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  • 1
    Publication Date: 2012-03-01
    Description: The human X and Y chromosomes evolved from an ordinary pair of autosomes during the past 200-300 million years. The human MSY (male-specific region of Y chromosome) retains only three percent of the ancestral autosomes' genes owing to genetic decay. This evolutionary decay was driven by a series of five 'stratification' events. Each event suppressed X-Y crossing over within a chromosome segment or 'stratum', incorporated that segment into the MSY and subjected its genes to the erosive forces that attend the absence of crossing over. The last of these events occurred 30 million years ago, 5 million years before the human and Old World monkey lineages diverged. Although speculation abounds regarding ongoing decay and looming extinction of the human Y chromosome, remarkably little is known about how many MSY genes were lost in the human lineage in the 25 million years that have followed its separation from the Old World monkey lineage. To investigate this question, we sequenced the MSY of the rhesus macaque, an Old World monkey, and compared it to the human MSY. We discovered that during the last 25 million years MSY gene loss in the human lineage was limited to the youngest stratum (stratum 5), which comprises three percent of the human MSY. In the older strata, which collectively comprise the bulk of the human MSY, gene loss evidently ceased more than 25 million years ago. Likewise, the rhesus MSY has not lost any older genes (from strata 1-4) during the past 25 million years, despite its major structural differences to the human MSY. The rhesus MSY is simpler, with few amplified gene families or palindromes that might enable intrachromosomal recombination and repair. We present an empirical reconstruction of human MSY evolution in which each stratum transitioned from rapid, exponential loss of ancestral genes to strict conservation through purifying selection.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3292678/" 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/PMC3292678/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hughes, Jennifer F -- Skaletsky, Helen -- Brown, Laura G -- Pyntikova, Tatyana -- Graves, Tina -- Fulton, Robert S -- Dugan, Shannon -- Ding, Yan -- Buhay, Christian J -- Kremitzki, Colin -- Wang, Qiaoyan -- Shen, Hua -- Holder, Michael -- Villasana, Donna -- Nazareth, Lynne V -- Cree, Andrew -- Courtney, Laura -- Veizer, Joelle -- Kotkiewicz, Holland -- Cho, Ting-Jan -- Koutseva, Natalia -- Rozen, Steve -- Muzny, Donna M -- Warren, Wesley C -- Gibbs, Richard A -- Wilson, Richard K -- Page, David C -- R01 HG000257/HG/NHGRI NIH HHS/ -- R01 HG000257-17/HG/NHGRI NIH HHS/ -- U54 HG003273/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Feb 22;483(7387):82-6. doi: 10.1038/nature10843.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA. jhughes@wi.mit.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22367542" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chromosomes, Human, Y/*genetics ; Conserved Sequence/*genetics ; Crossing Over, Genetic/genetics ; *Evolution, Molecular ; Gene Amplification/genetics ; *Gene Deletion ; Humans ; In Situ Hybridization, Fluorescence ; Macaca mulatta/*genetics ; Male ; Models, Genetic ; Molecular Sequence Data ; Pan troglodytes/genetics ; Radiation Hybrid Mapping ; Selection, Genetic/genetics ; Time Factors ; Y Chromosome/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2014-04-25
    Description: The human X and Y chromosomes evolved from an ordinary pair of autosomes, but millions of years ago genetic decay ravaged the Y chromosome, and only three per cent of its ancestral genes survived. We reconstructed the evolution of the Y chromosome across eight mammals to identify biases in gene content and the selective pressures that preserved the surviving ancestral genes. Our findings indicate that survival was nonrandom, and in two cases, convergent across placental and marsupial mammals. We conclude that the gene content of the Y chromosome became specialized through selection to maintain the ancestral dosage of homologous X-Y gene pairs that function as broadly expressed regulators of transcription, translation and protein stability. We propose that