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BACKGROUND Elucidating the genetic architecture of neuropsychiatric disorders remains a major scientific and medical challenge. Emerging genomic technologies now permit the analysis of somatic mosaicism in human tissues. The measured frequencies of single-nucleotide variants (SNVs), small insertion/deletion (indel) mutations, structural variants [including copy number variants (CNVs), inversions, translocations, and whole-chromosome gains or losses], and mobile genetic element insertions (MEIs) indicate that each neuron may harbor hundreds of somatic mutations. Given the long life span of neurons and their central role in neural circuits and behavior, somatic mosaicism represents a potential mechanism that may contribute to neuronal diversity and the etiology of numerous neuropsychiatric disorders. ADVANCES Somatic mutations that confer cellular proliferative or cellular survival phenotypes have been identified in patients with cortical malformations. These data have led to the hypothesis that somatic mutations may also confer phenotypes to subsets of neurons, which could increase the risk of developing certain neuropsychiatric disorders. Genomic technologies, including advances in long-read, next-generation DNA sequencing technologies, single-cell genomics, and cutting-edge bioinformatics, can now make it possible to determine the types and frequencies of somatic mutations within the human brain. However, a comprehensive understanding of the contribution of somatic mosaicism to neurotypical brain development and neuropsychiatric disease requires a coordinated, multi-institutional effort. The National Institute of Mental Health (NIMH) has formed a network of 18 investigative teams representing 15 institutions called the Brain Somatic Mosaicism Network (BSMN). Each research team will use an array of genomic technologies to exploit well-curated human tissue repositories in an effort to define the frequency and pattern of somatic mutations in neurotypical individuals and in schizophrenia, autism spectrum disorder, bipolar disorder, Tourette syndrome, and epilepsy patient populations. Collectively, these efforts are estimated to generate a community resource of more than 10,000 DNA-sequencing data sets and will enable a cross-platform integrated analysis with other NIMH initiatives, such as the PsychENCODE project and the CommonMind Consortium. OUTLOOK A fundamental open question in neurodevelopmental genetics is whether and how somatic mosaicism may contribute to neuronal diversity within the neurotypical spectrum and in diseased brains. Healthy individuals may harbor known pathogenic somatic mutations at subclinical frequencies, and the local composition of neural cell types may be altered by mutations conferring prosurvival phenotypes in subsets of neurons. By extension, the neurotypical architecture of somatic mutations may confer circuit-level differences that would not be present if every neuron had an identical genome. Given the apparent abundance of somatic mutations within neurons, an in-depth understanding of how different types of somatic mosaicism affect neural function could yield mechanistic insight into the etiology of neurodevelopmental and neuropsychiatric disorders. The BSMN will examine large collections of postmortem brain tissue from neurotypical individuals and patients with neuropsychiatric disorders. By sequencing brain DNA and single neuronal genomes directly, rather than genomic DNA derived from peripheral blood or other somatic tissues, the BSMN will test the hypothesis that brain somatic variants contribute to neuropsychiatric disease. Notably, it is also possible that some inherited germline variants confer susceptibility to disease, which is later exacerbated by somatic mutations. Confirming such a scenario could increase our understanding of the genetic risk architecture of neuropsychiatric disease and may, in part, explain discordant neuropsychiatric phenotypes between identical twins. Results from these studies may lead to the discovery of biomarkers and genetic targets to improve the treatment of neuropsychiatric disease and may offer hope for improving the lives of patients and their families.