Somatic mutations in disorders with disrupted brain connectivity

Mutations occur during cell division in all somatic lineages. Because neurogenesis persists throughout human life, somatic mutations in the brain arise during development and accumulate with the aging process. The human brain consists of 100 billion neurons that form an extraordinarily intricate network of connections to achieve higher level cognitive functions. Due to this network architecture, perturbed neuronal functions are rarely restricted to a focal area; instead, they are often spread via the neuronal network to affect other connected areas. Although somatic diversity is an evident feature of the brain, the extent to which somatic mutations affect the neuronal structure and function and their contribution to neurological disorders associated with disrupted brain connectivity remain largely unexplored. Notably, recent reports indicate that brain somatic mutations can indeed play a critical role that leads to the structural and functional abnormalities of the brain observed in several neurodevelopmental disorders. Here, I review the extent and significance of brain somatic mutations and provide my perspective regarding these mutations as potential molecular lesions underlying relatively common conditions with disrupted brain connectivity. Moreover, I discuss emerging technical platforms that will facilitate the detection of low-frequency somatic mutations and validate the biological functions of the identified mutations in the context of brain connectivity. Studying mutations in the brain could greatly improve understanding of unexplained disorders linked to disrupted connectivity of brain cells. Jeong Ho Lee of the Korea Advanced Institute of Science and Technology, in Daejeon, South Korea reviews the extent and significance of “somatic” mutations. These mutations arise during cell division in a person's lifetime, unlike germline mutations that are inherited from parents. The significance of somatic mutations in brain disorders is relatively unknown, other than their well-documented role in brain tumors. Recent research and increasing understanding of ongoing cell division in the brain throughout life suggests somatic mutations may be involved in conditions such as epilepsy, autism, Alzheimer's disease, schizophrenia and depression. Advances in genetic technologies, neuroimaging and electrophysiology are making somatic mutations in dividing brain cells more accessible for scientific investigation.