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  • 1
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    Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-01-20
    Description: Mitochondrial morphology is shaped by fusion and division of their membranes. Here, we found that adult myocardial function depends on balanced mitochondrial fusion and fission, maintained by processing of the dynamin-like guanosine triphosphatase OPA1 by the mitochondrial peptidases YME1L and OMA1. Cardiac-specific ablation of Yme1l in mice activated OMA1 and accelerated OPA1 proteolysis, which triggered mitochondrial fragmentation and altered cardiac metabolism. This caused dilated cardiomyopathy and heart failure. Cardiac function and mitochondrial morphology were rescued by Oma1 deletion, which prevented OPA1 cleavage. Feeding mice a high-fat diet or ablating Yme1l in skeletal muscle restored cardiac metabolism and preserved heart function without suppressing mitochondrial fragmentation. Thus, unprocessed OPA1 is sufficient to maintain heart function, OMA1 is a critical regulator of cardiomyocyte survival, and mitochondrial morphology and cardiac metabolism are intimately linked.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wai, Timothy -- Garcia-Prieto, Jaime -- Baker, Michael J -- Merkwirth, Carsten -- Benit, Paule -- Rustin, Pierre -- Ruperez, Francisco Javier -- Barbas, Coral -- Ibanez, Borja -- Langer, Thomas -- New York, N.Y. -- Science. 2015 Dec 4;350(6265):aad0116. doi: 10.1126/science.aad0116.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Genetics, University of Cologne, 50674 Cologne, Germany. Max-Planck-Institute for Biology of Aging, Cologne, Germany. ; Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain. ; Institute for Genetics, University of Cologne, 50674 Cologne, Germany. ; INSERM UMR 1141, Hopital Robert Debre, Paris, France. Universite Paris 7, Faculte de Medecine Denis Diderot, Paris, France. ; Centre for Metabolomics and Bioanalysis (CEMBIO), Faculty of Pharmacy, Universidad San Pablo CEU, Campus Monteprincipe, Boadilla del Monte, 28668 Madrid, Spain. ; Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain. Department of Cardiology, Instituto de Investigacion Sanitaria (IIS), Fundacion Jimenez Diaz Hospital, Madrid, Spain. thomas.langer@uni-koeln.de bibanez@cnic.es. ; Institute for Genetics, University of Cologne, 50674 Cologne, Germany. Max-Planck-Institute for Biology of Aging, Cologne, Germany. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany. Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany. thomas.langer@uni-koeln.de bibanez@cnic.es.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26785494" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cardiomyopathy, Dilated/genetics/metabolism/pathology ; Diet, High-Fat ; Embryonic Development ; Female ; GTP Phosphohydrolases ; Gene Deletion ; Heart/embryology ; Heart Failure/genetics/*metabolism/pathology ; Male ; Metalloendopeptidases/genetics ; Metalloproteases/genetics/metabolism ; Mice ; Mice, Knockout ; Mitochondria, Heart/*metabolism/ultrastructure ; *Mitochondrial Degradation ; *Mitochondrial Dynamics ; Mitochondrial Proteins/genetics/metabolism ; Muscle, Skeletal/enzymology ; Myocardium/*metabolism/pathology ; Myocytes, Cardiac/enzymology/pathology ; Proteolysis
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 2
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    Health and population effects of rare gene knockouts in adult humans with related parents (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-03-05
    Description: Examining complete gene knockouts within a viable organism can inform on gene function. We sequenced the exomes of 3222 British adults of Pakistani heritage with high parental relatedness, discovering 1111 rare-variant homozygous genotypes with predicted loss of function (knockouts) in 781 genes. We observed 13.7% fewer homozygous knockout genotypes than we expected, implying an average load of 1.6 recessive-lethal-equivalent loss-of-function (LOF) variants per adult. When genetic data were linked to the individuals' lifelong health records, we observed no significant relationship between gene knockouts and clinical consultation or prescription rate. In this data set, we identified a healthy PRDM9-knockout mother and performed phased genome sequencing on her, her child, and control individuals. Our results show that meiotic recombination sites are localized away from PRDM9-dependent hotspots. Thus, natural LOF variants inform on essential genetic loci and demonstrate PRDM9 redundancy in humans.