Genome-Wide Signatures of ‘Rearrangement Hotspots’ within Segmental Duplications in Humans
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{"title"=>"Genome-wide signatures of 'rearrangement hotspots' within segmental duplications in humans", "type"=>"journal", "authors"=>[{"first_name"=>"Mohammed", "last_name"=>"Uddin", "scopus_author_id"=>"55787037800"}, {"first_name"=>"Mitch", "last_name"=>"Sturge", "scopus_author_id"=>"24825360600"}, {"first_name"=>"Lynette", "last_name"=>"Peddle", "scopus_author_id"=>"6602727364"}, {"first_name"=>"Darren D.", "last_name"=>"O'Rielly", "scopus_author_id"=>"6505622842"}, {"first_name"=>"Proton", "last_name"=>"Rahman", "scopus_author_id"=>"7003863858"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "scopus"=>"2-s2.0-83355170620", "pui"=>"363076200", "doi"=>"10.1371/journal.pone.0028853", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "sgr"=>"83355170620", "pmid"=>"22194928"}, "id"=>"cb59ea38-1a3d-3db7-a3ac-d3d21f40f39b", "abstract"=>"The primary objective of this study was to create a genome-wide high resolution map (i.e., >100 bp) of 'rearrangement hotspots' which can facilitate the identification of regions capable of mediating de novo deletions or duplications in humans. A hierarchical method was employed to fragment segmental duplications (SDs) into multiple smaller SD units. Combining an end space free pairwise alignment algorithm with a 'seed and extend' approach, we have exhaustively searched 409 million alignments to detect complex structural rearrangements within the reference-guided assembly of the NA18507 human genome (18× coverage), including the previously identified novel 4.8 Mb sequence from de novo assembly within this genome. We have identified 1,963 rearrangement hotspots within SDs which encompass 166 genes and display an enrichment of duplicated gene nucleotide variants (DNVs). These regions are correlated with increased non-allelic homologous recombination (NAHR) event frequency which presumably represents the origin of copy number variations (CNVs) and pathogenic duplications/deletions. Analysis revealed that 20% of the detected hotspots are clustered within the proximal and distal SD breakpoints flanked by the pathogenic deletions/duplications that have been mapped for 24 NAHR-mediated genomic disorders. FISH Validation of selected complex regions revealed 94% concordance with in silico localization of the highly homologous derivatives. Other results from this study indicate that intra-chromosomal recombination is enhanced in genic compared with agenic duplicated regions, and that gene desert regions comprising SDs may represent reservoirs for creation of novel genes. The generation of genome-wide signatures of 'rearrangement hotspots', which likely serve as templates for NAHR, may provide a powerful approach towards understanding the underlying mutational mechanism(s) for development of constitutional and acquired diseases.", "link"=>"http://www.mendeley.com/research/genomewide-signatures-rearrangement-hotspots-within-segmental-duplications-humans", "reader_count"=>39, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>5, "Student > Doctoral Student"=>2, "Researcher"=>12, "Student > Ph. D. Student"=>17, "Student > Master"=>1, "Student > Bachelor"=>2}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>5, "Student > Doctoral Student"=>2, "Researcher"=>12, "Student > Ph. D. Student"=>17, "Student > Master"=>1, "Student > Bachelor"=>2}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>4, "Agricultural and Biological Sciences"=>29, "Medicine and Dentistry"=>5, "Physics and Astronomy"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>5}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>29}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}}, "reader_count_by_country"=>{"Sweden"=>1, "Austria"=>1, "United States"=>1, "Brazil"=>1, "Denmark"=>1, "Germany"=>1}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/703945"], "description"=>"<p>A 40 kbp region within 16p12.1 is illustrated with its corresponding derivative copies which were localized by hierarchical analysis. This region consists of the <i>NPIPL3</i> gene derivatives. The inter- and intra-chromosomal localization of the copies is approximated in the physical map within the chromosome contig (18p11.21). The alignments are color coded for chromosomes (i.e., color coded rectangles below the read depth plot) and FISH validation is illustrated for both inter- and intra-chromosomal localization. The pathogenic deletions and duplications located within these regions <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0028853#pone.0028853-Nagamani1\" target=\"_blank\">[27]</a>–<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0028853#pone.0028853-Tokutomi1\" target=\"_blank\">[32]</a> are depicted in red and green bars, respectively The blue bars under the contig represent the approximated inversions previously reported by Antonacci, F. <i>et al </i><a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0028853#pone.0028853-Antonacci1\" target=\"_blank\">[26]</a>. <b>b</b>) Analysis of a 37 kbp duplicated region within 22q11.21 revealed it is comprised of a core 2.7 kbp tandem duplicon copied from different chromosomes. Black lines represent the read depth (x-axis), green shade represent an SD unit, and blue bars represent the region with common repeat elements. The horizontal blocks (color coded according to chromosomes) are the rearrangement (intra/inter) fragments with >90% sequence similarity and >100 bp in length.</p>", "links"=>[], "tags"=>["rearrangement", "hotspots", "located"], "article_id"=>374311, "categories"=>["Biological Sciences", "Genetics", "Evolutionary Biology"], "users"=>["Mohammed Uddin", "Mitch Sturge", "Lynette Peddle", "Darren D. O'Rielly", "Proton Rahman"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0028853.g005", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Signature_of_rearrangement_hotspots_located_at_a_16p12_1_and_b_22q11_21_/374311", "title"=>"Signature of rearrangement hotspots located at a) 16p12.1 and b) 22q11.21.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-12-14 01:11:51"}
