Genomic Disorders: Molecular Mechanisms for Rearrangements and Conveyed Phenotypes
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{"title"=>"Genomic disorders: Molecular mechanisms for rearrangements and conveyed phenotypes", "type"=>"generic", "authors"=>[{"first_name"=>"James R.", "last_name"=>"Lupski", "scopus_author_id"=>"7103394224"}, {"first_name"=>"Pawel", "last_name"=>"Stankiewicz", "scopus_author_id"=>"56091724200"}], "year"=>2005, "source"=>"PLoS Genetics", "identifiers"=>{"sgr"=>"34547664096", "doi"=>"10.1371/journal.pgen.0010049", "pui"=>"135775046", "issn"=>"15537390", "pmid"=>"16444292", "isbn"=>"1553-7404 (Electronic)", "scopus"=>"2-s2.0-34547664096"}, "id"=>"b3446949-3ed9-398d-92f7-fd4e29926d53", "abstract"=>"Rearrangements of our genome can be responsible for inherited as well as sporadic traits. The analyses of chromosome breakpoints in the proximal short arm of Chromosome 17 (17p) reveal nonallelic homologous R recombination (NAHR) as a major mechanism for recurrent rearrangements whereas nonhomologous end-joining (NHEJ) can be responsible for many of the nonrecurrent rearrangements. Genome architectural features consisting of low-copy repeats (LCRs), or segmental duplications, can stimulate and mediate NAHR, and there are hotspots for the crossovers within the LCRs. Rearrangements introduce variation into our genome for selection to act upon and as such serve an evolutionary function analogous to base pair changes. Genomic rearrangements may cause Mendelian diseases, produce complex traits such as behaviors, or represent benign polymorphic changes. The mechanisms by which rearrangements convey phenotypes are diverse and include gene dosage, gene interruption, generation of a fusion gene, position effects, unmasking of recessive coding region mutations (single nucleotide polymorphisms, SNPs, in coding DNA) or other functional SNPs, and perhaps by effects on transvection", "link"=>"http://www.mendeley.com/research/genomic-disorders-molecular-mechanisms-rearrangements-conveyed-phenotypes", "reader_count"=>229, "reader_count_by_academic_status"=>{"Unspecified"=>3, "Professor > Associate Professor"=>17, "Researcher"=>56, "Student > Doctoral Student"=>15, "Student > Ph. D. Student"=>59, "Student > Postgraduate"=>15, "Other"=>13, "Student > Master"=>20, "Student > Bachelor"=>20, "Lecturer > Senior Lecturer"=>4, "Professor"=>7}, "reader_count_by_user_role"=>{"Unspecified"=>3, "Professor > Associate Professor"=>17, "Researcher"=>56, "Student > Doctoral Student"=>15, "Student > Ph. D. Student"=>59, "Student > Postgraduate"=>15, "Other"=>13, "Student > Master"=>20, "Student > Bachelor"=>20, "Lecturer > Senior Lecturer"=>4, "Professor"=>7}, "reader_count_by_subject_area"=>{"Unspecified"=>5, "Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>41, "Mathematics"=>1, "Agricultural and Biological Sciences"=>146, "Medicine and Dentistry"=>27, "Physics and Astronomy"=>1, "Chemistry"=>1, "Social Sciences"=>1, "Computer Science"=>4, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>27}, "Chemistry"=>{"Chemistry"=>1}, "Social Sciences"=>{"Social Sciences"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>146}, "Computer Science"=>{"Computer Science"=>4}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>41}, "Mathematics"=>{"Mathematics"=>1}, "Unspecified"=>{"Unspecified"=>5}, "Environmental Science"=>{"Environmental Science"=>1}}, "reader_count_by_country"=>{"Netherlands"=>3, "Belgium"=>1, "United States"=>7, "Italy"=>2, "United Kingdom"=>4, "Switzerland"=>1, "Germany"=>1, "Iceland"=>3, "Spain"=>2}, "group_count"=>10}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/960789"], "description"=>"<p>Six models are depicted and include (A) gene dosage, where there is a dosage sensitive gene within the rearrangement; (B) gene interruption, wherein the rearrangement breakpoint interrupts a gene; (C) gene fusion whereby a fusion gene is created at the breakpoint that either fuses coding sequences or a novel regulatory sequence to the gene; (D) position effect, in which the rearrangement has effects on expression/regulation of a gene near the breakpoint, potentially by removing or altering a regulatory sequence; (E) unmasking recessive allele, where a deletion results in hemizygous expression of a recessive mutation or further uncovers/exacerbates effects of a functional polymorphism; and (F) by potentially interrupting effects of transvection, where the deletion of a gene and its surrounding regulatory sequences affects the communication between alleles. In each model, both chromosome homologs are depicted as horizontal lines. The rearranged genomic interval is enclosed by brackets—dashed lines indicate genomic regions either deleted or duplicated, an absent line indicates deletion with phenotypic effects from the remaining allele unmasked because of the rearrangement, and a dotted line represents deletion but where phenotypic effects result from the absence of interactions between alleles (i.e., transvection effects). Gene is depicted by filled horizontal rectangle, while regulatory region is shown as a hatch-marked rectangle. Asterisks denote point mutations.</p>", "links"=>[], "tags"=>["mechanisms", "genomic"], "article_id"=>630800, "categories"=>["Genetics"], "users"=>["James R Lupski", "Pawel Stankiewicz"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.0010049.g003", "stats"=>{"downloads"=>2, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Molecular_Mechanisms_for_Genomic_Disorders_/630800", "title"=>"Molecular Mechanisms for Genomic Disorders", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-22 08:52:42"}