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Narasimhan, Vagheesh M -- Hunt, Karen A -- Mason, Dan -- Baker, Christopher L -- Karczewski, Konrad J -- Barnes, Michael R -- Barnett, Anthony H -- Bates, Chris -- Bellary, Srikanth -- Bockett, Nicholas A -- Giorda, Kristina -- Griffiths, Christopher J -- Hemingway, Harry -- Jia, Zhilong -- Kelly, M Ann -- Khawaja, Hajrah A -- Lek, Monkol -- McCarthy, Shane -- McEachan, Rosie -- O'Donnell-Luria, Anne -- Paigen, Kenneth -- Parisinos, Constantinos A -- Sheridan, Eamonn -- Southgate, Laura -- Tee, Louise -- Thomas, Mark -- Xue, Yali -- Schnall-Levin, Michael -- Petkov, Petko M -- Tyler-Smith, Chris -- Maher, Eamonn R -- Trembath, Richard C -- MacArthur, Daniel G -- Wright, John -- Durbin, Richard -- van Heel, David A -- GM 099640/GM/NIGMS NIH HHS/ -- MR/M009017/1/Medical Research Council/United Kingdom -- R01 GM104371/GM/NIGMS NIH HHS/ -- R01GM104371/GM/NIGMS NIH HHS/ -- WT098051/Wellcome Trust/United Kingdom -- WT099769/Wellcome Trust/United Kingdom -- WT101597/Wellcome Trust/United Kingdom -- WT102627/Wellcome Trust/United Kingdom -- British Heart Foundation/United Kingdom -- Arthritis Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- Department of Health/United Kingdom -- Chief Scientist Office/United Kingdom -- New York, N.Y. -- Science. 2016 Apr 22;352(6284):474-7. doi: 10.1126/science.aac8624. Epub 2016 Mar 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. ; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK. ; Bradford Institute for Health Research, Bradford Teaching Hospitals National Health Service (NHS) Foundation Trust, Bradford BD9 6RJ, UK. ; Center for Genome Dynamics, The Jackson Laboratory, Bar Harbor, ME 04609, USA. ; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. ; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK. ; Diabetes and Endocrine Centre, Heart of England NHS Foundation Trust and University of Birmingham, Birmingham B9 5SS, UK. ; TPP, Mill House, Troy Road, Leeds LS18 5TN, UK. ; Aston Research Centre for Healthy Ageing, Aston University, Birmingham B4 7ET, UK. ; 10X Genomics, 7068 Koll Center Parkway, Suite 415, Pleasanton, CA 94566, USA. ; Farr Institute of Health Informatics Research, London NW1 2DA, UK. Institute of Health Informatics, University College London, London NW1 2DA, UK. ; School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK. ; Department of Medical Genetics, University of Cambridge and National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Box 238, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. ; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK. Faculty of Life Sciences and Medicine, King's College London, London SE1 1UL, UK. ; Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. rd@sanger.ac.uk d.vanheel@qmul.ac.uk. ; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK. rd@sanger.ac.uk d.vanheel@qmul.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26940866" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; *Consanguinity ; DNA Mutational Analysis ; Drug Prescriptions ; Exome/genetics ; Female ; Fertility ; Gene Knockout Techniques ; Genes, Lethal ; Genetic Loci ; Genome, Human ; Great Britain ; *Health ; Histone-Lysine N-Methyltransferase/*genetics ; Homologous Recombination ; Homozygote ; Humans ; Male ; Mothers ; Pakistan/ethnology ; Phenotype
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 3
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    Long-read sequence assembly of the gorilla genome (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-04-02
    Description: Accurate sequence and assembly of genomes is a critical first step for studies of genetic variation. We generated a high-quality assembly of the gorilla genome using single-molecule, real-time sequence technology and a string graph de novo assembly algorithm. The new assembly improves contiguity by two to three orders of magnitude with respect to previously released assemblies, recovering 87% of missing reference exons and incomplete gene models. Although regions of large, high-identity segmental duplications remain largely unresolved, this comprehensive assembly provides new biological insight into genetic diversity, structural variation, gene loss, and representation of repeat structures within the gorilla genome. The approach provides a path forward for the routine assembly of mammalian genomes at a level approaching that of the current quality of the human genome.