ALBERT

Description: Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis, is a major cause of morbidity and mortality worldwide. Efforts to control it are hampered by difficulties with diagnosis, prevention and treatment. Most people infected with M. tuberculosis remain asymptomatic, termed latent TB, with a 10% lifetime risk of developing active TB disease. Current tests, however, cannot identify which individuals will develop disease. The immune response to M. tuberculosis is complex and incompletely characterized, hindering development of new diagnostics, therapies and vaccines. Here we identify a whole-blood 393 transcript signature for active TB in intermediate and high-burden settings, correlating with radiological extent of disease and reverting to that of healthy controls after treatment. A subset of patients with latent TB had signatures similar to those in patients with active TB. We also identify a specific 86-transcript signature that discriminates active TB from other inflammatory and infectious diseases. Modular and pathway analysis revealed that the TB signature was dominated by a neutrophil-driven interferon (IFN)-inducible gene profile, consisting of both IFN-gamma and type I IFN-alphabeta signalling. Comparison with transcriptional signatures in purified cells and flow cytometric analysis suggest that this TB signature reflects changes in cellular composition and altered gene expression. Although an IFN-inducible signature was also observed in whole blood of patients with systemic lupus erythematosus (SLE), their complete modular signature differed from TB, with increased abundance of plasma cell transcripts. Our studies demonstrate a hitherto underappreciated role of type I IFN-alphabeta signalling in the pathogenesis of TB, which has implications for vaccine and therapeutic development. Our study also provides a broad range of transcriptional biomarkers with potential as diagnostic and prognostic tools to combat the TB epidemic.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492754/" 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/PMC3492754/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Berry, Matthew P R -- Graham, Christine M -- McNab, Finlay W -- Xu, Zhaohui -- Bloch, Susannah A A -- Oni, Tolu -- Wilkinson, Katalin A -- Banchereau, Romain -- Skinner, Jason -- Wilkinson, Robert J -- Quinn, Charles -- Blankenship, Derek -- Dhawan, Ranju -- Cush, John J -- Mejias, Asuncion -- Ramilo, Octavio -- Kon, Onn M -- Pascual, Virginia -- Banchereau, Jacques -- Chaussabel, Damien -- O'Garra, Anne -- 088316/Wellcome Trust/United Kingdom -- 1 U19 AI082715-01/AI/NIAID NIH HHS/ -- MC_U117565642/Medical Research Council/United Kingdom -- MC_U117588499/Medical Research Council/United Kingdom -- P01 CA084512/CA/NCI NIH HHS/ -- P50 ARO54083/PHS HHS/ -- R01 AR050770-01/AR/NIAMS NIH HHS/ -- U01 AI082110/AI/NIAID NIH HHS/ -- U117565642/Medical Research Council/United Kingdom -- U117588499(88499)/Medical Research Council/United Kingdom -- U19 AI082715/AI/NIAID NIH HHS/ -- U19 AIO57234-02/PHS HHS/ -- England -- Nature. 2010 Aug 19;466(7309):973-7. doi: 10.1038/nature09247.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Immunoregulation, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20725040" target="_blank"〉PubMed〈/a〉

Description: Sirtuins are NAD(+)-dependent protein deacetylases. They mediate adaptive responses to a variety of stresses, including calorie restriction and metabolic stress. Sirtuin 3 (SIRT3) is localized in the mitochondrial matrix, where it regulates the acetylation levels of metabolic enzymes, including acetyl coenzyme A synthetase 2 (refs 1, 2). Mice lacking both Sirt3 alleles appear phenotypically normal under basal conditions, but show marked hyperacetylation of several mitochondrial proteins. Here we report that SIRT3 expression is upregulated during fasting in liver and brown adipose tissues. During fasting, livers from mice lacking SIRT3 had higher levels of fatty-acid oxidation intermediate products and triglycerides, associated with decreased levels of fatty-acid oxidation, compared to livers from wild-type mice. Mass spectrometry of mitochondrial proteins