A transposase-derived gene responsible for human brain development

Vertebrate brain development is associated with prominent neuronal cell death and DNA breaks, but their causes and functions are not well understood. DNA transposable elements and transposase-derived genes could contribute to DNA breaks and somatic genome rearrangements, however their contributions to brain development are largely unknown. PiggyBac Transposable Element Derived 5 (PGBD5) is an evolutionarily conserved vertebrate DNA transposase-derived gene with retained nuclease activity in human cells. Here, we show that PGBD5 contributes to normal brain development in mice and humans, and 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 brain genome rearrangements. In the cerebral cortex, loss of Pgbd5 leads to aberrant differentiation and gene expression of distinct neuronal populations, including specific types of glutamatergic neurons, which can explain the features of PGBD5 deficiency in humans. Thus, PGBD5 is a transposase-derived gene required for brain development in mammals.