Identification of somatic mutations in postmortem human brains by whole genome sequencing and their implications for psychiatric disorders

摘要

Aim Somatic mutations in the human brain are hypothesized to contribute to the functional diversity of brain cells as well as the pathophysiology of neuropsychiatric diseases. However, there are still few reports on somatic mutations in nonneoplastic human brain tissues. This study attempted to unveil the landscape of somatic mutations in the human brain. Methods We explored the landscape of somatic mutations in human brain tissues derived from three individuals with no neuropsychiatric diseases by wholegenome deep sequencing at a depth of around 100. The candidate mutations underwent multilayered filtering, and were validated by ultradeep target amplicon sequencing at a depth of around 200 000. Results Thirtyone somatic mutations were identified in the human brain, demonstrating the utility of wholegenome sequencing of bulk brain tissue. The mutations were enriched in neuronexpressed genes, and twothirds of the identified somatic single nucleotide variants in the brain tissues were cytosinetothymine transitions, half of which were in CpG dinucleotides. Conclusion Our developed filtering and validation approaches will be useful to identify somatic mutations in the human brain. The vulnerability of neuronexpressed genes to mutational events suggests their potential relevance to neuropsychiatric diseases.