Abstract
Although inherited DNA sequences have a well-demonstrated role in psychiatric disease risk, for even the most heritable mental disorders, monozygotic twins are discordant at a significant rate. The genetic variation associated with mental disorders has heretofore been based on the search for rare or common variation in blood cells. This search is based on the premise that every somatic cell shares an identical DNA sequence, so that variation found in lymphocytes should reflect variation present in brain cells. Evidence from the study of cancer cells, stem cells and now neurons demonstrate that this premise is false. Somatic mutation is common in human cells and has been implicated in a range of diseases beyond cancer. The exuberant proliferation of cortical precursors during fetal development provides a likely environment for somatic mutation in neuronal and glial lineages. Studies of rare neurodevelopmental disorders, such as hemimegencephaly, demonstrate somatic mutations in affected cortical cells that cannot be detected in unaffected parts of the brain or in peripheral cells. This perspective argues for the need to investigate somatic variation in the brain as an explanation of the discordance in monozygotic twins, a proximate cause of mental disorders in individuals with inherited risk, and a potential guide to novel treatment targets.
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Acknowledgements
I am grateful to Andrea Beckel-Michener, Thomas Lehner, Francis McMahon, David Panchision and Nenad Sestan for helpful comments on this manuscript.
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Since the acceptance of this commentary, the first single-cell analysis of endogenous human frontal cortex neurons was published, revealing that 13–41% of neurons have at least one megabase-scale de novo CNV, that deletions are twice as common as duplications, and that a subset of neurons have highly aberrant genomes marked by multiple alterations (McConnell MJ, Lindberg MR, Brennan KJ, Piper JC, Voet T, Cowing-Zitron C et al. Mosaic copy number variation in human neurons. Science 2013; 342: 632–637).
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Insel, T. Brain somatic mutations: the dark matter of psychiatric genetics?. Mol Psychiatry 19, 156–158 (2014). https://doi.org/10.1038/mp.2013.168
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DOI: https://doi.org/10.1038/mp.2013.168
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