1. Characterization of an eutherian gene cluster generated after transposon domestication identifies Bex3 as relevant for advanced neurological functions
- Author
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Pol Cuscó, Demian Burguera, Salvatore D'Aniello, Cristina Vicente-García, Bru Cormand, Enrique Navas-Perez, José Luis Ferran, Jordi Garcia-Fernàndez, Carlos Herrera-Úbeda, Marta Alaiz-Noya, Rafael Falcón-Moya, Angel M. Carrión, Serena Mirra, Irene Suárez-Pereira, Gemma Marfany, Fausto Ulloa, Eduardo Soriano, Noèlia Fernàndez-Castillo, Ester Antón-Galindo, Jaime J. Carvajal, Antonio Rodríguez-Moreno, Macarena López-Mayorga, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), European Commission, Junta de Andalucía, Centro de Investigación Biomédica en Red Enfermedades Raras (España), [Navas-Pérez,E, Mirra,S, Burguera,D, Fernàndez-Castillo,N, Antón-Galindo,E, Herrera-Úbeda,C, Cormand,B, Marfany,G, Garcia-Fernàndez,J] Department of Genetics, Microbiology and Statistics, Faculty of Biology, and Institut de Biomedicina (IBUB), University of Barcelona, Barcelona, Spain. [Vicente-García,C, López-Mayorga,M, Carvajal,JJ] Centro Andaluz de Biología del Desarrollo, CSIC-UPO-JA, Universidad Pablo de Olavide, Sevilla, Spain. [Mirra,S, Ulloa,F, Soriano,E] Department of Cell Biology, Physiology and Immunology, and Institute of Neurosciences, University of Barcelona, Barcelona, Spain. [Mirra,S, Marfany,G] Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. [Mirra,S, Soriano,E] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. [Burguera,D] Department of Zoology, Charles University, Prague, Czech Republic. [Fernàndez-Castillo,N, Marfany,G] Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Barcelona, Spain. [Ferrán,JL] Department of Human Anatomy, School of Medicine, University of Murcia and IMIB-Arrixaca Institute, Murcia, Spain. [Alaiz-Noya,M, Suárez-Pereira,I, Falcón-Moya,R, Rodríguez-Moreno,A, Carrión,AM] Department of Physiology, Anatomy and Cell Biology, Universidad Pablo de Olavide, Sevilla, Spain. [Alaiz-Noya,M] Present Address: Instituto de Neurociencias de Alicante (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas), Alicante, Spain. [Suárez-Pereira,I] Present Address: Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Neuropsychopharmacology and psychobiology research group, UCA, INiBICA, Cádiz, Spain. [Cuscó,P] Genome Architecture, Gene Regulation, Stem Cells and Cancer Programme, Centre for Genomic Regulation (CRG), the Barcelona Institute of Science and Technology, Barcelona, Spain. [Cuscó,P] Universitat Pompeu Fabra (UPF), Barcelona, Spain. [D'Aniello,S] Department of Biology and Evolution of Marine Organisms, Stazione Zoologica Anton Dohrn, Naples, Italy. [Soriano,E] Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain., and Major financial support for this research was received from Spanish 'Ministerio de Ciencia, Innovación y Universidades.' Grants BFU2015-68655-P and BFU2017-861152-P to J.G.F., RTI2018-100968-B-I00, 2017-SGR-738, H2020/2014-2020 under grant agreements n°667302, n°643051, and n°728018 to B.C., PGC2018-098229-B-I00 to J.L.F., BES-2016-077374 to E.A.-G., CVI-7290 Junta de Andalucía to A.R.M., SAF2016-80937-R (Ministerio de Economía y Competitividad/FEDER) to G.M., Institutional Grant MDM-2016-0687 (Maria de Maeztu Excellence Unit, Department of Gene Regulation and Morphogenesis at CABD) and BFU2017-83150-P to J.J.C, BFU2017-89780-R and P12-CTS-2257 to A.M.C. and SAF2016-76340-R and María de Maeztu Excellence Unit, Institute of Neurosciences to E.S.. E.N.P. held an FPI pre-doctoral fellowship (Spanish 'Ministerio de Ciencia, Innovación y Universidades'). S.M. was first supported by a contract with the 'Centro de Investigación Biomédica en Enfermedades Neurodegenerativas,' and later by 'Centro de Investigación Biomédica en Red de Enfermedades Raras' (CIBERER). N.F.C. is also under contract by CIBERER. This study makes use of data generated by the DECIPHER community. A full list of centres who contributed to the generation of the data is available at http://decipher.sanger.ac.uk and via email from decipher@sanger.ac.uk. Funding for the project was provided by the Wellcome Trust.