shows that long-chain acyl coenzyme A dehydrogenase (LCAD) is hyperacetylated at lysine 42 in the absence of SIRT3. LCAD is deacetylated in wild-type mice under fasted conditions and by SIRT3 in vitro and in vivo; and hyperacetylation of LCAD reduces its enzymatic activity. Mice lacking SIRT3 exhibit hallmarks of fatty-acid oxidation disorders during fasting, including reduced ATP levels and intolerance to cold exposure. These findings identify acetylation as a novel regulatory mechanism for mitochondrial fatty-acid oxidation and demonstrate that SIRT3 modulates mitochondrial intermediary metabolism and fatty-acid use during fasting.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2841477/" 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/PMC2841477/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hirschey, Matthew D -- Shimazu, Tadahiro -- Goetzman, Eric -- Jing, Enxuan -- Schwer, Bjoern -- Lombard, David B -- Grueter, Carrie A -- Harris, Charles -- Biddinger, Sudha -- Ilkayeva, Olga R -- Stevens, Robert D -- Li, Yu -- Saha, Asish K -- Ruderman, Neil B -- Bain, James R -- Newgard, Christopher B -- Farese, Robert V Jr -- Alt, Frederick W -- Kahn, C Ronald -- Verdin, Eric -- DK019514-29/DK/NIDDK NIH HHS/ -- DK59637/DK/NIDDK NIH HHS/ -- K01 DK076573/DK/NIDDK NIH HHS/ -- K08 AG022325/AG/NIA NIH HHS/ -- K08 AG022325-01A1/AG/NIA NIH HHS/ -- P01 HL068758/HL/NHLBI NIH HHS/ -- P01 HL068758-06A1/HL/NHLBI NIH HHS/ -- P30 DK026743/DK/NIDDK NIH HHS/ -- P30 DK026743-26A1/DK/NIDDK NIH HHS/ -- R01 DK019514/DK/NIDDK NIH HHS/ -- R01 DK019514-29/DK/NIDDK NIH HHS/ -- R01 DK067509/DK/NIDDK NIH HHS/ -- R01 DK067509-04/DK/NIDDK NIH HHS/ -- U24 DK059637/DK/NIDDK NIH HHS/ -- U24 DK059637-01/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Mar 4;464(7285):121-5. doi: 10.1038/nature08778.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gladstone Institute of Virology and Immunology, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20203611" target="_blank"〉PubMed〈/a〉

Description: It is now possible to perform whole-genome shotgun sequencing as well as capture of specific genomic regions for extinct organisms. However, targeted resequencing of large parts of nuclear genomes has yet to be demonstrated for ancient DNA. Here we show that hybridization capture on microarrays can successfully recover more than a megabase of target regions from Neandertal DNA even in the presence of approximately 99.8% microbial DNA. Using this approach, we have sequenced approximately 14,000 protein-coding positions inferred to have changed on the human lineage since the last common ancestor shared with chimpanzees. By generating the sequence of one Neandertal and 50 present-day humans at these positions, we have identified 88 amino acid substitutions that have become fixed in humans since our divergence from the Neandertals.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140021/" 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/PMC3140021/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Burbano, Hernan A -- Hodges, Emily -- Green, Richard E -- Briggs, Adrian W -- Krause, Johannes -- Meyer, Matthias -- Good, Jeffrey M -- Maricic, Tomislav -- Johnson, Philip L F -- Xuan, Zhenyu -- Rooks, Michelle -- Bhattacharjee, Arindam -- Brizuela, Leonardo -- Albert, Frank W -- de la Rasilla, Marco -- Fortea, Javier -- Rosas, Antonio -- Lachmann, Michael -- Hannon, Gregory J -- Paabo, Svante -- P01 CA013106/CA/NCI NIH HHS/ -- P01 CA013106-38/CA/NCI NIH HHS/ -- P01 CA013106-39/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2010 May 7;328(5979):723-5. doi: 10.1126/science.1188046.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute for Evolutionary Anthropology, D-04103 Leipzig, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20448179" target="_blank"〉PubMed〈/a〉