  • {"files"=>["https://ndownloader.figshare.com/files/356898", "https://ndownloader.figshare.com/files/357085"], "description"=>"<div><p>The primary objective of this study was to create a genome-wide high resolution map (i.e., >100 bp) of ‘rearrangement hotspots’ which can facilitate the identification of regions capable of mediating <em>de novo</em> deletions or duplications in humans. A hierarchical method was employed to fragment segmental duplications (SDs) into multiple smaller SD units. Combining an end space free pairwise alignment algorithm with a ‘seed and extend’ approach, we have exhaustively searched 409 million alignments to detect complex structural rearrangements within the reference-guided assembly of the NA18507 human genome (18× coverage), including the previously identified novel 4.8 Mb sequence from <em>de novo</em> assembly within this genome. We have identified 1,963 rearrangement hotspots within SDs which encompass 166 genes and display an enrichment of duplicated gene nucleotide variants (DNVs). These regions are correlated with increased non-allelic homologous recombination (NAHR) event frequency which presumably represents the origin of copy number variations (CNVs) and pathogenic duplications/deletions. Analysis revealed that 20% of the detected hotspots are clustered within the proximal and distal SD breakpoints flanked by the pathogenic deletions/duplications that have been mapped for 24 NAHR-mediated genomic disorders. FISH Validation of selected complex regions revealed 94% concordance with <em>in silico</em> localization of the highly homologous derivatives. Other results from this study indicate that intra-chromosomal recombination is enhanced in genic compared with agenic duplicated regions, and that gene desert regions comprising SDs may represent reservoirs for creation of novel genes. The generation of genome-wide signatures of ‘rearrangement hotspots’, which likely serve as templates for NAHR, may provide a powerful approach towards understanding the underlying mutational mechanism(s) for development of constitutional and acquired diseases.</p> </div>", "links"=>[], "tags"=>["genome-wide", "signatures", "segmental", "duplications", "humans"], "article_id"=>130531, "categories"=>["Biological Sciences", "Genetics", "Evolutionary Biology"], "users"=>["Mohammed Uddin", "Mitch Sturge", "Lynette Peddle", "Darren D. O'Rielly", "Proton Rahman"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0028853.s001", "https://dx.doi.org/10.1371/journal.pone.0028853.s002"], "stats"=>{"downloads"=>23, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Genome_Wide_Signatures_of_Rearrangement_Hotspots_within_Segmental_Duplications_in_Humans/130531", "title"=>"Genome-Wide Signatures of ‘Rearrangement Hotspots’ within Segmental Duplications in Humans", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2011-12-14 00:08:51"}
  • {"files"=>["https://ndownloader.figshare.com/files/703346"], "description"=>"<p>mrsFAST was used to obtain read depth distribution of the NA18507 human genome with maximum mismatch (<i>n</i> = 2) was allowed against the repeat masked reference human genome (build 36). A mean-based approach was utilized to computationally predict the boundaries of regions associated with excessive read depth. MAQ was used to obtain the consensus genome (mapping quality <i>Q</i>>30 and <i>n</i> = 2) from the NA18507 genome assembly. The consensus sequence for highly excessive read depth regions was obtained in order to apply a window-based alignment algorithm. The previously identified novel 4.8 Mb sequence from de novo assembly within this genome was also included in the rearrangement analysis.</p>", "links"=>[], "tags"=>["schematic", "illustrating", "hierarchical"], "article_id"=>373716, "categories"=>["Biological Sciences", "Genetics", "Evolutionary Biology"], "users"=>["Mohammed Uddin", "Mitch Sturge", "Lynette Peddle", "Darren D. O'Rielly", "Proton Rahman"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0028853.g001", "stats"=>{"downloads"=>1, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_A_schematic_illustrating_our_hierarchical_approach_/373716", "title"=>"A schematic illustrating our hierarchical approach.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-12-14 01:01:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/703548"], "description"=>"<p>The physical position of rearrangement hotspots that has been mapped within the proximal/distal breakpoints of a pathogenic deletion (red horizontal block) or duplication (green horizontal block).