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gordon, David -- Huddleston, John -- Chaisson, Mark J P -- Hill, Christopher M -- Kronenberg, Zev N -- Munson, Katherine M -- Malig, Maika -- Raja, Archana -- Fiddes, Ian -- Hillier, LaDeana W -- Dunn, Christopher -- Baker, Carl -- Armstrong, Joel -- Diekhans, Mark -- Paten, Benedict -- Shendure, Jay -- Wilson, Richard K -- Haussler, David -- Chin, Chen-Shan -- Eichler, Evan E -- HG002385/HG/NHGRI NIH HHS/ -- HG003079/HG/NHGRI NIH HHS/ -- HG007234/HG/NHGRI NIH HHS/ -- HG007635/HG/NHGRI NIH HHS/ -- HG007990/HG/NHGRI NIH HHS/ -- R01 HG002385/HG/NHGRI NIH HHS/ -- U41 HG007635/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Apr 1;352(6281):aae0344. doi: 10.1126/science.aae0344.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA. Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA. ; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA. ; Genomics Institute, University of California Santa Cruz and Howard Hughes Medical Institute, Santa Cruz, CA 95064, USA. ; McDonnell Genome Institute, Department of Medicine, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63108, USA. ; Pacific Biosciences of California, Menlo Park, CA 94025, USA. ; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA. Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA. eee@gs.washington.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27034376" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Contig Mapping ; Evolution, Molecular ; Expressed Sequence Tags ; Female ; Genetic Variation ; Genome, Human ; Genomics ; Gorilla gorilla/*genetics ; Humans ; Sequence Alignment ; Sequence Analysis, DNA/*methods
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 4
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    Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan (2016)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2016-02-04
    Description: Cellular senescence, a stress-induced irreversible growth arrest often characterized by expression of p16(Ink4a) (encoded by the Ink4a/Arf locus, also known as Cdkn2a) and a distinctive secretory phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing. Senescent cells accumulate in various tissues and organs over time, and have been speculated to have a role in ageing. To explore the physiological relevance and consequences of naturally occurring senescent cells, here we use a previously established transgene, INK-ATTAC, to induce apoptosis in p16(Ink4a)-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. We show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. The clearance of p16(Ink4a)-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels and adipocytes, respectively. Thus, p16(Ink4a)-positive cells that accumulate during adulthood negatively influence lifespan and promote age-dependent changes in several organs, and their therapeutic removal may be an attractive approach to extend healthy lifespan.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Baker, Darren J -- Childs, Bennett G -- Durik, Matej -- Wijers, Melinde E -- Sieben, Cynthia J -- Zhong, Jian -- Saltness, Rachel A -- Jeganathan, Karthik B -- Verzosa, Grace Casaclang -- Pezeshki, Abdulmohammad -- Khazaie, Khashayarsha -- Miller, Jordan D -- van Deursen, Jan M -- AG041122/AG/NIA NIH HHS/ -- HL111121/HL/NHLBI NIH HHS/ -- P01 AG041122/AG/NIA NIH HHS/ -- R01 CA096985/CA/NCI NIH HHS/ -- R01CA96985/CA/NCI NIH HHS/ -- England -- Nature. 2016 Feb 11;530(7589):184-9. doi: 10.1038/nature16932. Epub 2016 Feb 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. ; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. ; Division of Cardiovascular Surgery, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. ; Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26840489" target="_blank"〉PubMed〈/a〉
    Keywords: Adipocytes/cytology/pathology/physiology ; Aging/*pathology/*physiology ; Animals ; Apoptosis ; Cell Aging/*physiology ; Cell Separation ; Cell Transformation, Neoplastic/pathology ; Cyclin-Dependent Kinase Inhibitor p16/*metabolism ; Epithelial Cells/cytology/pathology ; Female ; *Health ; Kidney/cytology/pathology/physiology/physiopathology ; Lipodystrophy/pathology ; Longevity/*physiology ; Male ; Mice ; Myocardium/cytology/metabolism/pathology ; Organ Specificity ; Stem Cells/cytology/pathology ; Time Factors
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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