Somatic mosaicism in the human genome

Abstract

Somatic mosaicism refers to the occurrence of two genetically distinct populations of cells within an individual, derived from a postzygotic mutation. In contrast to inherited mutations, somatic mosaic mutations may affect only a portion of the body and are not transmitted to progeny. These mutations affect varying genomic sizes ranging from single nucleotides to entire chromosomes and have been implicated in disease, most prominently cancer. The phenotypic consequences of somatic mosaicism are dependent upon many factors including the developmental time at which the mutation occurs, the areas of the body that are affected, and the pathophysiological effect(s) of the mutation. The advent of second-generation sequencing technologies has augmented existing array-based and cytogenetic approaches for the identification of somatic mutations. We outline the strengths and weaknesses of these techniques and highlight recent insights into the role of somatic mosaicism in causing cancer, neurodegenerative, monogenic, and complex disease.

Figure 1

Overview of categories of variation including inherited (panels A–C), de novo (panels D,E), and somatic variation (panels F,G). Inherited mutations are always transmitted through the germline (A); although a parent may also have a mosaic mutation (this combination of somatic and germline mosaicism is occasionally termed gonadal mosaicism) (B); In such cases, a child may inherit the variant as a heterozygous mutation with a more severe clinical phenotype. A parent may also have germline mosaicism that may be inherited by progeny (C); De novo mutations are operationally defined as genotypes observed in a child but not in either parent. They may originate in a parental germ cell (as may be inferred in a pedigree having multiple affected offspring) (D) or postzygotically (E); Somatic mutation may occur relatively early in development (F) or at any later time throughout the lifespan (G), generally affecting fewer cells.

Figure 2

Tissue-specific effects of mutations in GNAQ (A); GNAS (B); and AKT1, AKT2, and AKT3 (C). Constitutively activating mutations in GNAQ may lead to either Sturge-Weber syndrome, nonsyndromic port-wine stains, or uveal melanoma (A). Somatic activating mutations in GNAS lead to McCune-Albright syndrome, which may involve variable hyperthyroidism, café au lait macules and sexual precocity (B). Activating mutations in all three of the AKT genes cause cellular overgrowth phenotypes with mutations in AKT2 also implicated in abnormal insulin signaling (C).

Figure 3

Cell death may reduce the total number of cells harboring somatic mutation. Mosaic mutations may cause cell-type-specific lethality (A); Mosaic loss of an essential juxtacrine signaling factor may cause localized death of cells that are not adjacent to unaffected tissues (B).

Figure 4

Three intracellular signaling pathways are shown schematically. (At left), receptor tyrosine kinase activity leads to activation of PIK3CA, AKT, and mechanistic target of rapamycin (mTOR) [187,188]. mTOR participates in complexes (TORC1, activated by RHEB; TORC2, inhibited by RHEB) that regulate cell growth, proliferation, survival, and cell cycle progression. This pathway includes genes that are frequently mutated in tumors such as PIK3CA and PTEN (not shown); (At center), secreted growth factors bind to receptor tyrosine kinase receptors on the cell surface leading to activation of the low molecular weight G protein Ras and subsequent activation of Raf, MEK 1/2, and ERK 1/2 (official gene symbols MAPK3, MAPK1); (At right), a G-protein coupled receptor (GPCR) pathway is shown [189,190]. Ligands such as vasopressin, endothelin, glutamate, or norepinephrine bind to a GPCR. When bound by ligand, the receptor activates a G protein alpha subunit such as Gαq that binds and hydrolyzes GTP. This leads to activation of phospholipase Cβ producing inositol 1,4,5-triphosphate (IP₃) and membrane-associated diacylglycerol (DAG). DAG, through activation of protein kinase C, may activate the Raf/MEK/ERK pathway. IP₃ may bind to an IP₃ receptor activating calcium signaling pathways (not shown). Other G protein α subunits (such as Gαs encoded by GNAS) activate membrane-bound adenylate cyclase, producing cyclic AMP (cAMP) that activates protein kinase A (not shown).