beyond its roles in testis determination and spermatogenesis, the Y chromosome is essential for male viability, and has unappreciated roles in Turner's syndrome and in phenotypic differences between the sexes in health and disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4139287/" 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/PMC4139287/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bellott, Daniel W -- Hughes, Jennifer F -- Skaletsky, Helen -- Brown, Laura G -- Pyntikova, Tatyana -- Cho, Ting-Jan -- Koutseva, Natalia -- Zaghlul, Sara -- Graves, Tina -- Rock, Susie -- Kremitzki, Colin -- Fulton, Robert S -- Dugan, Shannon -- Ding, Yan -- Morton, Donna -- Khan, Ziad -- Lewis, Lora -- Buhay, Christian -- Wang, Qiaoyan -- Watt, Jennifer -- Holder, Michael -- Lee, Sandy -- Nazareth, Lynne -- Alfoldi, Jessica -- Rozen, Steve -- Muzny, Donna M -- Warren, Wesley C -- Gibbs, Richard A -- Wilson, Richard K -- Page, David C -- P51 RR013986/RR/NCRR NIH HHS/ -- U54 HG003079/HG/NHGRI NIH HHS/ -- U54 HG003273/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Apr 24;508(7497):494-9. doi: 10.1038/nature13206.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute, Howard Hughes Medical Institute, & Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. ; The Genome Institute, Washington University School of Medicine, St. Louis, Missouri 63108, USA. ; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24759411" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chromosomes, Human, X/genetics ; Chromosomes, Human, Y/genetics ; Disease ; *Evolution, Molecular ; Female ; Gene Dosage/*genetics ; Gene Expression Regulation ; Health ; Humans ; Male ; Mammals/*genetics ; Marsupialia/genetics ; Molecular Sequence Annotation ; Molecular Sequence Data ; Protein Biosynthesis/genetics ; Protein Stability ; Selection, Genetic/genetics ; Sequence Homology ; Sex Characteristics ; Spermatogenesis/genetics ; Testis/metabolism ; Transcription, Genetic/genetics ; Turner Syndrome/genetics ; X Chromosome/genetics ; Y Chromosome/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2015-11-19
    Description: Acorn worms, also known as enteropneust (literally, 'gut-breathing') hemichordates, are marine invertebrates that share features with echinoderms and chordates. Together, these three phyla comprise the deuterostomes. Here we report the draft genome sequences of two acorn worms, Saccoglossus kowalevskii and Ptychodera flava. By comparing them with diverse bilaterian genomes, we identify shared traits that were probably inherited from the last common deuterostome ancestor, and then explore evolutionary trajectories leading from this ancestor to hemichordates, echinoderms and chordates. The hemichordate genomes exhibit extensive conserved synteny with amphioxus and other bilaterians, and deeply conserved non-coding sequences that are candidates for conserved gene-regulatory elements. Notably, hemichordates possess a deuterostome-specific genomic cluster of four ordered transcription factor genes, the expression of which is associated with the development of pharyngeal 'gill' slits, the foremost morphological innovation of early deuterostomes, and is probably central to their filter-feeding lifestyle. Comparative analysis reveals numerous deuterostome-specific gene novelties, including genes found in deuterostomes and marine microbes, but not other animals. The putative functions of these genes can be linked to physiological, metabolic and developmental specializations of the filter-feeding ancestor.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729200/" 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/PMC4729200/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Simakov, Oleg -- Kawashima, Takeshi -- Marletaz, Ferdinand -- Jenkins, Jerry -- Koyanagi, Ryo -- Mitros, Therese -- Hisata, Kanako -- Bredeson, Jessen -- Shoguchi, Eiichi -- Gyoja, Fuki -- Yue, Jia-Xing -- Chen, Yi-Chih -- Freeman, Robert M Jr -- Sasaki, Akane -- Hikosaka-Katayama, Tomoe -- Sato, Atsuko -- Fujie, Manabu -- Baughman, Kenneth W -- Levine, Judith -- Gonzalez, Paul -- Cameron, Christopher -- Fritzenwanker, Jens H -- Pani, Ariel M -- Goto, Hiroki -- Kanda, Miyuki -- Arakaki, Nana -- Yamasaki, Shinichi -- Qu, Jiaxin -- Cree, Andrew -- Ding, Yan -- Dinh, Huyen H -- Dugan, Shannon -- Holder, Michael -- Jhangiani, Shalini N -- Kovar, Christie L -- Lee, Sandra L -- Lewis, Lora R -- Morton, Donna -- Nazareth, Lynne V -- Okwuonu, Geoffrey -- Santibanez, Jireh -- Chen, Rui -- Richards, Stephen -- Muzny, Donna M -- Gillis, Andrew -- Peshkin, Leonid -- Wu, Michael -- Humphreys, Tom -- Su, Yi-Hsien -- Putnam, Nicholas H -- Schmutz, Jeremy -- Fujiyama, Asao -- Yu, Jr-Kai -- Tagawa, Kunifumi -- Worley, Kim C -- Gibbs, Richard A -- Kirschner, Marc W -- Lowe, Christopher J -- Satoh, Noriyuki -- Rokhsar, Daniel S -- Gerhart, John -- HD37277/HD/NICHD NIH HHS/ -- HD42724/HD/NICHD NIH HHS/ -- R01 HD037277/HD/NICHD NIH HHS/ -- R01 HD073104/HD/NICHD NIH HHS/ -- R01HD073104/HD/NICHD NIH HHS/ -- T32 HD055164/HD/NICHD NIH HHS/ -- U54 HG003273/HG/NHGRI NIH HHS/ -- England -- Nature. 2015 Nov 26;527(7579):459-65. doi: 10.1038/nature16150. Epub 2015 Nov 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Genetics Unit, Okinawa Institute of Science and Technology Graduate University, Onna, Okinawa 904-0495, Japan. ; Department of Molecular Evolution, Centre for Organismal Studies, University of Heidelberg, 69115 Heidelberg, Germany. ; Marine Genomics Unit, Okinawa Institute of Science and Technology Graduate University, Onna, Okinawa 904-0495, Japan. ; Department of Zoology, University of Oxford, Oxford OX1 3PS, UK. ; HudsonAlpha Institute of Biotechnology, Huntsville, Alabama 35806, USA. ; DNA Sequencing Section, Okinawa Institute of Science and Technology Graduate University, Onna, Okinawa 904-0495, Japan. ; Department of Molecular and Cell Biology, University of California, Berkeley California 94720-3200, USA. ; Department of Ecology and Evolutionary Biology, Rice University, Houston, Texas 77005, USA. ; Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 11529, Taiwan. ; Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Marine Biological Laboratory, Graduate School of Science, Hiroshima University, Onomichi, Hiroshima 722-0073, Japan. ; Natural Science Center for Basic Research and Development, Gene Science Division, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8527, Japan. ; Marine Biological Association of the UK, The Laboratory, Citadel Hill, Plymouth PL1 2PB, UK. ; Department of Biology, Hopkins Marine Station, Stanford University, Pacific Grove, California 93950, USA. ; Department de sciences biologiques, University of Montreal, Quebec H3C 3J7, Canada. ; University of North Caroline at Chapel Hill, North Carolina 27599, USA. ; Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, MS BCM226, Houston, Texas 77030, USA. ; Department of Zoology, University of Cambridge, Cambridge CB2 3EJ, UK. ; Institute for Biogenesis Research, University of Hawaii, Hawaii 96822, USA. ; National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan. ; US Department of Energy Joint Genome Institute, Walnut Creek, California 94598, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26580012" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chordata, Nonvertebrate/classification/*genetics ; Conserved Sequence/genetics ; Echinodermata/classification/genetics ; *Evolution, Molecular ; Genome/*genetics ; Multigene Family/genetics ; Phylogeny ; Signal Transduction ; Synteny/genetics ; Transforming Growth Factor beta
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2011-09-02
    Description: Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) 〈/= 18.5 kg per m(2) in adults and 〈/= -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a approximately 600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3637175/" 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/PMC3637175/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jacquemont, Sebastien -- Reymond, Alexandre -- Zufferey, Flore -- Harewood, Louise -- Walters, Robin G -- Kutalik, Zoltan -- Martinet, Danielle -- Shen, Yiping -- Valsesia, Armand -- Beckmann, Noam D -- Thorleifsson, Gudmar -- Belfiore, Marco -- Bouquillon, Sonia -- Campion, Dominique -- de Leeuw, Nicole -- de Vries, Bert B A -- Esko, Tonu -- Fernandez, Bridget A -- Fernandez-Aranda, Fernando -- Fernandez-Real, Jose Manuel -- Gratacos, Monica -- Guilmatre, Audrey -- Hoyer, Juliane -- Jarvelin, Marjo-Riitta -- Kooy, R Frank -- Kurg, Ants -- Le Caignec, Cedric -- Mannik, Katrin -- Platt, Orah