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  • 1
    Publication Date: 2014-11-21
    Description: Eukaryotic chromosomes replicate in a temporal order known as the replication-timing program. In mammals, replication timing is cell-type-specific with at least half the genome switching replication timing during development, primarily in units of 400-800 kilobases ('replication domains'), whose positions are preserved in different cell types, conserved between species, and appear to confine long-range effects of chromosome rearrangements. Early and late replication correlate, respectively, with open and closed three-dimensional chromatin compartments identified by high-resolution chromosome conformation capture (Hi-C), and, to a lesser extent, late replication correlates with lamina-associated domains (LADs). Recent Hi-C mapping has unveiled substructure within chromatin compartments called topologically associating domains (TADs) that are largely conserved in their positions between cell types and are similar in size to replication domains. However, TADs can be further sub-stratified into smaller domains, challenging the significance of structures at any particular scale. Moreover, attempts to reconcile TADs and LADs to replication-timing data have not revealed a common, underlying domain structure. Here we localize boundaries of replication domains to the early-replicating border of replication-timing transitions and map their positions in 18 human and 13 mouse cell types. We demonstrate that, collectively, replication domain boundaries share a near one-to-one correlation with TAD boundaries, whereas within a cell type, adjacent TADs that replicate at similar times obscure replication domain boundaries, largely accounting for the previously reported lack of alignment. Moreover, cell-type-specific replication timing of TADs partitions the genome into two large-scale sub-nuclear compartments revealing that replication-timing transitions are indistinguishable from late-replicating regions in chromatin composition and lamina association and accounting for the reduced correlation of replication timing to LADs and heterochromatin. Our results reconcile cell-type-specific sub-nuclear compartmentalization and replication timing with developmentally stable structural domains and offer a unified model for large-scale chromosome structure and function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251741/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251741/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pope, Benjamin D -- Ryba, Tyrone -- Dileep, Vishnu -- Yue, Feng -- Wu, Weisheng -- Denas, Olgert -- Vera, Daniel L -- Wang, Yanli -- Hansen, R Scott -- Canfield, Theresa K -- Thurman, Robert E -- Cheng, Yong -- Gulsoy, Gunhan -- Dennis, Jonathan H -- Snyder, Michael P -- Stamatoyannopoulos, John A -- Taylor, James -- Hardison, Ross C -- Kahveci, Tamer -- Ren, Bing -- Gilbert, David M -- DK065806/DK/NIDDK NIH HHS/ -- F31 CA165863/CA/NCI NIH HHS/ -- F31CA165863/CA/NCI NIH HHS/ -- GM083337/GM/NIGMS NIH HHS/ -- GM085354/GM/NIGMS NIH HHS/ -- HG003991/HG/NHGRI NIH HHS/ -- HG005573/HG/NHGRI NIH HHS/ -- HG005602/HG/NHGRI NIH HHS/ -- P01 GM085354/GM/NIGMS NIH HHS/ -- R01 DA033775/DA/NIDA NIH HHS/ -- R01 DK065806/DK/NIDDK NIH HHS/ -- R01 GM083337/GM/NIGMS NIH HHS/ -- R56 DK065806/DK/NIDDK NIH HHS/ -- RC2 HG005573/HG/NHGRI NIH HHS/ -- U54 HG006997/HG/NHGRI NIH HHS/ -- England -- Nature. 2014 Nov 20;515(7527):402-5. doi: 10.1038/nature13986.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Science, 319 Stadium Drive, Florida State University, Tallahassee, Florida 32306, USA. ; Division of Natural Sciences, 5800 Bay Shore Road, New College of Florida, Sarasota, Florida 34243, USA. ; 1] Department of Biochemistry and Molecular Biology, School of Medicine, The Pennsylvania State University, Hershey, Pennsylvania 17033, USA [2] Bioinformatics and Genomics Program, Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA. ; Center for Comparative Genomics and Bioinformatics, Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA. ; Departments of Biology and Mathematics and Computer Science, Emory University, O. Wayne Rollins Research Center, 1510 Clifton Road NE, Atlanta, Georgia 30322, USA. ; Bioinformatics and Genomics Program, Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA. ; Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA. ; Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA. ; Department of Genetics, Stanford University, 300 Pasteur Drive, MC-5477 Stanford, California 94305, USA. ; Computer and Information Sciences and Engineering, University of Florida, Gainesville, Florida 32611, USA. ; Ludwig Institute for Cancer Research and University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25409831" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Compartmentation ; Chromatin/*chemistry/*genetics/metabolism ; Chromatin Assembly and Disassembly ; DNA/*biosynthesis/genetics ; *DNA Replication Timing ; Genome/genetics ; Heterochromatin/chemistry/genetics/metabolism ; Humans ; Mice ; Organ Specificity ; Time Factors
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
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    Abstract: Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A〉C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G〉A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G〉A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G〉T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789-99. (c)2017 AACR.
    Type of Publication: Journal article published
    PubMed ID: 28283652
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  • 5
    Publication Date: 2018-09-07
    Description: High Trapped Fields in C-doped MgB 2 Bulk Superconductors Fabricated by Infiltration and Growth Process High Trapped Fields in C-doped MgB〈sub〉2〈/sub〉 Bulk Superconductors Fabricated by Infiltration and Growth Process, Published online: 06 September 2018; doi:10.1038/s41598-018-31416-3 High Trapped Fields in C-doped MgB 2 Bulk Superconductors Fabricated by Infiltration and Growth Process
    Electronic ISSN: 2045-2322
    Topics: Natural Sciences in General
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