</p>", "links"=>[], "tags"=>["rearrangement", "hotspots", "been", "mapped", "breakpoints", "pathogenic", "deletion", "horizontal", "duplication"], "article_id"=>373905, "categories"=>["Biological Sciences", "Genetics", "Evolutionary Biology"], "users"=>["Mohammed Uddin", "Mitch Sturge", "Lynette Peddle", "Darren D. O'Rielly", "Proton Rahman"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0028853.g003", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_physical_position_of_rearrangement_hotspots_that_has_been_mapped_within_the_proximal_distal_breakpoints_of_a_pathogenic_deletion_red_horizontal_block_or_duplication_green_horizontal_block_/373905", "title"=>"The physical position of rearrangement hotspots that has been mapped within the proximal/distal breakpoints of a pathogenic deletion (red horizontal block) or duplication (green horizontal block).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-12-14 01:05:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/703458"], "description"=>"<p><b>a</b>) A total of 1963 SD complex units (i.e., ≥10 rearrangements) were identified that were significantly different (p<1.0×10<sup>−6</sup>) compared with the rest of the NA18507 genome duplicated regions. The plot illustrates the concordance of the predicted autosomal complex regions compared with previous studies <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0028853#pone.0028853-Conrad2\" target=\"_blank\">[17]</a>, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0028853#pone.0028853-Sudmant1\" target=\"_blank\">[19]</a>. <b>b</b>) Genes that completely or partially overlapped with detected SD units in which 73% (41/56) of the most variable genes in three different populations were detected in our analysis of the NA18507 human genome. Among the 1626 genes identified in this study, 10% (i.e., 166/1626) of genes that overlapped with a SD unit revealed extreme inter- and intra-chromosomal rearrangements, 50% of which have been previously validated <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0028853#pone.0028853-Conrad2\" target=\"_blank\">[17]</a>. <b>c</b>) Observed gene content transfer between hotspot and non-hotspot agenic SD units. <b>d</b>) scatter plot illustrating DNV count for hotspot and non-hotspot SD units. <b>e</b>) A histogram illustrating the mean read depth (RD) of the computationally predicted SD unit breakpoints. The blue bars represent the mean read depth for each of the 20,237 SD unit breakpoints and the red bars represent the mean read depth for hotspot regions.</p>", "links"=>[], "tags"=>["duplication", "units", "rearrangements", "na18507"], "article_id"=>373826, "categories"=>["Biological Sciences", "Genetics", "Evolutionary Biology"], "users"=>["Mohammed Uddin", "Mitch Sturge", "Lynette Peddle", "Darren D. O'Rielly", "Proton Rahman"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0028853.g002", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Segmental_duplication_SD_units_which_represent_the_most_complex_rearrangements_within_the_NA18507_human_genome_/373826", "title"=>"Segmental duplication (SD) units which represent the most complex rearrangements within the NA18507 human genome.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-12-14 01:03:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/703719"], "description"=>"<p>Chromosomal rearrangements located within duplicated regions are plotted against the human genome. Green bars represent the signature of intra-chromosomal rearrangements, black bars represent inter-chromosomal rearrangements and red bars represent ‘rearrangement hotspots’. Cytobands with duplications for each chromosome and selected genes that completely or partially overlapped with SD units are also indicated.</p>", "links"=>[], "tags"=>["chromosomal", "rearrangements", "na18507"], "article_id"=>374085, "categories"=>["Biological Sciences", "Genetics", "Evolutionary Biology"], "users"=>["Mohammed Uddin", "Mitch Sturge", "Lynette Peddle", "Darren D. O'Rielly", "Proton Rahman"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0028853.g004", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Landscape_of_chromosomal_rearrangements_in_the_NA18507_human_genome_/374085", "title"=>"Landscape of chromosomal rearrangements in the NA18507 human genome.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-12-14 01:08:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/704097"], "description"=>"<p>Validation of a gene desert where extreme intra-chromosomal rearrangement without any signature of inter-chromosomal duplication observed in our <i>in silico</i> predictions. The rearrangement consists of gene fragments from the <i>NBPF</i> gene family located within the p and q arm of chromosome 1.</p>", "links"=>[], "tags"=>["hotspots", "comprising", "68", "kb", "located"], "article_id"=>374451, "categories"=>["Biological Sciences", "Genetics", "Evolutionary Biology"], "users"=>["Mohammed Uddin", "Mitch Sturge", "Lynette Peddle", "Darren D. O'Rielly", "Proton Rahman"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0028853.g006", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Rearrangement_hotspots_comprising_a_68_kb_gene_desert_located_within_1q21_1_region_/374451", "title"=>"Rearrangement hotspots comprising a 68 kb gene desert located within 1q21.1 region.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-12-14 01:14:11"}

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Relative Metric

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