Description: Systematic sequencing of human cancer genomes has identified many recurrent mutations in the protein-coding regions of genes but rarely in gene regulatory regions. Here, we describe two independent mutations within the core promoter of telomerase reverse transcriptase (TERT), the gene coding for the catalytic subunit of telomerase, which collectively occur in 50 of 70 (71%) melanomas examined. These mutations generate de novo consensus binding motifs for E-twenty-six (ETS) transcription factors, and in reporter assays, the mutations increased transcriptional activity from the TERT promoter by two- to fourfold. Examination of 150 cancer cell lines derived from diverse tumor types revealed the same mutations in 24 cases (16%), with preliminary evidence of elevated frequency in bladder and hepatocellular cancer cells. Thus, somatic mutations in regulatory regions of the genome may represent an important tumorigenic mechanism.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423787/" 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/PMC4423787/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Franklin W -- Hodis, Eran -- Xu, Mary Jue -- Kryukov, Gregory V -- Chin, Lynda -- Garraway, Levi A -- DP2 OD002750/OD/NIH HHS/ -- DP2OD002750/OD/NIH HHS/ -- R33 CA126674/CA/NCI NIH HHS/ -- R33CA126674/CA/NCI NIH HHS/ -- T32 CA009172/CA/NCI NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- T32GM07753/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2013 Feb 22;339(6122):957-9. doi: 10.1126/science.1229259. Epub 2013 Jan 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23348506" target="_blank"〉PubMed〈/a〉

Description: The genetic changes underlying the initial steps of animal domestication are still poorly understood. We generated a high-quality reference genome for the rabbit and compared it to resequencing data from populations of wild and domestic rabbits. We identified more than 100 selective sweeps specific to domestic rabbits but only a relatively small number of fixed (or nearly fixed) single-nucleotide polymorphisms (SNPs) for derived alleles. SNPs with marked allele frequency differences between wild and domestic rabbits were enriched for conserved noncoding sites. Enrichment analyses suggest that genes affecting brain and neuronal development have often been targeted during domestication. We propose that because of a truly complex genetic background, tame behavior in rabbits and other domestic animals evolved by shifts in allele frequencies at many loci, rather than by critical changes at only a few domestication loci.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Carneiro, Miguel -- Rubin, Carl-Johan -- Di Palma, Federica -- Albert, Frank W -- Alfoldi, Jessica -- Barrio, Alvaro Martinez -- Pielberg, Gerli -- Rafati, Nima -- Sayyab, Shumaila -- Turner-Maier, Jason -- Younis, Shady -- Afonso, Sandra -- Aken, Bronwen -- Alves, Joel M -- Barrell, Daniel -- Bolet, Gerard -- Boucher, Samuel -- Burbano, Hernan A -- Campos, Rita -- Chang, Jean L -- Duranthon, Veronique -- Fontanesi, Luca -- Garreau, Herve -- Heiman, David -- Johnson, Jeremy -- Mage, Rose G -- Peng, Ze -- Queney, Guillaume -- Rogel-Gaillard, Claire -- Ruffier, Magali -- Searle, Steve -- Villafuerte, Rafael -- Xiong, Anqi -- Young, Sarah -- Forsberg-Nilsson, Karin -- Good, Jeffrey M -- Lander, Eric S -- Ferrand, Nuno -- Lindblad-Toh, Kerstin -- Andersson, Leif -- 095908/Wellcome Trust/United Kingdom -- U54 HG003067/HG/NHGRI NIH HHS/ -- WT095908/Wellcome Trust/United Kingdom -- WT098051/Wellcome Trust/United Kingdom -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2014 Aug 29;345(6200):1074-9. doi: 10.1126/science.1253714.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉CIBIO/InBIO, Centro de Investigacao em Biodiversidade e Recursos Geneticos, Campus Agrario de Vairao, Universidade do Porto, 4485-661, Vairao, Portugal. ; Science for Life Laboratory Uppsala, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden. ; Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA. Vertebrate and Health Genomics, The Genome Analysis Centre, Norwich, UK. ; Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany. ; Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA. ; Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden. ; Science for Life Laboratory Uppsala, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden. Department of Animal Production, Ain Shams University, Shoubra El-Kheima, Cairo, Egypt. ; Wellcome Trust Sanger Institute, Hinxton, UK. European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. ; CIBIO/InBIO, Centro de Investigacao em Biodiversidade e Recursos Geneticos, Campus Agrario de Vairao, Universidade do Porto, 4485-661, Vairao, Portugal. Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK. ; Institut National de la Recherche Agronomique (INRA), UMR1388 Genetique, Physiologie et Systemes d'Elevage, F-31326 Castanet-Tolosan, France. ; Labovet Conseil, BP539, 85505 Les Herbiers Cedex, France. ; INRA, UMR1198 Biologie du Developpement et Reproduction, F-78350 Jouy-en-Josas, France. ; Department of Agricultural and Food Sciences, Division of Animal Sciences, University of Bologna, 40127 Bologna, Italy. ; Laboratory of Immunology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD 20892, USA. ; U.S. Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, 2800 Mitchell Drive, Walnut Creek, CA 94598, USA. ; ANTAGENE, Animal Genomics Laboratory, Lyon, France. ; INRA, UMR1313 Genetique Animale et Biologie Integrative, F- 78350, Jouy-en-Josas, France. ; Wellcome Trust Sanger Institute, Hinxton, UK. ; Instituto de Estudios Sociales Avanzados, (IESA-CSIC) Campo Santo de los Martires 7, Cordoba, Spain. ; Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. ; Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany. Division of Biological Sciences, The University of Montana, Missoula, MT 59812, USA. ; CIBIO/InBIO, Centro de Investigacao em Biodiversidade e Recursos Geneticos, Campus Agrario de Vairao, Universidade do Porto, 4485-661, Vairao, Portugal. Departamento de Biologia, Faculdade de Ciencias, Universidade do Porto, Rua do Campo Alegre sn. 4169-007 Porto, Portugal. ; Science for Life Laboratory Uppsala, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA. kersli@broadinstitute.org leif.andersson@imbim.uu.se. ; Science for Life Laboratory Uppsala, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden. Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden. Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843-4458, USA. kersli@broadinstitute.org leif.andersson@imbim.uu.se.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25170157" target="_blank"〉PubMed〈/a〉

Description: Classical non-homologous DNA end-joining (NHEJ) is a major mammalian DNA double-strand-break (DSB) repair pathway. Deficiencies for classical NHEJ factors, such as XRCC4, abrogate lymphocyte development, owing to a strict requirement for classical NHEJ to join V(D)J recombination DSB intermediates. The XRCC4-like factor (XLF; also called NHEJ1) is mutated in certain immunodeficient human patients and has been implicated in classical NHEJ; however, XLF-deficient mice have relatively normal lymphocyte development and their lymphocytes support normal V(D)J recombination. The ataxia telangiectasia-mutated protein (ATM) detects DSBs and activates DSB responses by phosphorylating substrates including histone H2AX. However, ATM deficiency causes only modest V(D)J recombination and lymphocyte developmental defects, and H2AX deficiency does not have a measurable impact on these processes. Here we show that XLF, ATM and H2AX all have fundamental roles in processing and joining DNA ends during V(D)J recombination, but that these roles have been masked by unanticipated functional redundancies. Thus, combined deficiency of ATM and XLF nearly blocks mouse lymphocyte development due to an inability to process and join chromosomal V(D)J recombination DSB intermediates. Combined XLF and ATM deficiency also severely impairs classical NHEJ, but not alternative end-joining, during IgH class switch recombination. Redundant ATM and XLF functions in classical NHEJ are mediated by ATM kinase activity and are not required for extra-chromosomal V(D)J recombination, indicating a role for chromatin-associated ATM substrates. Correspondingly, conditional H2AX inactivation in XLF-deficient pro-B lines leads to V(D)J recombination defects associated with marked degradation of unjoined V(D)J ends, revealing that H2AX has a role in this process.