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James R Lupski - One of the best experts on this subject based on the ideXlab platform.
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Copy number analysis of the Low-Copy Repeats at the primate NPHP1 locus by array comparative genomic hybridization.
Genomics data, 2016Co-Authors: Bo Yuan, Pengfei Liu, Jeffrey Rogers, James R LupskiAbstract:Array comparative genomic hybridization (aCGH) has been widely used to detect Copy number variants (CNVs) in both research and clinical settings. A customizable aCGH platform may greatly facilitate Copy number analyses in genomic regions with higher-order complexity, such as Low-Copy Repeats (LCRs). Here we present the aCGH analyses focusing on the 45 kb LCRs [1] at the NPHP1 region with diverse Copy numbers in humans. Also, the interspecies aCGH analysis comparing human and nonhuman primates revealed dynamic Copy number transitions of the human 45 kb LCR orthologues during primate evolution and therefore shed light on the origin of complexity at this locus. The original aCGH data are available at GEO under GSE73962.
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inverted Low Copy Repeats and genome instability a genome wide analysis
Human Mutation, 2013Co-Authors: Piotr Dittwald, Claudia M B Carvalho, James R Lupski, Pawel Stankiewicz, Tomasz Gambin, Anna Gambin, Claudia GonzagajaureguiAbstract:Inverse paralogous Low-Copy Repeats (IP-LCRs) can cause genome instability by nonallelic homologous recombination (NAHR)-mediated balanced inversions. When disrupting a dosage-sensitive gene(s), balanced inversions can lead to abnormal phenotypes. We delineated the genome-wide distribution of IP-LCRs >1 kB in size with >95% sequence identity and mapped the genes, potentially intersected by an inversion, that overlap at least one of the IP-LCRs. Remarkably, our results show that 12.0% of the human genome is potentially susceptible to such inversions and 942 genes, 99 of which are on the X chromosome, are predicted to be disrupted secondary to such an inversion! In addition, IP-LCRs larger than 800 bp with at least 98% sequence identity (duplication/triplication facilitating IP-LCRs, DTIP-LCRs) were recently implicated in the formation of complex genomic rearrangements with a duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) structure by a replication-based mechanism involving a template switch between such inverted Repeats. We identified 1,551 DTIP-LCRs that could facilitate DUP-TRP/INV-DUP formation. Remarkably, 1,445 disease-associated genes are at risk of undergoing Copy-number gain as they map to genomic intervals susceptible to the formation of DUP-TRP/INV-DUP complex rearrangements. We implicate inverted LCRs as a human genome architectural feature that could potentially be responsible for genomic instability associated with many human disease traits.
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Inverted Low‐Copy Repeats and Genome Instability—A Genome‐Wide Analysis
Human mutation, 2012Co-Authors: Piotr Dittwald, Claudia M B Carvalho, James R Lupski, Pawel Stankiewicz, Tomasz Gambin, Claudia Gonzaga-jauregui, Anna GambinAbstract:Inverse paralogous Low-Copy Repeats (IP-LCRs) can cause genome instability by nonallelic homologous recombination (NAHR)-mediated balanced inversions. When disrupting a dosage-sensitive gene(s), balanced inversions can lead to abnormal phenotypes. We delineated the genome-wide distribution of IP-LCRs >1 kB in size with >95% sequence identity and mapped the genes, potentially intersected by an inversion, that overlap at least one of the IP-LCRs. Remarkably, our results show that 12.0% of the human genome is potentially susceptible to such inversions and 942 genes, 99 of which are on the X chromosome, are predicted to be disrupted secondary to such an inversion! In addition, IP-LCRs larger than 800 bp with at least 98% sequence identity (duplication/triplication facilitating IP-LCRs, DTIP-LCRs) were recently implicated in the formation of complex genomic rearrangements with a duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) structure by a replication-based mechanism involving a template switch between such inverted Repeats. We identified 1,551 DTIP-LCRs that could facilitate DUP-TRP/INV-DUP formation. Remarkably, 1,445 disease-associated genes are at risk of undergoing Copy-number gain as they map to genomic intervals susceptible to the formation of DUP-TRP/INV-DUP complex rearrangements. We implicate inverted LCRs as a human genome architectural feature that could potentially be responsible for genomic instability associated with many human disease traits.
