Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage
Chen, Zhongbo (Department of Genetics and Genomic Medicine. Great Ormond Street Institute of Child Health. University College London)
Zhang, David (Department of Genetics and Genomic Medicine. Great Ormond Street Institute of Child Health. University College London)
Reynolds, Regina H. (Department of Genetics and Genomic Medicine. Great Ormond Street Institute of Child Health. University College London)
Gustavsson, Emil K. (Department of Genetics and Genomic Medicine. Great Ormond Street Institute of Child Health. University College London)
García-Ruiz, Sonia (Department of Genetics and Genomic Medicine. Great Ormond Street Institute of Child Health. University College London)
D'Sa, Karishma (Department of Genetics and Genomic Medicine. Great Ormond Street Institute of Child Health. University College London)
Fairbrother-Browne, Aine (Department of Genetics and Genomic Medicine. Great Ormond Street Institute of Child Health. University College London)
Vandrovcova, Jana (UCL Queen Square Institute of Neurology (Regne Unit))
Noyce, Alastair J. (UCL Queen Square Institute of Neurology (Regne Unit))
Kaiyrzhanov, Rauan (UCL Queen Square Institute of Neurology (Regne Unit))
Middlehurst, Ben (Institute of Translational Medicine. University of Liverpool)
Kia, Demis A. (UCL Queen Square Institute of Neurology (Regne Unit))
Tan, Manuela (UCL Queen Square Institute of Neurology (Regne Unit))
Morris, Huw R. (UCL Queen Square Institute of Neurology (Regne Unit))
Plun-Favreau, Helen (UCL Queen Square Institute of Neurology (Regne Unit))
Holmans, Peter (MRC Centre for Neuropsychiatric Genetics & Genomics)
Trabzuni, Daniah (Department of Genetics. King Faisal Specialist Hospital and Research Centre)
Bras, Jose (UCL Queen Square Institute of Neurology (Regne Unit))
Quinn, John (Institute of Translational Medicine. University of Liverpool)
Mok, Kin Y. (UCL Queen Square Institute of Neurology (Regne Unit))
Kinghorn, Kerri J. (Institute of Healthy Ageing. University College London (UCL))
Billingsley, Kimberley (Institute of Translational Medicine. University of Liverpool)
Wood, Nicholas W.. (UCL Queen Square Institute of Neurology (Regne Unit))
Lewis, Patrick (University of Reading)
Schreglmann, Sebastian (UCL Queen Square Institute of Neurology (Regne Unit))
Guerreiro, Rita (UK Dementia Research Institute. University College London (UCL))
Lovering, Ruth (Institute of Cardiovascular Science. University College London (UCL))
R'Bibo, Lea (UCL Queen Square Institute of Neurology (Regne Unit))
Manzoni, Claudia (University of Reading)
Rizig, Mie (UCL Queen Square Institute of Neurology (Regne Unit))
Guelfi, Sebastian (Department of Neurodegenerative Disease. Queen Square Institute of Neurology. University College London (UCL))
Escott-Price, Valentina (Cardiff University School of Medicine)
Chelban, Viorica (UCL Queen Square Institute of Neurology (Regne Unit))
Foltynie, Thomas (UCL Queen Square Institute of Neurology (Regne Unit))
Williams, Nigel (Cardiff University School of Medicine)
Brice, Alexis (Institut du Cerveau et de la Moelle épinière (París, França))
Danjou, Fabrice (Institut du Cerveau et de la Moelle épinière (París, França))
Lesage, Suzanne (Institut du Cerveau et de la Moelle épinière (París, França))
Corvol, Jean-Christophe (Institut du Cerveau et de la Moelle épinière (París, França))
Martinez Rande, Maria (INSERM UMR 1220 and Paul Sabatier University)
Schulte, Claudia (German Center for Neurodegenerative Diseases)
Brockmann, Kathrin (German Center for Neurodegenerative Diseases)
