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