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a microhomology mediated break induced replication model for the origin of human Copy number variation
PLOS Genetics, 2009Co-Authors: P J Hastings, James R LupskiAbstract:Chromosome structural changes with nonrecurrent endpoints associated with genomic disorders offer windows into the mechanism of origin of Copy number variation (CNV). A recent report of nonrecurrent duplications associated with Pelizaeus-Merzbacher disease identified three distinctive characteristics. First, the majority of events can be seen to be complex, showing discontinuous duplications mixed with deletions, inverted duplications, and triplications. Second, junctions at endpoints show microhomology of 2–5 base pairs (bp). Third, endpoints occur near pre-existing Low Copy Repeats (LCRs). Using these observations and evidence from DNA repair in other organisms, we derive a model of microhomology-mediated break-induced replication (MMBIR) for the origin of CNV and, ultimately, of LCRs. We propose that breakage of replication forks in stressed cells that are deficient in homologous recombination induces an aberrant repair process with features of break-induced replication (BIR). Under these circumstances, single-strand 3′ tails from broken replication forks will anneal with microhomology on any single-stranded DNA nearby, priming Low-processivity polymerization with multiple template switches generating complex rearrangements, and eventual re-establishment of processive replication.
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A DNA Replication Mechanism for Generating Nonrecurrent Rearrangements Associated with Genomic Disorders
Cell, 2007Co-Authors: Claudia M B Carvalho, James R LupskiAbstract:Summary The prevailing mechanism for recurrent and some nonrecurrent rearrangements causing genomic disorders is nonallelic homologous recombination (NAHR) between region-specific Low-Copy Repeats (LCRs). For other nonrecurrent rearrangements, nonhomologous end joining (NHEJ) is implicated. Pelizaeus-Merzbacher disease (PMD) is an X-linked dysmyelinating disorder caused most frequently (60%–70%) by nonrecurrent duplication of the dosage-sensitive proteolipid protein 1 ( PLP1 ) gene but also by nonrecurrent deletion or point mutations. Many PLP1 duplication junctions are refractory to breakpoint sequence analysis, an observation inconsistent with a simple recombination mechanism. Our current analysis of junction sequences in PMD patients confirms the occurrence of simple tandem PLP1 duplications but also uncovers evidence for sequence complexity at some junctions. These data are consistent with a replication-based mechanism that we term FoSTeS, for replication Fo rk S talling and Te mplate S witching. We propose that complex duplication and deletion rearrangements associated with PMD, and potentially other nonrecurrent rearrangements, may be explained by this replication-based mechanism.
Bernice E. Morrow - One of the best experts on this subject based on the ideXlab platform.
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Nested Inversion Polymorphisms Predispose Chromosome 22q11.2 to Meiotic Rearrangements.
American journal of human genetics, 2017Co-Authors: Wolfram Demaerel, Matthew S. Hestand, Ann Swillen, Elfi Vergaelen, Beverly S Emanuel, Elaine H Zackai, Marcos López-sánchez, Luis A. Pérez-jurado, D M Mcdonald-mcginn, Bernice E. MorrowAbstract:Inversion polymorphisms between Low-Copy Repeats (LCRs) might predispose chromosomes to meiotic non-allelic homologous recombination (NAHR) events and thus lead to genomic disorders. However, for the 22q11.2 deletion syndrome (22q11.2DS), the most common genomic disorder, no such inversions have been uncovered as of yet. Using fiber-FISH, we demonstrate that parents transmitting the de novo 3 Mb LCR22A–D 22q11.2 deletion, the reciprocal duplication, and the smaller 1.5 Mb LCR22A–B 22q11.2 deletion carry inversions of LCR22B–D or LCR22C–D. Hence, the inversions predispose chromosome 22q11.2 to meiotic rearrangements and increase the individual risk for transmitting rearrangements. Interestingly, the inversions are nested or flanking rather than coinciding with the deletion or duplication sizes. This finding raises the possibility that inversions are a prerequisite not only for 22q11.2 rearrangements but also for all NAHR-mediated genomic disorders.