Simón-Sánchez, Javier (German Center for Neurodegenerative Diseases)
Heutink, Peter (German Center for Neurodegenerative Diseases)
Rizzu, Patrizia (German Center for Neurodegenerative Diseases)
Sharma, Manu (Centre for Genetic Epidemiology. Institute for Clinical Epidemiology and Applied Biometry. University of Tubingen)
Gasser, Thomas (German Center for Neurodegenerative Diseases)
Nicolas, Aude (National Institute on Aging (Estats Units d'Amèrica))
Cookson, Mark R (National Institute on Aging (Estats Units d'Amèrica))
Bandres-Ciga, Sara (National Institute on Aging (Estats Units d'Amèrica))
Blauwendraat, Cornelis (National Institute of Neurological Disorders and Stroke)
Craig, David W (Department of Translational Genomics. Keck School of Medicine. University of Southern California)
Faghri, Faraz (Department of Computer Science. University of Illinois at Urbana-Champaign)
Gibbs, J.Raphael (National Institute on Aging (Estats Units d'Amèrica))
Hernandez, Dena G. (National Institute on Aging (Estats Units d'Amèrica))
Van Keuren-Jensen, Kendall (Neurogenomics Division. TGen)
Shulman, Joshua M. (Jan and Dan Duncan Neurological Research Institute. Texas Children's Hospital)
Leonard, Hampton L. (Laboratory of Neurogenetics. National Institute on Aging)
Nalls, Mike A. (Data Tecnica International)
Robak, Laurie (Jan and Dan Duncan Neurological Research Institute. Texas Children's Hospital)
Lubbe, Steven (Ken and Ruth Davee Department of Neurology. Northwestern University Feinberg School of Medicine)
Finkbeiner, Steven (Taube/Koret Center for Neurodegenerative Disease Research)
Mencacci, Niccolo E. (Northwestern University Feinberg School of Medicine)
Lungu, Codrin (National Institutes of Health Division of Clinical Research. NINDS. National Institutes of Health)
Singleton, Andrew B. (Laboratory of Neurogenetics. National Institute on Aging)
Scholz, Sonja (Neurodegenerative Diseases Research Unit. National Institute of Neurological Disorders and Stroke)
Reed, Xylena (Laboratory of Neurogenetics. National Institute on Aging)
Alcalay, Roy N (Taub Institute for Research on Alzheimer's Disease and the Aging Brain. College of Physicians and Surgeons. Columbia University Medical Center)
Gan-Or, Ziv (McGill University)
Rouleau, Guy A. (McGill University)
Krohn, Lynne (McGill University)
van Hilten, Jacobus J. (Department of Neurology. Leiden University Medical Center)
Marinus, Johan (Department of Neurology. Leiden University Medical Center)
Adarmes-Gómez, A.D (Instituto de Biomedicina de Sevilla)
Aguilar Barberà, Miquel (Fundacio per la Recerca Biomedica i Social Mutua Terrassa)
Alvarez, Ignacio (Hospital Universitari MútuaTerrassa (Terrassa, Catalunya))
Alvarez, Victoria (Hospital Universitario Central de Asturias)
Barrero, Francisco Javier (Hospital Universitario San Cecilio (Granada))
Bergareche Yarza, Jesús Alberto (Biodonostia Osasun Ikerketako Institutura (País Basc))
Bernal-Bernal, Inmaculada (Hospital Clínic i Provincial de Barcelona)
Blázquez Estrada, Marta (Hospital Universitario Central de Asturias)
Bonilla-Toribio, Marta (Hospital Clínic i Provincial de Barcelona)
Botía, Juan (Universidad de Murcia. Departamento de Ingeniería de la Información y las Comunicaciones)
Boungiorno, M. T (Fundacio per la Recerca Biomedica i Social Mutua Terrassa)
Buiza-Rueda, Dolores (Instituto de Biomedicina de Sevilla)
Cámara, Ana (Hospital Clínic i Provincial de Barcelona)
Carrillo, Fátima (Instituto de Biomedicina de Sevilla)
Carrión-Claro, M (Instituto de Biomedicina de Sevilla)