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058373/" 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/PMC3058373/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zha, Shan -- Guo, Chunguang -- Boboila, Cristian -- Oksenych, Valentyn -- Cheng, Hwei-Ling -- Zhang, Yu -- Wesemann, Duane R -- Yuen, Grace -- Patel, Harin -- Goff, Peter H -- Dubois, Richard L -- Alt, Frederick W -- AI007376/AI/NIAID NIH HHS/ -- AI020047/AI/NIAID NIH HHS/ -- AI076210/AI/NIAID NIH HHS/ -- K08 AI089972/AI/NIAID NIH HHS/ -- K08 AI089972-01/AI/NIAID NIH HHS/ -- P01 AI076210/AI/NIAID NIH HHS/ -- P01 AI076210-03/AI/NIAID NIH HHS/ -- R01 AI020047/AI/NIAID NIH HHS/ -- R01 AI020047-28/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Jan 13;469(7329):250-4. doi: 10.1038/nature09604. Epub 2010 Dec 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, The Children's Hospital, the Immune Disease Institute and the Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21160472" target="_blank"〉PubMed〈/a〉

Description: Geographic atrophy (GA), an untreatable advanced form of age-related macular degeneration, results from retinal pigmented epithelium (RPE) cell degeneration. Here we show that the microRNA (miRNA)-processing enzyme DICER1 is reduced in the RPE of humans with GA, and that conditional ablation of Dicer1, but not seven other miRNA-processing enzymes, induces RPE degeneration in mice. DICER1 knockdown induces accumulation of Alu RNA in human RPE cells and Alu-like B1 and B2 RNAs in mouse RPE. Alu RNA is increased in the RPE of humans with GA, and this pathogenic RNA induces human RPE cytotoxicity and RPE degeneration in mice. Antisense oligonucleotides targeting Alu/B1/B2 RNAs prevent DICER1 depletion-induced RPE degeneration despite global miRNA downregulation. DICER1 degrades Alu RNA, and this digested Alu RNA cannot induce RPE degeneration in mice. These findings reveal a miRNA-independent cell survival function for DICER1 involving retrotransposon transcript degradation, show that Alu RNA can directly cause human pathology, and identify new targets for a major cause of blindness.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077055/" 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/PMC3077055/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kaneko, Hiroki -- Dridi, Sami -- Tarallo, Valeria -- Gelfand, Bradley D -- Fowler, Benjamin J -- Cho, Won Gil -- Kleinman, Mark E -- Ponicsan, Steven L -- Hauswirth, William W -- Chiodo, Vince A -- Kariko, Katalin -- Yoo, Jae Wook -- Lee, Dong-ki -- Hadziahmetovic, Majda -- Song, Ying -- Misra, Smita -- Chaudhuri, Gautam -- Buaas, Frank W -- Braun, Robert E -- Hinton, David R -- Zhang, Qing -- Grossniklaus, Hans E -- Provis, Jan M -- Madigan, Michele C -- Milam, Ann H -- Justice, Nikki L -- Albuquerque, Romulo J C -- Blandford, Alexander D -- Bogdanovich, Sasha -- Hirano, Yoshio -- Witta, Jassir -- Fuchs, Elaine -- Littman, Dan R -- Ambati, Balamurali K -- Rudin, Charles M -- Chong, Mark M W -- Provost, Patrick -- Kugel, Jennifer F -- Goodrich, James A -- Dunaief, Joshua L -- Baffi, Judit Z -- Ambati, Jayakrishna -- NIHU10EY013729/EY/NEI NIH HHS/ -- P30 EY006360/EY/NEI NIH HHS/ -- P30 EY014800/EY/NEI NIH HHS/ -- P30 EY014800-07/EY/NEI NIH HHS/ -- P30 EY021721/EY/NEI NIH HHS/ -- P30EY003040/EY/NEI NIH HHS/ -- P30EY008571/EY/NEI NIH HHS/ -- P30EY06360/EY/NEI NIH HHS/ -- R01 EY018350/EY/NEI NIH HHS/ -- R01 EY018350-05/EY/NEI NIH HHS/ -- R01 EY018836/EY/NEI NIH HHS/ -- R01 EY018836-04/EY/NEI NIH HHS/ -- R01 EY020672/EY/NEI NIH HHS/ -- R01 EY020672-02/EY/NEI NIH HHS/ -- R01 GM068414/GM/NIGMS NIH HHS/ -- R01EY001545/EY/NEI NIH HHS/ -- R01EY011123/EY/NEI NIH HHS/ -- R01EY015240/EY/NEI NIH HHS/ -- R01EY015422/EY/NEI NIH HHS/ -- R01EY017182/EY/NEI NIH HHS/ -- R01EY017950/EY/NEI NIH HHS/ -- R01EY018350/EY/NEI NIH HHS/ -- R01EY018836/EY/NEI NIH HHS/ -- R01EY020672/EY/NEI NIH HHS/ -- R01GM068414/GM/NIGMS NIH HHS/ -- R01HD027215/HD/NICHD NIH HHS/ -- R21 EY019778/EY/NEI NIH HHS/ -- R21 EY019778-02/EY/NEI NIH HHS/ -- R21AI076757/AI/NIAID NIH HHS/ -- R21EY019778/EY/NEI NIH HHS/ -- RC1 EY020442/EY/NEI NIH HHS/ -- RC1 EY020442-02/EY/NEI NIH HHS/ -- RC1EY020442/EY/NEI NIH HHS/ -- T32HL091812/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Mar 17;471(7338):325-30. doi: 10.1038/nature09830. Epub 2011 Feb 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40506, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21297615" target="_blank"〉PubMed〈/a〉