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hominoid lineage specific amplification of Low Copy Repeats on 22q11 2 lcr22s associated with velo cardio facial digeorge syndrome
Human Molecular Genetics, 2007Co-Authors: Melanie Babcock, James R Lupski, Svetlana A. Yatsenko, Janet A. Hopkins, Matthew D. Brenton, Qing Cao, Pieter J. De Jong, Pawel Stankiewicz, James M. Sikela, Bernice E. MorrowAbstract:Segmental duplications or Low-Copy Repeats (LCRs) constitute ∼5% of the sequenced portion of the human genome and are associated with many human congenital anomaly disorders. The Low-Copy Repeats on chromosome 22q11.2 (LCR22s) mediate chromosomal rearrangements resulting in deletions, duplications and translocations. The evolutionary mechanisms leading to LCR22 formation is unknown. Four genes, USP18, BCR, GGTLA and GGT, map adjacent to the LCR22s and pseudogene copies are located within them. It has been hypothesized that gene duplication occurred during primate evolution, folLowed by recombination events, forming pseudogene copies. We investigated whether gene duplication could be detected in non-human hominoid species. FISH mapping was performed using probes to the four functional gene loci. There was evidence for a single Copy in humans but additional copies in hominoid species. We then compared LCR22 Copy number using LCR22 FISH probes. Lineage specific LCR22 variation was detected in the hominoid species supporting the hypothesis. To independently validate initial findings, real time PCR, and screening of gorilla BAC library filters were performed. This was compared to array comparative genome hybridization data available. The most striking finding was a dramatic amplification of LCR22s in the gorilla. The LCR22s localized to the telomeric or subtelomeric bands of gorilla chromosomes. The most parsimonious explanation is that the LCR22s became amplified by inter-chromosomal recombination between telomeric bands. In summary, our results are consistent with a lineage specific coupling between gene and LCR22 duplication events. The LCR22s thus serve as an important model for evolution of genome variation.
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Hominoid lineage specific amplification of Low-Copy Repeats on 22q11.2 (LCR22s) associated with velo-cardio-facial/digeorge syndrome
Human molecular genetics, 2007Co-Authors: Melanie Babcock, James R Lupski, Svetlana A. Yatsenko, Janet A. Hopkins, Matthew D. Brenton, Qing Cao, Pieter J. De Jong, Pawel Stankiewicz, James M. Sikela, Bernice E. MorrowAbstract:Segmental duplications or Low-Copy Repeats (LCRs) constitute ∼5% of the sequenced portion of the human genome and are associated with many human congenital anomaly disorders. The Low-Copy Repeats on chromosome 22q11.2 (LCR22s) mediate chromosomal rearrangements resulting in deletions, duplications and translocations. The evolutionary mechanisms leading to LCR22 formation is unknown. Four genes, USP18, BCR, GGTLA and GGT, map adjacent to the LCR22s and pseudogene copies are located within them. It has been hypothesized that gene duplication occurred during primate evolution, folLowed by recombination events, forming pseudogene copies. We investigated whether gene duplication could be detected in non-human hominoid species. FISH mapping was performed using probes to the four functional gene loci. There was evidence for a single Copy in humans but additional copies in hominoid species. We then compared LCR22 Copy number using LCR22 FISH probes. Lineage specific LCR22 variation was detected in the hominoid species supporting the hypothesis. To independently validate initial findings, real time PCR, and screening of gorilla BAC library filters were performed. This was compared to array comparative genome hybridization data available. The most striking finding was a dramatic amplification of LCR22s in the gorilla. The LCR22s localized to the telomeric or subtelomeric bands of gorilla chromosomes. The most parsimonious explanation is that the LCR22s became amplified by inter-chromosomal recombination between telomeric bands. In summary, our results are consistent with a lineage specific coupling between gene and LCR22 duplication events. The LCR22s thus serve as an important model for evolution of genome variation.
