FIG. 3.

Schematic of genetic and epigenetic mechanisms underlying phenotypic heterogeneity. (A) Germline instability of a CAG triplet repeat expansion (dynamic mutation). (B) A de novo mutation (thunderbolt) occurring during the gametogenesis in a healthy individual is transmitted to the offspring (germline mosaicism). (C) Somatic mosaicism resulting from a de novo mutation (thunderbolt) in a postzygotic cell which is only carried by a fraction of somatic cells. (D) Modulation of gene expression resulting from intragenic intra‐allelic interaction (cis‐interaction). (E) Modulation of gene expression resulting from intragenic inter‐allelic interaction (trans‐interaction). (F) Modulation of gene expression by a modifier or epistatic gene which can map on the same (left) or another chromosome (right). (G) Mitochondrial inheritance deriving from random segregation of mitochondria during cell replication. The dashed line represents the “phenotypic threshold level” for the mutation of mitochondrial DNA to manifest (wild‐type mitochondria are blue, mutant mitochondria are pink). (H) Genomic imprinting through epigenetic mechanisms enables postzygotic cells to retain memory of the parental origin of an allele. In the example, a mutation in a gene maternally imprinted is not expressed in the offspring when transmitted by the mother. (I) X‐chromosome inactivation leads to functional inactivation of one copy of chromosome X in cells of female individuals to provide dosage compensation between the sexes. Skewed X‐inactivation occurs when the inactivation of one X‐chromosome is favored over the other (wild‐type allele is white, mutant allele is black).