Description: Immunoglobulin heavy chain (IgH) variable region exons are assembled from V(H), D and J(H) gene segments in developing B lymphocytes. Within the 2.7-megabase mouse Igh locus, V(D)J recombination is regulated to ensure specific and diverse antibody repertoires. Here we report in mice a key Igh V(D)J recombination regulatory region, termed intergenic control region 1 (IGCR1), which lies between the V(H) and D clusters. Functionally, IGCR1 uses CTCF looping/insulator factor-binding elements and, correspondingly, mediates Igh loops containing distant enhancers. IGCR1 promotes normal B-cell development and balances antibody repertoires by inhibiting transcription and rearrangement of D(H)-proximal V(H) gene segments and promoting rearrangement of distal V(H) segments. IGCR1 maintains ordered and lineage-specific V(H)(D)J(H) recombination by suppressing V(H) joining to D segments not joined to J(H) segments, and V(H) to DJ(H) joins in thymocytes, respectively. IGCR1 is also required for feedback regulation and allelic exclusion of proximal V(H)-to-DJ(H) recombination. Our studies elucidate a long-sought Igh V(D)J recombination control region and indicate a new role for the generally expressed CTCF protein.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342812/" 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/PMC3342812/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guo, Chunguang -- Yoon, Hye Suk -- Franklin, Andrew -- Jain, Suvi -- Ebert, Anja -- Cheng, Hwei-Ling -- Hansen, Erica -- Despo, Orion -- Bossen, Claudia -- Vettermann, Christian -- Bates, Jamie G -- Richards, Nicholas -- Myers, Darienne -- Patel, Harin -- Gallagher, Michael -- Schlissel, Mark S -- Murre, Cornelis -- Busslinger, Meinrad -- Giallourakis, Cosmas C -- Alt, Frederick W -- AI40227/AI/NIAID NIH HHS/ -- CA054198-20/CA/NCI NIH HHS/ -- K08 AI070839/AI/NIAID NIH HHS/ -- P30 DK043351/DK/NIDDK NIH HHS/ -- R01 AI020047/AI/NIAID NIH HHS/ -- R01 AI020047-27/AI/NIAID NIH HHS/ -- R01 AI020047-28/AI/NIAID NIH HHS/ -- R01 AI020047-29/AI/NIAID NIH HHS/ -- R01 AI20047/AI/NIAID NIH HHS/ -- R01 HL48702/HL/NHLBI NIH HHS/ -- R37 AI040227/AI/NIAID NIH HHS/ -- T32 CA009151/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Sep 11;477(7365):424-30. doi: 10.1038/nature10495.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, The Children's Hospital, The Immune Disease Institute, Department of Genetics, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21909113" target="_blank"〉PubMed〈/a〉

Description: There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using approximately 170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of approximately 0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3564953/" 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/PMC3564953/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Jian -- Loos, Ruth J F -- Powell, Joseph E -- Medland, Sarah E -- Speliotes, Elizabeth K -- Chasman, Daniel I -- Rose, Lynda M -- Thorleifsson, Gudmar -- Steinthorsdottir, Valgerdur -- Magi, Reedik -- Waite, Lindsay -- Smith, Albert Vernon -- Yerges-Armstrong, Laura M -- Monda, Keri L -- Hadley, David -- Mahajan, Anubha -- Li, Guo -- Kapur, Karen -- Vitart, Veronique -- Huffman, Jennifer E -- Wang, Sophie R -- Palmer, Cameron -- Esko, Tonu -- Fischer, Krista -- Zhao, Jing Hua -- Demirkan, Ayse -- Isaacs, Aaron -- Feitosa, Mary F -- Luan, Jian'an -- Heard-Costa, Nancy L -- White, Charles -- Jackson, Anne U -- Preuss, Michael -- Ziegler, Andreas -- Eriksson, Joel -- Kutalik, Zoltan -- Frau, Francesca -- Nolte, Ilja M -- Van Vliet-Ostaptchouk, Jana V -- Hottenga, Jouke-Jan -- Jacobs, Kevin B -- Verweij, Niek -- Goel, Anuj -- Medina-Gomez, Carolina -- Estrada, Karol -- Bragg-Gresham, Jennifer Lynn -- Sanna, Serena -- Sidore, Carlo -- Tyrer, Jonathan -- Teumer, Alexander -- Prokopenko, Inga -- Mangino, Massimo -- Lindgren, Cecilia M -- Assimes, Themistocles L -- Shuldiner, Alan R -- Hui, Jennie -- Beilby, John P -- McArdle, Wendy L -- Hall, Per -- Haritunians, Talin -- Zgaga, Lina -- Kolcic, Ivana -- Polasek, Ozren -- Zemunik, Tatijana -- Oostra, Ben A -- Junttila, M Juhani -- Gronberg, Henrik -- Schreiber, Stefan -- Peters, Annette -- Hicks, Andrew A -- Stephens, Jonathan -- Foad, Nicola S -- Laitinen, Jaana -- Pouta, Anneli -- Kaakinen, Marika -- Willemsen, Gonneke -- Vink, Jacqueline M -- Wild, Sarah H -- Navis, Gerjan -- Asselbergs, Folkert W -- Homuth, Georg -- John, Ulrich -- Iribarren, Carlos -- Harris, Tamara -- Launer, Lenore -- Gudnason, Vilmundur -- O'Connell, Jeffrey R -- Boerwinkle, Eric -- Cadby, Gemma -- Palmer, Lyle J -- James, Alan L -- Musk, Arthur W -- Ingelsson, Erik -- Psaty, Bruce M -- Beckmann, Jacques S -- Waeber, Gerard -- Vollenweider, Peter -- Hayward, Caroline -- Wright, Alan F -- Rudan, Igor -- Groop, Leif C -- Metspalu, Andres -- Khaw, Kay Tee -- van Duijn, Cornelia M -- Borecki, Ingrid B -- Province, Michael A -- Wareham, Nicholas J -- Tardif, Jean-Claude -- Huikuri, Heikki V -- Cupples, L Adrienne -- Atwood, Larry D -- Fox, Caroline S -- Boehnke, Michael -- Collins, Francis S -- Mohlke, Karen L -- Erdmann, Jeanette -- Schunkert, Heribert -- Hengstenberg, Christian -- Stark, Klaus -- Lorentzon, Mattias -- Ohlsson, Claes -- Cusi, Daniele -- Staessen, Jan A -- Van der Klauw, Melanie M -- Pramstaller, Peter P -- Kathiresan, Sekar -- Jolley, Jennifer D -- Ripatti, Samuli -- Jarvelin, Marjo-Riitta -- de Geus, Eco J C -- Boomsma, Dorret I -- Penninx, Brenda -- Wilson, James F -- Campbell, Harry -- Chanock, Stephen J -- van der Harst, Pim -- Hamsten, Anders -- Watkins, Hugh -- Hofman, Albert -- Witteman, Jacqueline C -- Zillikens, M Carola -- Uitterlinden, Andre G -- Rivadeneira, Fernando -- Kiemeney, Lambertus A -- Vermeulen, Sita H -- Abecasis, Goncalo R -- Schlessinger, David -- Schipf, Sabine -- Stumvoll, Michael -- Tonjes, Anke -- Spector, Tim D -- North, Kari E -- Lettre, Guillaume -- McCarthy, Mark I -- Berndt, Sonja I -- Heath, Andrew C -- Madden, Pamela A F -- Nyholt, Dale R -- Montgomery, Grant W -- Martin, Nicholas G -- McKnight, Barbara -- Strachan, David P -- Hill, William G -- Snieder, Harold -- Ridker, Paul M -- Thorsteinsdottir, Unnur -- Stefansson, Kari -- Frayling, Timothy M -- Hirschhorn, Joel N -- Goddard, Michael E -- Visscher, Peter M -- 090532/Wellcome Trust/United Kingdom -- 14136/Cancer Research UK/United Kingdom -- AA014041/AA/NIAAA NIH HHS/ -- AA07535/AA/NIAAA NIH HHS/ -- AA10248/AA/NIAAA NIH HHS/ -- AA13320/AA/NIAAA NIH HHS/ -- AA13321/AA/NIAAA NIH HHS/ -- AA13326/AA/NIAAA NIH HHS/ -- CZB/4/710/Chief Scientist Office/United Kingdom -- DA12854/DA/NIDA NIH HHS/ -- F32 AR059469/AR/NIAMS NIH HHS/ -- F32 DK079466/DK/NIDDK NIH HHS/ -- G0601261/Medical Research Council/United Kingdom -- G1000143/Medical Research Council/United Kingdom -- GM057091/GM/NIGMS NIH HHS/ -- HHSN268201100005C/HL/NHLBI NIH HHS/ -- HHSN268201100006C/HL/NHLBI NIH HHS/ -- HHSN268201100007C/HL/NHLBI NIH HHS/ -- HHSN268201100008C/HL/NHLBI NIH HHS/ -- HHSN268201100009C/HL/NHLBI NIH HHS/ -- HHSN268201100010C/HL/NHLBI NIH HHS/ -- HHSN268201100011C/HL/NHLBI NIH HHS/ -- HHSN268201100012C/HL/NHLBI NIH HHS/ -- K05 AA017688/AA/NIAAA NIH HHS/ -- K23 DK080145/DK/NIDDK NIH HHS/ -- MC_PC_U127561128/Medical Research Council/United Kingdom -- MC_U106179471/Medical Research Council/United Kingdom -- MC_U127561128/Medical Research Council/United Kingdom -- N01 AG012100/AG/NIA NIH HHS/ -- N01 HC015103/HC/NHLBI NIH HHS/ -- N01 HC025195/HC/NHLBI NIH HHS/ -- N01 HC035129/HC/NHLBI NIH HHS/ -- N01 HC045133/HC/NHLBI NIH HHS/ -- N01 HC055222/HC/NHLBI NIH HHS/ -- N01 HC075150/HC/NHLBI NIH HHS/ -- N01 HC085079/HC/NHLBI NIH HHS/ -- N01 HG065403/HG/NHGRI NIH HHS/ -- N01HC85086/HL/NHLBI NIH HHS/ -- N02 HL64278/HL/NHLBI NIH HHS/ -- P30 DK063491/DK/NIDDK NIH HHS/ -- P30 DK072488/DK/NIDDK NIH HHS/ -- R01 AA007535/AA/NIAAA NIH HHS/ -- R01 AA013320/AA/NIAAA NIH HHS/ -- R01 AA013321/AA/NIAAA NIH HHS/ -- R01 AA013326/AA/NIAAA NIH HHS/ -- R01 AA014041/AA/NIAAA NIH HHS/ -- R01 AG015928/AG/NIA NIH HHS/ -- R01 AG020098/AG/NIA NIH HHS/ -- R01 AG023629/AG/NIA NIH HHS/ -- R01 AG027058/AG/NIA NIH HHS/ -- R01 DA012854/DA/NIDA NIH HHS/ -- R01 DK062370/DK/NIDDK NIH HHS/ -- R01 DK072193/DK/NIDDK NIH HHS/ -- R01 DK073490/DK/NIDDK NIH HHS/ -- R01 DK075681/DK/NIDDK