SOMATIC MOSAICISM IN SCHIZOPHRENIA BRAIN REVEALS PRENATAL MUTATIONAL PROCESSES

We analyzed deep (239x) whole-genome sequencing (WGS) of DNA from cerebral cortical neurons isolated from 61 schizophrenia (SCZ) and 25 control postmortem brains to capture mutations occurring before or during fetal neurogenesis. SCZ cases showed a >15% increase in genome-wide somatic single nucleotide variants (sSNVs) compared to controls (p < 2 × 10-10). Remarkably, mosaic CpG transversions (CpG>GpG or CpG>ApG) and T>G mutations were were 107- and 24-fold enriched, respectively, at transcription factor binding sites (TFBS) in SCZ. This enrichment was not detected in controls. The CpG transversions are likely the byproduct of DNA demethylation resulting in abasic sites, while the T>G pattern might involve a repair deficiency-like mechanism. DNA repair deficiency or suppressed repair through interference between TF binding and DNA repair machinery has been shown to dramatically increase damage-induced mutation rate in cancer. Allele frequency analysis suggests that both localized mutational spikes occur in the first trimester. These mutational processes reflect as-yet unidentified prenatal factors and are present in a subset (∼13%) of SCZ cases.