An ancient DNA transposase responsible for human brain development

DNA transposable elements are present in most living things, including vertebrates, but most are of unknown function. PGBD5 is the oldest evolutionarily conserved DNA transposase with retained enzymatic activity in vertebrates. Vertebrate brain development is known to be associated with prominent neuronal cell death and DNA damage, but their developmental causes and functions remain unknown. Here, we show that PGBD5 contributes to normal brain development in mice and humans, where its deficiency causes a disorder of intellectual disability, movement and seizures. Loss of PGBD5 leads to increased numbers of cortical neurons, where it is required for the developmental induction of post-mitotic DNA breaks and PGBD5-dependent genome rearrangements. Together, these studies identify PGBD5 as the long-hypothesized neuronal DNA recombinase, whose activity is required for higher-order brain functions in mammals.