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eLS - Microdeletions and Microduplications: Mechanism
Encyclopedia of Life Sciences, 2006Co-Authors: Bernice E. MorrowAbstract:Microdeletions and microduplications in the genome are caused by chromosome misalignment between blocks of region-specific Low Copy Repeats and result in genomic disorders. Keywords: chromosome rearrangements; genomic disorders; 22q11; Low Copy Repeats; congenital anomaly disorders; homologous recombination
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Shuffling of Genes Within Low-Copy Repeats on 22q11 (LCR22) by Alu-Mediated Recombination Events During Evolution
Genome research, 2003Co-Authors: Melanie Babcock, Adam Pavlicek, Elizabeth Spiteri, Catherine D. Kashork, Ilya Ioshikhes, Lisa G. Shaffer, Jerzy Jurka, Bernice E. MorrowAbstract:Low-Copy Repeats, or segmental duplications, are highly dynamic regions in the genome. The Low-Copy Repeats on chromosome 22q11.2 (LCR22) are a complex mosaic of genes and pseudogenes formed by duplication processes; they mediate chromosome rearrangements associated with velo-cardio-facial syndrome/DiGeorge syndrome, der(22) syndrome, and cat-eye syndrome. The ability to trace the substrates and products of recombination events provides a unique opportunity to identify the mechanisms responsible for shaping LCR22s. We examined the genomic sequence of known LCR22 genes and their duplicated derivatives. We found Alu (SINE) elements at the breakpoints in the substrates and at the junctions in the truncated products of recombination for USP18, GGT, and GGTLA, consistent with Alu-mediated unequal crossing-over events. In addition, we were able to trace a likely interchromosomal Alu-mediated fusion between IGSF3 on 1p13.1 and GGT on 22q11.2. Breakpoints occurred inside Alu elements as well as in the 5' or 3' ends of them. A possible stimulus for the 5' or 3' terminal rearrangements may be the high sequence similarities between different Alu elements, combined with a potential recombinogenic role of retrotransposon target-site duplications flanking the Alu element, containing potentially kinkable DNA sites. Such sites may represent focal points for recombination. Thus, genome shuffling by Alu-mediated rearrangements has contributed to genome architecture during primate evolution.
Pawel Stankiewicz - One of the best experts on this subject based on the ideXlab platform.
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inverted Low Copy Repeats and genome instability a genome wide analysis
Human Mutation, 2013Co-Authors: Piotr Dittwald, Claudia M B Carvalho, James R Lupski, Pawel Stankiewicz, Tomasz Gambin, Anna Gambin, Claudia GonzagajaureguiAbstract:Inverse paralogous Low-Copy Repeats (IP-LCRs) can cause genome instability by nonallelic homologous recombination (NAHR)-mediated balanced inversions. When disrupting a dosage-sensitive gene(s), balanced inversions can lead to abnormal phenotypes. We delineated the genome-wide distribution of IP-LCRs >1 kB in size with >95% sequence identity and mapped the genes, potentially intersected by an inversion, that overlap at least one of the IP-LCRs. Remarkably, our results show that 12.0% of the human genome is potentially susceptible to such inversions and 942 genes, 99 of which are on the X chromosome, are predicted to be disrupted secondary to such an inversion! In addition, IP-LCRs larger than 800 bp with at least 98% sequence identity (duplication/triplication facilitating IP-LCRs, DTIP-LCRs) were recently implicated in the formation of complex genomic rearrangements with a duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) structure by a replication-based mechanism involving a template switch between such inverted Repeats. We identified 1,551 DTIP-LCRs that could facilitate DUP-TRP/INV-DUP formation. Remarkably, 1,445 disease-associated genes are at risk of undergoing Copy-number gain as they map to genomic intervals susceptible to the formation of DUP-TRP/INV-DUP complex rearrangements. We implicate inverted LCRs as a human genome architectural feature that could potentially be responsible for genomic instability associated with many human disease traits.
