Somatic mutations in the human brain: implications for psychiatric research

Abstract

Psychiatric disorders such as schizophrenia and bipolar disorder are caused by complex gene-environment interactions. While recent advances in genomic technologies have enabled the identification of several risk variants for psychiatric conditions, including single-nucleotide variants and copy-number variations, these factors can explain only a portion of the liability to these disorders. Although non-inherited factors had previously been attributed to environmental causes, recent genomic analyses have demonstrated that de novo mutations are among the main non-inherited risk factors for several psychiatric conditions. Somatic mutations in the brain may also explain how stochastic developmental events and environmental insults confer risk for a psychiatric disorder following fertilization. Here, we review evidence regarding somatic mutations in the brains of individuals with and without neuropsychiatric diseases. We further discuss the potential biological mechanisms underlying somatic mutations in the brain as well as the technical issues associated with the detection of somatic mutations in psychiatric research.

Fig. 1

De novo or somatic mutations and developmental stage. a De novo mutations occur before or during spermatogenesis/oocytogenesis. Mutations in the sperm or oocytes descend to the fertilized egg and are shared among all tissues in the proband. The descendants of the proband will inherit this de novo germline mutation with a probability of 50%. b Somatic mutation occurring early in development, before the differentiation of somatic tissues. Mutations occurring early in development are shared among various tissues, but not all somatic cells or tissues, in the proband. The mutation exists in limited tissues or limited parts of each tissue. The descendants of the proband have a possibility of inheriting the somatic mutation, but with probability of <50%. c Somatic mutation occurring later in development, after the differentiation of somatic tissues. Mutations occurring after tissue differentiation are limited to a part of one tissue (brain, in this example) in the proband. The allele fraction of this type of somatic mutation is usually lower than that of somatic mutations occurring earlier. If the mutation is limited to the brain, the descendants of the proband will not inherit the somatic mutation. d A multi-layered scheme of genetic variants in a proband. (i) polymorphisms and variants transmitted from ancestries, (ii) de novo germline mutations, (iii) somatic mutations occurring early in development, and (iv) somatic mutations occurring later in development (brain-specific) from the viewpoint of a proband are illustrated with a time-axis. The polymorphisms and variants transmitted from ancestries are inherited genetic factors, but the other three mutation types are non-inherited genetic factors. These four types of germline or somatic variants (mutations) would have an additive effect on the individual phenotype. Somatic mutations (iii and iv) are the main focus of this review

Fig. 2

Somatic mutation model explaining phenotypic differences between monozygotic (MZ) twins. MZ twins have identical genomes at the time of fertilization, but somatic mutation profiles diverge after fertilization. Somatic mutations during development may underlie phenotypic differences between the twins, including discordant risk for psychiatric disorders. In this illustrated model, MZ1 has somatic mutations in the relevant genes in development, which are shared between the neurons and blood cells, and has a psychiatric diagnosis. MZ2 has no somatic mutations in the relevant genes does not have a psychiatric diagnosis