NIH HHS/ -- R01 DK075787/DK/NIDDK NIH HHS/ -- R01 HG002651/HG/NHGRI NIH HHS/ -- R01 HL043851/HL/NHLBI NIH HHS/ -- R01 HL059367/HL/NHLBI NIH HHS/ -- R01 HL075366/HL/NHLBI NIH HHS/ -- R01 HL080295/HL/NHLBI NIH HHS/ -- R01 HL086694/HL/NHLBI NIH HHS/ -- R01 HL087641/HL/NHLBI NIH HHS/ -- R01 HL087647/HL/NHLBI NIH HHS/ -- R01 HL087652/HL/NHLBI NIH HHS/ -- R01 HL087676/HL/NHLBI NIH HHS/ -- R01 HL087679/HL/NHLBI NIH HHS/ -- R01 HL105756/HL/NHLBI NIH HHS/ -- R01 LM010098/LM/NLM NIH HHS/ -- R01 MH063706/MH/NIMH NIH HHS/ -- RL1 MH083268/MH/NIMH NIH HHS/ -- U01 DK062418/DK/NIDDK NIH HHS/ -- U01 HG004402/HG/NHGRI NIH HHS/ -- U01 HL054527/HL/NHLBI NIH HHS/ -- U01 HL069757/HL/NHLBI NIH HHS/ -- U01 HL072515/HL/NHLBI NIH HHS/ -- U01 HL084729/HL/NHLBI NIH HHS/ -- U01 HL084756/HL/NHLBI NIH HHS/ -- U54 RR020278/RR/NCRR NIH HHS/ -- UL1 RR033176/RR/NCRR NIH HHS/ -- Z01 HG000024-14/Intramural NIH HHS/ -- England -- Nature. 2012 Oct 11;490(7419):267-72. doi: 10.1038/nature11401. Epub 2012 Sep 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of Queensland Diamantina Institute, The University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22982992" target="_blank"〉PubMed〈/a〉

Description: The RAG1/RAG2 endonuclease (RAG) initiates the V(D)J recombination reaction that assembles immunoglobulin heavy (IgH) and light (IgL) chain variable region exons from germline gene segments to generate primary antibody repertoires. IgH V(D)J assembly occurs in progenitor (pro-) B cells followed by that of IgL in precursor (pre-) B cells. Expression of IgH mu and IgL (Igkappa or Iglambda) chains generates IgM, which is expressed on immature B cells as the B-cell antigen-binding receptor (BCR). Rag expression can continue in immature B cells, allowing continued Igkappa V(D)J recombination that replaces the initial VkappaJkappa exon with one that generates a new specificity. This 'receptor editing' process, which can also lead to Iglambda V(D)J recombination and expression, provides a mechanism whereby antigen encounter at the Rag-expressing immature B-cell stage helps shape pre-immune BCR repertoires. As the major site of postnatal B-cell development, the bone marrow is the principal location of primary immunoglobulin repertoire diversification in mice. Here we report that early B-cell development also occurs within the mouse intestinal lamina propria (LP), where the associated V(D)J recombination/receptor editing processes modulate primary LP immunoglobulin repertoires. At weanling age in normally housed mice, the LP contains a population of Rag-expressing B-lineage cells that harbour intermediates indicative of ongoing V(D)J recombination and which contain cells with pro-B, pre-B and editing phenotypes. Consistent with LP-specific receptor editing, Rag-expressing LP B-lineage cells have similar VH repertoires, but significantly different Vkappa repertoires, compared to those of Rag2-expressing bone marrow counterparts. Moreover, colonization of germ-free mice leads to an increased ratio of Iglambda-expressing versus Igkappa-expressing B cells specifically in the LP. We conclude that B-cell development occurs in the intestinal mucosa, where it is regulated by extracellular signals from commensal microbes that influence gut immunoglobulin repertoires.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3807868/" 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/PMC3807868/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wesemann, Duane R -- Portuguese, Andrew J -- Meyers, Robin M -- Gallagher, Michael P -- Cluff-Jones, Kendra -- Magee, Jennifer M -- Panchakshari, Rohit A -- Rodig, Scott J -- Kepler, Thomas B -- Alt, Frederick W -- AI020047/AI/NIAID NIH HHS/ -- AI89972/AI/NIAID NIH HHS/ -- HHSN272201000053C/PHS HHS/ -- K08 AI089972/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Sep 5;501(7465):112-5. doi: 10.1038/nature12496. Epub 2013 Aug 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program in Cellular and Molecular Medicine and Department of Medicine, Children's Hospital Boston, Boston, Massachusetts 02115, USA. dwesemann@research.bwh.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23965619" target="_blank"〉PubMed〈/a〉