Somatic Mutation, Genomic Variation, and Neurological Disease

Background Genetic mutations that cause human disease are conventionally considered to be inherited from one’s parents and present in all somatic (body) cells. We do know, however, that most mutations that cause cancer arise somatically, and we are becoming increasingly aware of mutations that cause other diseases and that arise de novo, meaning they are undetectable in the parents. Some such de novo mutations arise in the gamete of a parent, but some arise after fertilization during embryonic development, generating somatic mutations. Somatic mutations occur in several neurodevelopmental diseases associated with epilepsy, autism spectrum disorders, and intellectual disability, although their broader relevance for neurological disease is unknown. Cortical development—origins of pyramidal neurons and astrocytes in the cerebral cortex. (A) A neuroepithelial cell (red) at the ventricular zone serves as progenitor for both a pyramidal neuron (green-blue) as well as a radial glial cell (gold). (B) A newly differentiated neuron (blue) migrates along a radial glial process. (C) Neurons (blue) continue to migrate as intermediate progenitor cells (small yellow) form. (D) Intermediate progenitor cells begin to generate neurons (blue). (E) The progenitor cells in the ventricular zone begin to give rise to astrocytes (dark green). Interneurons (purple) generated elsewhere migrate tangentially. CP, cortical plate; IZ, intermediate zone; VZ, ventricular zone. The VZ early in development has a thickness of ~10 cell bodies (50 to 100 μm). The CP ranges in thickness from two to three cell bodies at the earliest stages of development, eventually forming a mature cerebral cortex that is 2 to 4 mm thick. Advances A key recent advance has been the increasing identification of somatic mutations in affected tissues. For example, somatic mutations in several genes (PIK3CA, AKT3, and mTOR) cause enlargement of just one hemisphere of the brain, a malformation called hemimegalencephaly that is highly associated with epilepsy. These mutations may or may not be found in the blood, the convenient source tissue for DNA analysis, thus presenting a challenge to disease gene identification. Remarkably, patients can show dysfunction of essentially an entire half of their cerebral cortex when only 8 to 35% of the brain cells carry the mutation, suggesting that a minority of cells with a somatic mutation can disrupt the function of widespread cortical circuits. These discoveries suggest that somatic, perhaps brain-only, mosaic mutations may be important for other neurodevelopmental diseases. However, finding the mutations and the affected cells may require special study designs and technology. In parallel with the discovery of somatic mutations responsible for neurological disease has been a continuing interest in the possibility that somatic mutations may occur in brain cells during normal development. New technologies, such as the study of the genomes of single neurons, promise to address some of these questions by allowing the systematic analysis of all types of somatic mutations in normal and diseased tissue. Outlook The role of somatic mutation in neurological disease is only beginning to be explored and may have relevance to many types of conditions from brain malformations to epilepsy, intellectual disability, and autism. Novel, highly sensitive technologies will allow more accurate evaluation of somatic mutations in neurodevelopmental disorders and during normal brain development. Genetic Mosaicism in Brain Development With the increased power now available in sequencing and genomic technologies has come the realization that within an organism, individual cellular genomes can diverge from one another. Poduri et al. (p. 10.1126/science.1237758) review how de novo mutations, which arise in the parental germ line, or during development of the child, are the cause of a variety of neurodevelopmental disorders. 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. Novel, highly sensitive technologies will allow more accurate evaluation of somatic mutations in neurodevelopmental disorders and during normal brain development.