  • {"files"=>["https://ndownloader.figshare.com/files/960697"], "description"=>"<p>Proximal 17p with its complex genome architecture and multiple LCRs. The centromere (cen) is to the right, telomere (tel) to the left. Filled, hatch-marked, and color-coded rectangles depict LCR regions of greater than 97% sequence identity, with horizontal arrows depicting orientation. The locations of the <i>RAI1</i> gene and isochromosome 17q breakpoint cluster regions are demarcated. Above is shown the region deleted in SMS patients with uncommon nonrecurrent deletions—the breakpoints are denoted by arrowheads. Below are shown the regions contained in the supernumerary marker chromosomes (SMCs). Also, below are shown the 17p11.2 breakpoints of the translocations.</p>", "links"=>[], "tags"=>["rearrangements", "proximal"], "article_id"=>630706, "categories"=>["Genetics"], "users"=>["James R Lupski", "Pawel Stankiewicz"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.0010049.g002", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Nonrecurrent_Rearrangements_in_Proximal_17p_/630706", "title"=>"Nonrecurrent Rearrangements in Proximal 17p", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-22 08:52:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/960888"], "description"=>"<p>Above is shown a gradient/threshold for trait manifestation. Whether or not a trait is manifested is a function of the dosage sensitivity of the gene(s) affected by the rearrangement. Below are examples of traits that can be due to DNA rearrangements. DGS, DiGeorge syndrome; dz, disease; IP, incontientia pigmenti; MR, mental retardation; PWS/AS, Prader-Willi syndrome/Angelman syndrome; WBS, Williams-Beuren syndrome.</p>", "links"=>[], "tags"=>["rearrangements", "phenotypic"], "article_id"=>630899, "categories"=>["Genetics"], "users"=>["James R Lupski", "Pawel Stankiewicz"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.0010049.g004", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Genomic_Rearrangements_and_Phenotypic_Traits_/630899", "title"=>"Genomic Rearrangements and Phenotypic Traits", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-22 08:53:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/960972"], "description"=>"<p>The two major mechanisms by which variation is introduced into our genome are shown. Such variations can be introduced by both endogenous and exogenous means. These mutations can cause a disease trait if they affect gene structure, function, or regulation, as well as through the alteration of dosage. SNP, single nucleotide polymorphism.</p>", "links"=>[], "tags"=>["nucleotide"], "article_id"=>630982, "categories"=>["Genetics"], "users"=>["James R Lupski", "Pawel Stankiewicz"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.0010049.g005", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CNVs_versus_Nucleotide_Changes_/630982", "title"=>"CNVs versus Nucleotide Changes", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-22 08:54:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/960574"], "description"=>"<p>The horizontal line represents proximal 17p with the telomere (TEL) to the left, the centromere (circle) to the right, and LCRs demarcated. The genomic regions duplicated in CMT1A (green horizontal rectangle) and deleted in HNPP (red horizontal rectangle) are shown above, and the recurrent deletions associated with SMS and duplication associated with dup(17)(p11.2p11.2) are shown below. The position of the isochromosome 17q breakpoint cluster region within a large cruciform structure (consisting of five subunits of ~40–50 kb each) is also shown.</p>", "links"=>[], "tags"=>["rearrangements", "proximal"], "article_id"=>630583, "categories"=>["Genetics"], "users"=>["James R Lupski", "Pawel Stankiewicz"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.0010049.g001", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Recurrent_Rearrangements_in_Proximal_17p_/630583", "title"=>"Recurrent Rearrangements in Proximal 17p", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-22 08:51:05"}

PMC Usage Stats | Further Information

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Relative Metric

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