Cerdan, Debora (Hospital General de Segovia)
Clarimón, Jordi (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
Compta, Yaroslau (Hospital Clínic i Provincial de Barcelona)
Diez-Fairen, Monica (Fundacio per la Recerca Biomedica i Social Mutua Terrassa)
Dols Icardo, Oriol (Institut d'Investigació Biomèdica Sant Pau)
Duarte, Jacinto (Hospital General de Segovia)
Duran, Raquel (Centro de Investigacion Biomedica. Universidad de Granada)
Escamilla-Sevilla, Francisco (Instituto de Investigación Sanitaria de Granada)
Ezquerra, Mario (Hospital Clínic i Provincial de Barcelona)
Feliz, Cici (Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz)
Fernández, Manel (Hospital Clínic i Provincial de Barcelona)
Fernández-Santiago, Rubén (Hospital Clínic i Provincial de Barcelona)
Garcia, Ciara (Hospital Universitario Central de Asturias)
García-Ruiz, Pedro (Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz)
Gómez-Garre, Pilar (Instituto de Biomedicina de Sevilla)
Gomez Heredia, Maria Jose (Hospital Universitario Virgen de la Victoria (Màlaga, Andalusia))
Gonzalez-Aramburu, Isabel (Instituto de Investigación Sanitaria Valdecilla (Santander, Cantàbria))
Gorostidi Pagola, Ana (Biodonostia Osasun Ikerketako Institutura (País Basc))
Hoenicka, Janet (Institut de Recerca Sant Joan de Déu)
Infante, Jon (Hospital Universitario Ramón y Cajal (Madrid))
Jesús, Silvia (Instituto de Biomedicina de Sevilla)
Jimenez-Escrig, Adriano (Hospital Universitario Ramón y Cajal (Madrid))
Kulisevsky, Jaime (Institut d'Investigació Biomèdica Sant Pau)
Labrador-Espinosa, Miguel A (Instituto de Biomedicina de Sevilla)
Lopez-Sendon, Jose Luis (Hospital Universitario Ramón y Cajal (Madrid))
López de Munain Arregui, Adolfo (Biodonostia Osasun Ikerketako Institutura (País Basc))
Macias, Daniel (Instituto de Biomedicina de Sevilla)
Martínez Torres, Irene (Hospital Universitari i Politècnic La Fe (València))
Marín, Juan (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
Marti, Maria Jose (Hospital Clínic i Provincial de Barcelona)
Martínez-Castrillo, Juan Carlos (Hospital Universitario Ramón y Cajal (Madrid))
Méndez-del-Barrio, Carlota (Instituto de Biomedicina de Sevilla)
Menéndez González, Manuel (Hospital Universitario Central de Asturias)
Mata, Marina (Hospital Universitario Infanta Sofía (San Sebastián de los Reyes))
Mínguez, Adolfo (Instituto de Investigación Sanitaria de Granada)
Mir, Pablo (Instituto de Biomedicina de Sevilla)
Mondragon Rezola, Elisabet (Biodonostia Osasun Ikerketako Institutura (País Basc))
Muñoz, Esteban (Instituto de Biomedicina de Sevilla)
Pagonabarraga Mora, Javier (Institut d'Investigació Biomèdica Sant Pau)
Pastor, Pau (Hospital Universitari MútuaTerrassa (Terrassa, Catalunya))
Perez Errazquin, Francisco (Hospital Universitario Virgen de la Victoria (Màlaga, Andalusia))
Periñán-Tocino, Teresa (Instituto de Biomedicina de Sevilla)
Ruiz-Martínez, Javier (Hospital Universitario Donostia. Instituto de Investigación Sanitaria Biodonostia)
Ruz, Clara (Centro de Investigacion Biomedica. Universidad de Granada)
Sanchez Rodriguez, Antonio (Instituto de Investigación Sanitaria Valdecilla (Santander, Cantàbria))
Sierra, María (Instituto de Investigación Sanitaria Valdecilla (Santander, Cantàbria))
Suarez-Sanmartin, Esther (Hospital Universitario Central de Asturias)
Tabernero, Cesar (Hospital General de Segovia)
Tartari, Juan Pablo (Hospital Universitari MútuaTerrassa (Terrassa, Catalunya))
Tejera-Parrado, Cristina (Instituto de Biomedicina de Sevilla)
Tolosa, Eduard (Hospital Clínic i Provincial de Barcelona)