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Inverted Low‐Copy Repeats and Genome Instability—A Genome‐Wide Analysis
Human mutation, 2012Co-Authors: Piotr Dittwald, Claudia M B Carvalho, James R Lupski, Pawel Stankiewicz, Tomasz Gambin, Claudia Gonzaga-jauregui, Anna GambinAbstract:Inverse paralogous Low-Copy Repeats (IP-LCRs) can cause genome instability by nonallelic homologous recombination (NAHR)-mediated balanced inversions. When disrupting a dosage-sensitive gene(s), balanced inversions can lead to abnormal phenotypes. We delineated the genome-wide distribution of IP-LCRs >1 kB in size with >95% sequence identity and mapped the genes, potentially intersected by an inversion, that overlap at least one of the IP-LCRs. Remarkably, our results show that 12.0% of the human genome is potentially susceptible to such inversions and 942 genes, 99 of which are on the X chromosome, are predicted to be disrupted secondary to such an inversion! In addition, IP-LCRs larger than 800 bp with at least 98% sequence identity (duplication/triplication facilitating IP-LCRs, DTIP-LCRs) were recently implicated in the formation of complex genomic rearrangements with a duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) structure by a replication-based mechanism involving a template switch between such inverted Repeats. We identified 1,551 DTIP-LCRs that could facilitate DUP-TRP/INV-DUP formation. Remarkably, 1,445 disease-associated genes are at risk of undergoing Copy-number gain as they map to genomic intervals susceptible to the formation of DUP-TRP/INV-DUP complex rearrangements. We implicate inverted LCRs as a human genome architectural feature that could potentially be responsible for genomic instability associated with many human disease traits.
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recurrent deletions and reciprocal duplications of 10q11 21q11 23 including chat and slc18a3 are likely mediated by complex Low Copy Repeats
Human Mutation, 2012Co-Authors: Pawel Stankiewicz, Tamim H. Shaikh, Samarth Bhatt, Zhilian Xia, Shashikant Kulkarni, Avinash V Dharmadhikari, Srirangan Sampath, Amber N Pursley, Lance M Cooper, Marwan ShinawiAbstract:We report 24 unrelated individuals with deletions and 17 additional cases with duplications at 10q11.21q21.1 identified by chromosomal microarray analysis. The rearrangements range in size from 0.3 to 12 Mb. Nineteen of the deletions and eight duplications are flanked by large, directly oriented segmental duplications of >98% sequence identity, suggesting that nonallelic homologous recombination (NAHR) caused these genomic rearrangements. Nine individuals with deletions and five with duplications have additional Copy number changes. Detailed clinical evaluation of 20 patients with deletions revealed variable clinical features, with developmental delay (DD) and/or intellectual disability (ID) as the only features common to a majority of individuals. We suggest that some of the other features present in more than one patient with deletion, including hypotonia, sleep apnea, chronic constipation, gastroesophageal and vesicoureteral refluxes, epilepsy, ataxia, dysphagia, nystagmus, and ptosis may result from deletion of the CHAT gene, encoding choline acetyltransferase, and the SLC18A3 gene, mapping in the first intron of CHAT and encoding vesicular acetylcholine transporter. The phenotypic diversity and presence of the deletion in apparently normal carrier parents suggest that subjects carrying 10q11.21q11.23 deletions may exhibit variable phenotypic expressivity and incomplete penetrance influenced by additional genetic and nongenetic modifiers.
