Somatic retrotransposition alters the genetic landscape of the human brain

Retrotransposons are mobile genetic elements that employ a germ line “copy-and-paste” mechanism to spread throughout metazoan genomes(1). At least 50% of the human genome is derived from retrotransposons, with three active families (L1, Alu and SVA) associated with insertional mutagenesis and disease(2-3). Epigenetic and post-transcriptional suppression block retrotransposition in somatic cells(4-5), excluding early embryo development and some malignancies(6-7). Recent reports of L1 expression(8-9) and copy number variation(10-11) (CNV) in the human brain suggest L1 mobilization may also occur during later development. However, the corresponding integration sites have not been mapped. Here we apply a high-throughput method to identify numerous L1, Alu and SVA germ line mutations, as well as 7,743 putative somatic L1 insertions in the hippocampus and caudate nucleus of three individuals. Surprisingly, we also found 13,692 and 1,350 somatic Alu and SVA insertions, respectively. Our results demonstrate that retrotransposons mobilize to protein-coding genes differentially expressed and active in the brain. Thus, somatic genome mosaicism driven by retrotransposition may reshape the genetic circuitry that underpins normal and abnormal neurobiological processes.