Valldeoriola, Francesc (Hospital Clínic i Provincial de Barcelona)
Vargas-González, Laura (Instituto de Biomedicina de Sevilla)
Vela, Lydia (Hospital Universitario Fundación Alcorcón)
Vives, Francisco (Centro de Investigacion Biomedica. Universidad de Granada)
Zimprich, Alexander (Department of Neurology. Medical University of Vienna)
Pihlstrom, Lasse (Oslo University Hospital (Oslo, Noruega))
Toft, Mathias (Oslo University Hospital (Oslo, Noruega))
Koks, Sulev (Department of Reproductive Biology. Estonian University of Life Sciences)
Taba, Pille (Department of Neurology and Neurosurgery. University of Tartu)
Hassin-Baer, Sharon (Sackler Faculty of Medicine. Tel Aviv University)
Hardy, John (Institute for Advanced Study. The Hong Kong University of Science and Technology. The Hong Kong University of Science and Technology)
Houlden, Henry (Department of Neuromuscular Disease. Queen Square Institute of Neurology. UCL)
Gagliano Taliun, Sarah A. (Montréal Heart Institute)
Botía, Juan (Universidad de Murcia. Departamento de Ingeniería de la Información y las Comunicaciones)
Ryten, Mina (Great Ormond Street Institute of Child Health (Londres, Regne Unit))
Universitat Autònoma de Barcelona

Fecha:	2021
Resumen:	Knowledge of genomic features specific to the human lineage may provide insights into brain-related diseases. We leverage high-depth whole genome sequencing data to generate a combined annotation identifying regions simultaneously depleted for genetic variation (constrained regions) and poorly conserved across primates. We propose that these constrained, non-conserved regions (CNCRs) have been subject to human-specific purifying selection and are enriched for brain-specific elements. We find that CNCRs are depleted from protein-coding genes but enriched within lncRNAs. We demonstrate that per-SNP heritability of a range of brain-relevant phenotypes are enriched within CNCRs. We find that genes implicated in neurological diseases have high CNCR density, including APOE, highlighting an unannotated intron-3 retention event. Using human brain RNA-sequencing data, we show the intron-3-retaining transcript to be more abundant in Alzheimer's disease with more severe tau and amyloid pathological burden. Thus, we demonstrate potential association of human-lineage-specific sequences in brain development and neurological disease.
Nota:	Altres ajuts: Leonard Wolfson Foundation; United Kingdom Medical Research Council (MRC, MR/N008324/1); DRI Limited; UK Medical Research Council; Alzheimer's Society and Alzheimer's Research UK; Medical Research Council (MR/N026004/1); Wellcome Trust (202903/Z/16/Z); Dolby Family Fund; National Institute for Health Research; University College London; Fundación Séneca, Agencia de Ciencia y Tecnología de la Región de Murcia (00007/COVI/20).
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Alzheimer Disease ; Apolipoproteins E ; Brain ; Chromosomes, Human, Pair 19 ; Conserved Sequence ; DNA, Intergenic ; Gene Ontology ; Genome, Human ; Humans ; Introns ; Linkage Disequilibrium ; Molecular Sequence Annotation ; Neurodegenerative Diseases ; Phenotype ; Phylogeny ; Polymorphism, Single Nucleotide ; Regression Analysis ; RNA, Long Noncoding ; RNA, Messenger
Publicado en:	Nature communications, Vol. 12 Núm. 1 (january 2021) , p. 2076, ISSN 2041-1723

DOI: 10.1038/s41467-021-22262-5
PMID: 33824317

13 p, 2.4 MB

El registro aparece en las colecciones:
Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut de Recerca Sant Pau
Artículos > Artículos de investigación
Artículos > Artículos publicados