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hominoid lineage specific amplification of Low Copy Repeats on 22q11 2 lcr22s associated with velo cardio facial digeorge syndrome
Human Molecular Genetics, 2007Co-Authors: Melanie Babcock, James R Lupski, Svetlana A. Yatsenko, Janet A. Hopkins, Matthew D. Brenton, Qing Cao, Pieter J. De Jong, Pawel Stankiewicz, James M. Sikela, Bernice E. MorrowAbstract:Segmental duplications or Low-Copy Repeats (LCRs) constitute ∼5% of the sequenced portion of the human genome and are associated with many human congenital anomaly disorders. The Low-Copy Repeats on chromosome 22q11.2 (LCR22s) mediate chromosomal rearrangements resulting in deletions, duplications and translocations. The evolutionary mechanisms leading to LCR22 formation is unknown. Four genes, USP18, BCR, GGTLA and GGT, map adjacent to the LCR22s and pseudogene copies are located within them. It has been hypothesized that gene duplication occurred during primate evolution, folLowed by recombination events, forming pseudogene copies. We investigated whether gene duplication could be detected in non-human hominoid species. FISH mapping was performed using probes to the four functional gene loci. There was evidence for a single Copy in humans but additional copies in hominoid species. We then compared LCR22 Copy number using LCR22 FISH probes. Lineage specific LCR22 variation was detected in the hominoid species supporting the hypothesis. To independently validate initial findings, real time PCR, and screening of gorilla BAC library filters were performed. This was compared to array comparative genome hybridization data available. The most striking finding was a dramatic amplification of LCR22s in the gorilla. The LCR22s localized to the telomeric or subtelomeric bands of gorilla chromosomes. The most parsimonious explanation is that the LCR22s became amplified by inter-chromosomal recombination between telomeric bands. In summary, our results are consistent with a lineage specific coupling between gene and LCR22 duplication events. The LCR22s thus serve as an important model for evolution of genome variation.
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Hominoid lineage specific amplification of Low-Copy Repeats on 22q11.2 (LCR22s) associated with velo-cardio-facial/digeorge syndrome
Human molecular genetics, 2007Co-Authors: Melanie Babcock, James R Lupski, Svetlana A. Yatsenko, Janet A. Hopkins, Matthew D. Brenton, Qing Cao, Pieter J. De Jong, Pawel Stankiewicz, James M. Sikela, Bernice E. MorrowAbstract:Segmental duplications or Low-Copy Repeats (LCRs) constitute ∼5% of the sequenced portion of the human genome and are associated with many human congenital anomaly disorders. The Low-Copy Repeats on chromosome 22q11.2 (LCR22s) mediate chromosomal rearrangements resulting in deletions, duplications and translocations. The evolutionary mechanisms leading to LCR22 formation is unknown. Four genes, USP18, BCR, GGTLA and GGT, map adjacent to the LCR22s and pseudogene copies are located within them. It has been hypothesized that gene duplication occurred during primate evolution, folLowed by recombination events, forming pseudogene copies. We investigated whether gene duplication could be detected in non-human hominoid species. FISH mapping was performed using probes to the four functional gene loci. There was evidence for a single Copy in humans but additional copies in hominoid species. We then compared LCR22 Copy number using LCR22 FISH probes. Lineage specific LCR22 variation was detected in the hominoid species supporting the hypothesis. To independently validate initial findings, real time PCR, and screening of gorilla BAC library filters were performed. This was compared to array comparative genome hybridization data available. The most striking finding was a dramatic amplification of LCR22s in the gorilla. The LCR22s localized to the telomeric or subtelomeric bands of gorilla chromosomes. The most parsimonious explanation is that the LCR22s became amplified by inter-chromosomal recombination between telomeric bands. In summary, our results are consistent with a lineage specific coupling between gene and LCR22 duplication events. The LCR22s thus serve as an important model for evolution of genome variation.
