Somatic mutation during brain development leads to CNS disorders. A missense mutation in GNAQ (R183Q) occurs in affected tissues of persons with Sturge–Weber disease, with a frequency in diseased brain and skin ranging from 3 to 36% (Freed et al, 2014). In hemimegalencephaly, somatic mutations in AKT3 were found in 8–35% of cells in the affected tissues (Freed et al, 2014). Somatic mutation in PSEN1 (P436Q) at a frequency of 18% in frontal cortex caused early-onset Alzheimer’s disease (Freed et al, 2014). One form of somatic mutation that can contribute to CNS disease risk is mediated by long interspersed nuclear element 1 (L1) retrotransposons (Kaer and Speek, 2013). L1s are 6 kb sequences that spread in the human genome by a copy and paste mechanism, and constitute 17% of the human genome (Upton et al, 2015). The frequency of de novo L1 retrotranspositions in normal brain is controversial (Upton et al, 2015). Most retrotransposition-competent L1s are prevented from retrotransposition by epigenetic mechanisms or interactions with inhibitory proteins (Goodier et al, 2013).

Whole genome sequencing of genomic DNA from dorsolateral prefrontal cortex (dlPFC) and liver of three persons with schizophrenia revealed increased de novo L1s in specific gene ontologies (GOs; see Table 1; Bundo et al, 2014). Using L1-based amplification of dlPFC neuronal DNA from 26 schizophrenia samples and 26 control samples, we confirmed an excess of L1 retrotransposons in genes within these GOs in schizophrenic, but not in control tissues. There was a fourfold increase of de novo L1s in ‘synapse part’ genes (over the random expectation) in our data. Of the 18 genes with putative de novo L1s in our ‘synapse part’ GO list, 9 were also detected by Bundo et al, 2014: DNM2, DNM3, DLGAP1, GRID2, GRIN2A, HOMER1, GPHN, SYNE1, and SYN3. These genes are ‘of interest’ in schizophrenia research because they support data showing associations with GWAS or animal models of schizophrenia.

Table 1 Gene Ontology Terms with Significant Gene Disruption by de novo LINE1 Elements

Methamphetamine and cocaine increased de novo L1s in neuronal cells in vitro (Okudaira et al, 2014). Thus, we conducted an L1 study of medial PFC neuronal DNA from 30 persons with cocaine addiction and controls. Strong evidence (p≈10−6^) for L1-mediated gene disruption was found in phosphate metabolism and kinase pathways, which were not significant among controls (Doyle et al, unpublished observation).

The evidence that somatic brain mutation causes brain disease warrants studies of a range of neuropsychiatric disorders (including rodent models) for similar risk-increasing somatic alleles. As somatic mutation does not convey heritable risk, it may be a mechanism to explain some of the environmental risk for neuropsychiatric diseases. There may be disease-specific L1-mediated gene disruption in certain GOs, such as has been found in schizophrenia and cocaine addiction. New drug development might be directed toward gene pathways disrupted by L1s. Reducing the risk for developmental factors that influence epigenetics (eg stress and nutrition) may limit L1 somatic mutation during CNS development.

Somatic mutation studies of neurodevelopmental disorders (autism, idiopathic epilepsy) may reveal brain-specific alleles that convey risk. Germlines may harbor only a fraction of the alleles of interest for CNS diseases.

Funding and Disclosure

Preparation of this paper was supported by R21 NS095756-01, 1R21MH101065, R21DA035607 to WHB. Mental Illness Research, Education and Clinical Center, VISN-4, David Oslin, MD, is PI. The authors declare no conflict of interest.