Germline mutations modulate the risk of developing schizophrenia (SCZ). Much less is known about the role of mosaic somatic mutations in the context of SCZ. Deep (239×) whole-genome sequencing (WGS) of brain neurons from 61 SCZ cases and 25 controls postmortem identified mutations occurring during prenatal neurogenesis. SCZ cases showed increased somatic variants in open chromatin, with increased mosaic CpG transversions (CpG>GpG) and T>G mutations at transcription factor binding sites (TFBSs) overlapping open chromatin, a result not seen in controls. Some of these variants alter gene expression, including SCZ risk genes and genes involved in neurodevelopment. Although these mutational processes can reflect a difference in factors indirectly involved in disease, increased somatic mutations at developmental TFBSs could also potentially contribute to SCZ.
Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network
Science | April 27, 2017 | Volume: 356 | Issue: 6336 | Pages: No page available
Single-cell diversity in the brain The cells that make up an organism may all start from one genome, but somatic mutations mean that somewhere along the line of development, an organism's individual cellular genomes diverge. McConnell et al. review the implications and causes of single-cell genomic diversity for brain function. Somatic mutations caused by mobile genetic elements or errors in DNA repair may underlie certain neuropsychiatric disorders. Science , this issue p. eaal1641