Anna Gambin - One of the best experts on this subject based on the ideXlab platform.
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Human endogenous retroviral elements promote genome instability via non-allelic homologous recombination
BMC biology, 2014Co-Authors: Ian M. Campbell, Piotr Dittwald, Tomasz Gambin, Anna Gambin, Ankita Patel, Christine R. Beck, Andrey Shuvarikov, Patricia Hixson, Chad A. Shaw, Jill A. RosenfeldAbstract:Background Recurrent rearrangements of the human genome resulting in disease or variation are mainly mediated by non-allelic homologous recombination (NAHR) between Low-Copy Repeats. However, other genomic structures, including AT-rich palindromes and retroviruses, have also been reported to underlie recurrent structural rearrangements. Notably, recurrent deletions of Yq12 conveying azoospermia, as well as non-pathogenic reciprocal duplications, are mediated by human endogenous retroviral elements (HERVs). We hypothesized that HERV elements throughout the genome can serve as substrates for genomic instability and result in human Copy-number variation (CNV).
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inverted Low Copy Repeats and genome instability a genome wide analysis
Human Mutation, 2013Co-Authors: Piotr Dittwald, Claudia M B Carvalho, James R Lupski, Pawel Stankiewicz, Tomasz Gambin, Anna Gambin, Claudia GonzagajaureguiAbstract:Inverse paralogous Low-Copy Repeats (IP-LCRs) can cause genome instability by nonallelic homologous recombination (NAHR)-mediated balanced inversions. When disrupting a dosage-sensitive gene(s), balanced inversions can lead to abnormal phenotypes. We delineated the genome-wide distribution of IP-LCRs >1 kB in size with >95% sequence identity and mapped the genes, potentially intersected by an inversion, that overlap at least one of the IP-LCRs. Remarkably, our results show that 12.0% of the human genome is potentially susceptible to such inversions and 942 genes, 99 of which are on the X chromosome, are predicted to be disrupted secondary to such an inversion! In addition, IP-LCRs larger than 800 bp with at least 98% sequence identity (duplication/triplication facilitating IP-LCRs, DTIP-LCRs) were recently implicated in the formation of complex genomic rearrangements with a duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) structure by a replication-based mechanism involving a template switch between such inverted Repeats. We identified 1,551 DTIP-LCRs that could facilitate DUP-TRP/INV-DUP formation. Remarkably, 1,445 disease-associated genes are at risk of undergoing Copy-number gain as they map to genomic intervals susceptible to the formation of DUP-TRP/INV-DUP complex rearrangements. We implicate inverted LCRs as a human genome architectural feature that could potentially be responsible for genomic instability associated with many human disease traits.
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Inverted Low‐Copy Repeats and Genome Instability—A Genome‐Wide Analysis
Human mutation, 2012Co-Authors: Piotr Dittwald, Claudia M B Carvalho, James R Lupski, Pawel Stankiewicz, Tomasz Gambin, Claudia Gonzaga-jauregui, Anna GambinAbstract:Inverse paralogous Low-Copy Repeats (IP-LCRs) can cause genome instability by nonallelic homologous recombination (NAHR)-mediated balanced inversions. When disrupting a dosage-sensitive gene(s), balanced inversions can lead to abnormal phenotypes. We delineated the genome-wide distribution of IP-LCRs >1 kB in size with >95% sequence identity and mapped the genes, potentially intersected by an inversion, that overlap at least one of the IP-LCRs. Remarkably, our results show that 12.0% of the human genome is potentially susceptible to such inversions and 942 genes, 99 of which are on the X chromosome, are predicted to be disrupted secondary to such an inversion! In addition, IP-LCRs larger than 800 bp with at least 98% sequence identity (duplication/triplication facilitating IP-LCRs, DTIP-LCRs) were recently implicated in the formation of complex genomic rearrangements with a duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) structure by a replication-based mechanism involving a template switch between such inverted Repeats. We identified 1,551 DTIP-LCRs that could facilitate DUP-TRP/INV-DUP formation. Remarkably, 1,445 disease-associated genes are at risk of undergoing Copy-number gain as they map to genomic intervals susceptible to the formation of DUP-TRP/INV-DUP complex rearrangements. We implicate inverted LCRs as a human genome architectural feature that could potentially be responsible for genomic instability associated with many human disease traits.
