A transposase-derived gene required for human brain development

DNA transposable elements and transposase-derived genes are present in most living organisms, including vertebrates, but their function is largely unknown. PiggyBac Transposable Element Derived 5 (PGBD5) is an evolutionarily conserved vertebrate DNA transposase-derived gene with retained nuclease activity in cells. Vertebrate brain development is known to be associated with prominent neuronal cell death and DNA breaks, but their causes and functions are not well understood. Here, we show that PGBD5 contributes to normal brain development in mice and humans, where its deficiency causes disorder of intellectual disability, movement, and seizures. In mice, Pgbd5 is required for the developmental induction of post-mitotic DNA breaks and recurrent somatic genome rearrangements. In the mouse cortex, loss of Pgbd5 leads to aberrant differentiation and gene expression of distinct neuronal populations, including multiple types of glutamatergic neurons, potentially explaining the features of PGBD5 deficiency in humans. Together, these studies nominate PGBD5 as the long-hypothesized neuronal DNA nuclease and transposase-derived gene required for brain function in mammals.