S -- Sanlaville, Damien -- Van Haelst, Mieke M -- Villatoro Gomez, Sergi -- Walha, Faida -- Wu, Bai-Lin -- Yu, Yongguo -- Aboura, Azzedine -- Addor, Marie-Claude -- Alembik, Yves -- Antonarakis, Stylianos E -- Arveiler, Benoit -- Barth, Magalie -- Bednarek, Nathalie -- Bena, Frederique -- Bergmann, Sven -- Beri, Mylene -- Bernardini, Laura -- Blaumeiser, Bettina -- Bonneau, Dominique -- Bottani, Armand -- Boute, Odile -- Brunner, Han G -- Cailley, Dorothee -- Callier, Patrick -- Chiesa, Jean -- Chrast, Jacqueline -- Coin, Lachlan -- Coutton, Charles -- Cuisset, Jean-Marie -- Cuvellier, Jean-Christophe -- David, Albert -- de Freminville, Benedicte -- Delobel, Bruno -- Delrue, Marie-Ange -- Demeer, Benedicte -- Descamps, Dominique -- Didelot, Gerard -- Dieterich, Klaus -- Disciglio, Vittoria -- Doco-Fenzy, Martine -- Drunat, Severine -- Duban-Bedu, Benedicte -- Dubourg, Christele -- El-Sayed Moustafa, Julia S -- Elliott, Paul -- Faas, Brigitte H W -- Faivre, Laurence -- Faudet, Anne -- Fellmann, Florence -- Ferrarini, Alessandra -- Fisher, Richard -- Flori, Elisabeth -- Forer, Lukas -- Gaillard, Dominique -- Gerard, Marion -- Gieger, Christian -- Gimelli, Stefania -- Gimelli, Giorgio -- Grabe, Hans J -- Guichet, Agnes -- Guillin, Olivier -- Hartikainen, Anna-Liisa -- Heron, Delphine -- Hippolyte, Loyse -- Holder, Muriel -- Homuth, Georg -- Isidor, Bertrand -- Jaillard, Sylvie -- Jaros, Zdenek -- Jimenez-Murcia, Susana -- Helas, Geraldine Joly -- Jonveaux, Philippe -- Kaksonen, Satu -- Keren, Boris -- Kloss-Brandstatter, Anita -- Knoers, Nine V A M -- Koolen, David A -- Kroisel, Peter M -- Kronenberg, Florian -- Labalme, Audrey -- Landais, Emilie -- Lapi, Elisabetta -- Layet, Valerie -- Legallic, Solenn -- Leheup, Bruno -- Leube, Barbara -- Lewis, Suzanne -- Lucas, Josette -- MacDermot, Kay D -- Magnusson, Pall -- Marshall, Christian -- Mathieu-Dramard, Michele -- McCarthy, Mark I -- Meitinger, Thomas -- Mencarelli, Maria Antonietta -- Merla, Giuseppe -- Moerman, Alexandre -- Mooser, Vincent -- Morice-Picard, Fanny -- Mucciolo, Mafalda -- Nauck, Matthias -- Ndiaye, Ndeye Coumba -- Nordgren, Ann -- Pasquier, Laurent -- Petit, Florence -- Pfundt, Rolph -- Plessis, Ghislaine -- Rajcan-Separovic, Evica -- Ramelli, Gian Paolo -- Rauch, Anita -- Ravazzolo, Roberto -- Reis, Andre -- Renieri, Alessandra -- Richart, Cristobal -- Ried, Janina S -- Rieubland, Claudine -- Roberts, Wendy -- Roetzer, Katharina M -- Rooryck, Caroline -- Rossi, Massimiliano -- Saemundsen, Evald -- Satre, Veronique -- Schurmann, Claudia -- Sigurdsson, Engilbert -- Stavropoulos, Dimitri J -- Stefansson, Hreinn -- Tengstrom, Carola -- Thorsteinsdottir, Unnur -- Tinahones, Francisco J -- Touraine, Renaud -- Vallee, Louis -- van Binsbergen, Ellen -- Van der Aa, Nathalie -- Vincent-Delorme, Catherine -- Visvikis-Siest, Sophie -- Vollenweider, Peter -- Volzke, Henry -- Vulto-van Silfhout, Anneke T -- Waeber, Gerard -- Wallgren-Pettersson, Carina -- Witwicki, Robert M -- Zwolinksi, Simon -- Andrieux, Joris -- Estivill, Xavier -- Gusella, James F -- Gustafsson, Omar -- Metspalu, Andres -- Scherer, Stephen W -- Stefansson, Kari -- Blakemore, Alexandra I F -- Beckmann, Jacques S -- Froguel, Philippe -- 090532/Wellcome Trust/United Kingdom -- 1RL1MH083268-01/MH/NIMH NIH HHS/ -- 5R01HL087679-02/HL/NHLBI NIH HHS/ -- 5R01MH63706:02/MH/NIMH NIH HHS/ -- AS2173/Autism Speaks/ -- G0500539/Medical Research Council/United Kingdom -- G0600705/Medical Research Council/United Kingdom -- G0801056/Medical Research Council/United Kingdom -- GM061354/GM/NIGMS NIH HHS/ -- MH071425/MH/NIMH NIH HHS/ -- MOP 74502/Canadian Institutes of Health Research/Canada -- Wellcome Trust/United Kingdom -- England -- Nature. 2011 Aug 31;478(7367):97-102. doi: 10.1038/nature10406.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21881559" target="_blank"〉PubMed〈/a〉
    Keywords: Adolescent ; Adult ; Aged ; Aging ; Body Height/genetics ; *Body Mass Index ; Case-Control Studies ; Child ; Child, Preschool ; Chromosomes, Human, Pair 16/*genetics ; Cohort Studies ; Comparative Genomic Hybridization ; Developmental Disabilities/genetics ; Energy Metabolism/genetics ; Europe ; Female ; Gene Dosage/*genetics ; Gene Duplication/genetics ; Gene Expression Profiling ; Genetic Predisposition to Disease/genetics ; Genome-Wide Association Study ; Head/anatomy & histology ; Heterozygote ; Humans ; Infant ; Infant, Newborn ; Male ; Mental Disorders/genetics ; Middle Aged ; Mutation/genetics ; North America ; Obesity/*genetics ; *Phenotype ; RNA, Messenger/analysis/genetics ; Sequence Deletion/genetics ; Thinness/*genetics ; Transcription, Genetic ; Young Adult