Robert D. Nicholls - One of the best experts on this subject based on the ideXlab platform.
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The Ancestral Gene for Transcribed, Low-Copy Repeats in the Prader-Willi/Angelman Region Encodes a Large Protein Implicated in Protein Trafficking, Which Is Deficient in Mice with Neuromuscular and Spermiogenic Abnormalities
Human molecular genetics, 1999Co-Authors: Mitchell J. Walkowicz, Karin Buiting, Dabney K. Johnson, Rocio E. Tarvin, Eugene M. Rinchik, Bernhard Horsthemke, Lisa Stubbs, Robert D. NichollsAbstract:Transcribed, Low-Copy repeat elements are associated with the breakpoint regions of common deletions in Prader-Willi and Angelman syndromes. We report here the identification of the ancestral gene ( HERC2 ) and a family of duplicated, truncated copies that comprise these Low-Copy Repeats. This gene encodes a highly conserved giant protein, HERC2, that is distantly related to p532 (HERC1), a guanine nucleotide exchange factor (GEF) implicated in vesicular trafficking. The mouse genome contains a single Herc2 locus, located in the jdf2 (juvenile development and fertility-2) interval of chromosome 7C. We have identified single nucleotide splice junction mutations in Herc2 in three independent N-ethyl-N-nitrosourea-induced jdf2 mutant alleles, each leading to exon skipping with premature termination of translation and/or deletion of conserved amino acids. Therefore, mutations in Herc2 lead to the neuromuscular secretory vesicle and sperm acrosome defects, other developmental abnormalities and juvenile lethality of jdf2 mice. Combined, these findings suggest that HERC2 is an important gene encoding a GEF involved in protein trafficking and degradation pathways in the cell.
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the ancestral gene for transcribed Low Copy Repeats in the prader willi angelman region encodes a large protein implicated in protein trafficking which is deficient in mice with neuromuscular and spermiogenic abnormalities
Human Molecular Genetics, 1999Co-Authors: Mitchell J. Walkowicz, Karin Buiting, Dabney K. Johnson, Rocio E. Tarvin, Eugene M. Rinchik, Bernhard Horsthemke, Lisa Stubbs, Robert D. NichollsAbstract:Transcribed, Low-Copy repeat elements are associated with the breakpoint regions of common deletions in Prader-Willi and Angelman syndromes. We report here the identification of the ancestral gene ( HERC2 ) and a family of duplicated, truncated copies that comprise these Low-Copy Repeats. This gene encodes a highly conserved giant protein, HERC2, that is distantly related to p532 (HERC1), a guanine nucleotide exchange factor (GEF) implicated in vesicular trafficking. The mouse genome contains a single Herc2 locus, located in the jdf2 (juvenile development and fertility-2) interval of chromosome 7C. We have identified single nucleotide splice junction mutations in Herc2 in three independent N-ethyl-N-nitrosourea-induced jdf2 mutant alleles, each leading to exon skipping with premature termination of translation and/or deletion of conserved amino acids. Therefore, mutations in Herc2 lead to the neuromuscular secretory vesicle and sperm acrosome defects, other developmental abnormalities and juvenile lethality of jdf2 mice. Combined, these findings suggest that HERC2 is an important gene encoding a GEF involved in protein trafficking and degradation pathways in the cell.