- Subjects
Bex3 ,Tceal ,Placenta ,Autism ,Genome ,Neurodevelopmental disorders ,Familia de multigenes ,Domestication ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] ,Mice ,0302 clinical medicine ,Human genetics ,Pregnancy ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Nerve Tissue Proteins [Medical Subject Headings] ,Gene duplication ,Gene cluster ,Organisms::Eukaryota::Animals [Medical Subject Headings] ,Autism spectrum disorder ,Genetic novelty ,lcsh:QH301-705.5 ,Serina-treonina quinasas TOR ,Phylogeny ,Phenomena and Processes::Reproductive and Urinary Physiological Phenomena::Reproductive Physiological Phenomena::Reproductive Physiological Processes::Reproduction::Pregnancy [Medical Subject Headings] ,Mice, Knockout ,0303 health sciences ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Nuclear Proteins [Medical Subject Headings] ,Genètica humana ,Eutheria ,TOR Serine-Threonine Kinases ,Brain ,Nuclear Proteins ,DNA-Binding Proteins ,Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Genetically Modified::Mice, Transgenic::Mice, Knockout [Medical Subject Headings] ,Multigene Family ,Placental mammals ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::DNA-Binding Proteins [Medical Subject Headings] ,mTOR ,Female ,Transposon domestication ,Transposable element ,lcsh:QH426-470 ,Psychiatry and Psychology::Mental Disorders::Mental Disorders Diagnosed in Childhood::Child Development Disorders, Pervasive::Autistic Disorder [Medical Subject Headings] ,Nerve Tissue Proteins ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Intracellular Signaling Peptides and Proteins::Apoptosis Regulatory Proteins [Medical Subject Headings] ,Biology ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Transcription Factors [Medical Subject Headings] ,Evolution, Molecular ,03 medical and health sciences ,Trastornos del neurodesarrollo ,Animals ,Humans ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Intracellular Signaling Peptides and Proteins::TOR Serine-Threonine Kinases [Medical Subject Headings] ,Allele ,Gene ,030304 developmental biology ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings] ,Research ,Anatomy::Nervous System::Central Nervous System::Brain [Medical Subject Headings] ,Anatomy::Embryonic Structures::Placenta [Medical Subject Headings] ,Phenomena and Processes::Biological Phenomena::Biological Processes::Biological Evolution::Evolution, Molecular [Medical Subject Headings] ,Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Epigenesis, Genetic::Gene Silencing::CRISPR-Cas Systems [Medical Subject Headings] ,Mice, Inbred C57BL ,lcsh:Genetics ,Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Interspersed Repetitive Sequences::DNA Transposable Elements [Medical Subject Headings] ,lcsh:Biology (General) ,Check Tags::Female [Medical Subject Headings] ,Evolutionary biology ,DNA Transposable Elements ,Euterios ,Phenomena and Processes::Genetic Phenomena::Phylogeny [Medical Subject Headings] ,Trastorno del espectro autista ,CRISPR-Cas Systems ,Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Laboratory::Animals, Inbred Strains::Mice, Inbred Strains::Mice, Inbred C57BL [Medical Subject Headings] ,Autisme ,Apoptosis Regulatory Proteins ,Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Multigene Family [Medical Subject Headings] ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
[Background]: One of the most unusual sources of phylogenetically restricted genes is the molecular domestication of transposable elements into a host genome as functional genes. Although these kinds of events are sometimes at the core of key macroevolutionary changes, their origin and organismal function are generally poorly understood., [Results]: Here, we identify several previously unreported transposable element domestication events in the human and mouse genomes. Among them, we find a remarkable molecular domestication that gave rise to a multigenic family in placental mammals, the Bex/Tceal gene cluster. These genes, which act as hub proteins within diverse signaling pathways, have been associated with neurological features of human patients carrying genomic microdeletions in chromosome X. The Bex/Tceal genes display neural-enriched patterns and are differentially expressed in human neurological disorders, such as autism and schizophrenia. Two different murine alleles of the cluster member Bex3 display morphological and physiopathological brain modifications, such as reduced interneuron number and hippocampal electrophysiological imbalance, alterations that translate into distinct behavioral phenotypes., [Conclusions]: We provide an in-depth understanding of the emergence of a gene cluster that originated by transposon domestication and gene duplication at the origin of placental mammals, an evolutionary process that transformed a non-functional transposon sequence into novel components of the eutherian genome. These genes were integrated into existing signaling pathways involved in the development, maintenance, and function of the CNS in eutherians. At least one of its members, Bex3, is relevant for higher brain functions in placental mammals and may be involved in human neurological disorders., Major financial support for this research was received from Spanish “Ministerio de Ciencia, Innovación y Universidades.” Grants BFU2015-68655-P and BFU2017-861152-P to J.G.F., RTI2018-100968-B-I00, 2017-SGR-738, H2020/2014-2020 under grant agreements n°667302, n°643051, and n°728018 to B.C., PGC2018-098229-B-I00 to J.L.F., BES-2016-077374 to E.A.-G., CVI-7290 Junta de Andalucía to A.R.M., SAF2016-80937-R (Ministerio de Economía y Competitividad/FEDER) to G.M., Institutional Grant MDM-2016-0687 (Maria de Maeztu Excellence Unit, Department of Gene Regulation and Morphogenesis at CABD) and BFU2017-83150-P to J.J.C, BFU2017-89780-R and P12-CTS-2257 to A.M.C. and SAF2016-76340-R and María de Maeztu Excellence Unit, Institute of Neurosciences to E.S.. E.N.P. held an FPI pre-doctoral fellowship (Spanish “Ministerio de Ciencia, Innovación y Universidades”). S.M. was first supported by a contract with the “Centro de Investigación Biomédica en Enfermedades Neurodegenerativas,” and later by “Centro de Investigación Biomédica en Red de Enfermedades Raras” (CIBERER). N.F.C. is also under contract by CIBERER.
- Published
- 2020