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Abstract: Genotoxicity models are extremely important to assess retroviral vector biosafety before gene therapy. We have developed an in utero model that demonstrates that hepatocellular carcinoma (HCC) development is restricted to mice receiving nonprimate (np) lentiviral vectors (LV) and does not occur when a primate (p) LV is used regardless of woodchuck post-translation regulatory element (WPRE) mutations to prevent truncated X gene expression. Analysis of 839 npLV and 244 pLV integrations in the liver genomes of vector-treated mice revealed clear differences between vector insertions in gene dense regions and highly expressed genes, suggestive of vector preference for insertion or clonal outgrowth. In npLV-associated clonal tumors, 56% of insertions occurred in oncogenes or genes associated with oncogenesis or tumor suppression and surprisingly, most genes examined (11/12) had reduced expression as compared with control livers and tumors. Two examples of vector-inserted genes were the Park 7 oncogene and Uvrag tumor suppressor gene. Both these genes and their known interactive partners had differential expression profiles. Interactive partners were assigned to networks specific to liver disease and HCC via ingenuity pathway analysis. The fetal mouse model not only exposes the genotoxic potential of vectors intended for gene therapy but can also reveal genes associated with liver oncogenesis.
    Type of Publication: Journal article published
    PubMed ID: 23299800
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  • 6
  • 7
  • 8
    Keywords: CLASSIFICATION ; DIAGNOSIS ; RISK ; GANCICLOVIR ; EBV ; B-LYMPHOCYTES ; POSTTRANSPLANT-LYMPHOPROLIFERATIVE-DISORDER ; SOLID-ORGAN TRANSPLANT ; CHRONIC ALLOGRAFT INJURY ; VIRAL LOAD CARRIAGE
    Abstract: Background. The epidemiology and morbidity of Epstein-Barr virus (EBV) infection in pediatric renal transplant recipients have been characterized insufficiently. Methods. In a prospective, multicenter study among 106 pediatric kidney allograft recipients aged 11.4 +/- 5.9 years, we investigated the epidemiology of EBV infection and the relationship between EBV load, EBV serology, and EBV-related morbidity (posttransplant lymphoproliferative disease [PTLD] or symptomatic EBV infection, defined as flu-like symptoms or infectious mononucleosis). Results. EBV primary infection occurred in 27 of 43 (63%) seronegative patients and reactivation/reinfection in 28 of 63 (44%) seropositive patients. There was no association between the degree or duration of EBV load and EBV-related morbidity: The vast majority (17 of 18 [94%]) of patients with a high, persistent EBV load remained PTLD-free throughout a follow-up of 5.0 +/- 1.3 years, while 2 of 3 (66%) patients with EBV-related PTLD exhibited only a low EBV load beforehand. Eight of 18 (44%) patients with a high, persistent EBV load remained asymptomatic during a follow-up of 5.3 +/- 2.9 years. Multivariate analysis identified the EBV high-risk (D(+)/R(-)) serostatus (odds ratio [OR], 7.07; P 〈 .05), the presence of human leukocyte antigen (HLA)-DR7 (OR, 5.65; P 〈 .05), and the intensity of the immunosuppressive therapy (OR, 1.53; P 〈 .01) as independent risk factors for the development of a symptomatic EBV infection. Conclusions. Presence of EBV high-risk seroconstellation, HLA-DR7, and intensity of immunosuppressive therapy are significant risk factors for a symptomatic EBV infection, whereas there is no close association between the degree or duration of EBV load and EBV-related morbidity. Clinical Trials Registration. NCT00963248.
    Type of Publication: Journal article published
    PubMed ID: 23042966
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  • 9
    ISSN: 0168-9002
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 0370-2693
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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