Somatic mosaicism, in the brain or in other tissue in the body, is the phenomenon where not all cells have an identical DNA sequence due to the occurrence of mutations during the normal developmental process. These variations may be single nucleotide variants, copy number variants, structural variants, and retrotransposon insertions. Such variations could alter the epigenome and transcriptome, and contribute to functional diversity among cells.

 

There is increasing evidence of somatic mosaicism in the brain, but the extent of such variation and its functional significance in normal brain development and in psychiatric disorders remain poorly understood. Identifying the architecture of genetic perturbations in somatic cells of normal and diseased brains may provide new insights into genetic susceptibility of complex psychiatric disorders.

 

The BSMN is made up of 18 principle investigators across 12 research sites and involves more than 60 members worldwide. The BSMN project nodes use advances in DNA sequencing, single-cell genomics, computational biology, and genome engineering to determine the extent of normal brain mosaicism and to determine if aberrant brain mosaicism is associated with genetically complex neurological disorders. Collectively, the BSMN aims to examine large numbers of neurons from neurotypic controls alongside matched individuals with schizophrenia, autism, epilepsy, bipolar disorder, and Tourette’s syndrome to test the general hypothesis that common brain somatic mutations can account for elusive genetic components of neurological disease. If true, the increased understanding of disease pathology may lead to new targets for drug development. Beyond investigating these specific disorders, the BSMN teams will generate and share large datasets of primary neuronal and non-neuronal genomes from various brain regions in hundreds of individuals. Significant effort is being invested to produce an accessible community resource that is well integrated with other large-scale brain datasets.