Somatic Mutation, Genomic Variation, and Neurological Disease

Professor Christopher A. Walsh, Chief, Division of Genetics and Genomics and Investigator, Howard Hughes Medical Institute, Boston Children’s Hospital; Bullard Professor of Pediatrics and Neurology, Harvard Medical School

Genetic mutations causing human disease are conventionally thought to be inherited through the germ line from one’s parents and present in all somatic (body) cells, except for most cancer mutations, which arise somatically. Increasingly, somatic mutations are being identified in diseases other than cancer, including neurodevelopmental diseases. Somatic mutations can arise during the course of prenatal brain development and cause neurological disease—even when present at low levels of mosaicism, for example—resulting in brain malformations associated with epilepsy and intellectual disability. Isolation of single neurons from human postmortem brain, and amplification and sequencing of the whole genomes of these single cells, is beginning to give insights into the degree of spontaneous mutation that distinguishes single cells in the brain and presumably other organs. Single neuron genomes contain multiple mutation types including spontaneous retrotransposon insertions, point mutations, and copy number variations. The broader significance of somatic mutations in the brain for other neurodevelopmental disorders is unknown.