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.

Centro Andaluz de Biología del Desarrollo CSIC UPO JA Universidad Pablo de Olavide 41013 Sevilla Spain

Centro de Investigación Biomédica en Red de Enfermedades Raras Madrid Spain

Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas 28029 Madrid Spain

Department of Biology and Evolution of Marine Organisms Stazione Zoologica Anton Dohrn 80121 Naples Italy

Department of Cell Biology Physiology and Immunology and Institute of Neurosciences University of Barcelona 08028 Barcelona Spain

Department of Genetics Microbiology and Statistics Faculty of Biology and Institut de Biomedicina University of Barcelona 08028 Barcelona Spain

Department of Human Anatomy School of Medicine University of Murcia and IMIB Arrixaca Institute 30120 Murcia Spain

Department of Physiology Anatomy and Cell Biology Universidad Pablo de Olavide 41013 Sevilla Spain

Department of Zoology Charles University Vinicna 7 12844 Prague Czech Republic

Genome Architecture Gene Regulation Stem Cells and Cancer Programme Centre for Genomic Regulation the Barcelona Institute of Science and Technology 08003 Barcelona Spain

Institució Catalana de Recerca i Estudis Avançats 08010 Barcelona Spain

Institut de Recerca Sant Joan de Déu Esplugues de Llobregat 08950 Barcelona Spain

Present Address Centro de Investigación Biomédica en Red de Salud Mental Neuropsychopharmacology and psychobiology research group UCA INiBICA Cádiz Spain

Present Address Instituto de Neurociencias de Alicante Alicante Spain

Universitat Pompeu Fabra 08003 Barcelona Spain

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