, hyperactivity, repetitive behaviors, and recognition memory deficits, whereas Dup/+ mice showed the opposite phenotypes and Del/Dup individuals displayed no changes. Alterations in social interaction were also observed in Del/+ and Dup/+ animals on a mixed genetic background. Transcriptomic analysis revealed that the majority of genes located on the Sult1a1-Spn were dosage-sensitive and potentially implicated in the opposite phenotypes described above on the neurocognitive aspect. Nevertheless, the outcome of the 16p11 region genetic dosage on metabolism depends on different genetic contributions between human and mouse.
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Project description:Inverted duplications are a common type of copy number variation (CNV) in germline and somatic genomes. Large duplications that include many genes can lead to both neurodevelopmental phenotypes in children and gene amplifications in tumors. There are several models for inverted duplication formation, most of which include a dicentric chromosome intermediate followed by breakage-fusion-bridge (BFB) cycles, but the mechanisms that give rise to the inverted dicentric chromosome in most inverted duplications remain unknown. Here we have combined high-resolution array CGH, custom sequence capture, next-generation sequencing, and long-range PCR to analyze the breakpoints of 50 nonrecurrent inverted duplications in patients with intellectual disability, autism, and congenital anomalies. Sequence analysis of breakpoint junctions reveals a normal-copy disomic spacer between inverted and non-inverted copies of the duplication. Further, short inverted repeats are present at the boundary of the disomic spacer and the inverted duplication. These data support a mechanism of inverted duplication formation whereby a chromosome with a double-strand break intrastrand pairs with itself to form a “hairpin” intermediate that, after DNA replication, produces a dicentric inverted chromosome with a disomic spacer corresponding to the site of the hairpin. We also find evidence of short insertions and inversions at inverted duplication junctions, consistent with a DNA replication-based CNV mechanism. This process can give rise to inverted duplications adjacent to terminal deletions, inverted duplications juxtaposed to translocations, and inverted duplication ring chromosomes
2013-04-03 | GSE45395 | GEO
Project description:Inverted duplications are a common type of copy number variation (CNV) in germline and somatic genomes. Large duplications that include many genes can lead to both neurodevelopmental phenotypes in children and gene amplifications in tumors. There are several models for inverted duplication formation, most of which include a dicentric chromosome intermediate followed by breakage-fusion-bridge (BFB) cycles, but the mechanisms that give rise to the inverted dicentric chromosome in most inverted duplications remain unknown. Here we have combined high-resolution array CGH, custom sequence capture, next-generation sequencing, and long-range PCR to analyze the breakpoints of 50 nonrecurrent inverted duplications in patients with intellectual disability, autism, and congenital anomalies. Sequence analysis of breakpoint junctions reveals a normal-copy disomic spacer between inverted and non-inverted copies of the duplication. Further, short inverted repeats are present at the boundary of the disomic spacer and the inverted duplication. These data support a mechanism of inverted duplication formation whereby a chromosome with a double-strand break intrastrand pairs with itself to form a “hairpin” intermediate that, after DNA replication, produces a dicentric inverted chromosome with a disomic spacer corresponding to the site of the hairpin. We also find evidence of short insertions and inversions at inverted duplication junctions, consistent with a DNA replication-based CNV mechanism. This process can give rise to inverted duplications adjacent to terminal deletions, inverted duplications juxtaposed to translocations, and inverted duplication ring chromosomes High resolution array CGH; two-color experiment, clinical patient vs. normal control gDNA; sex mis-matched
2013-04-03 | E-GEOD-45395 | biostudies-arrayexpress