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  • Review Article
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Human genetics and disease

Mechanisms and consequences of somatic mosaicism in humans

Nature Reviews Genetics volume 3, pages 748–758 (2002)Cite this article

Key Points

  • Mechanisms of mosaicism (the presence of genetically distinct populations of cells in a given organism) include DNA structural abnormalities, epigenetic changes, and the abnormal distribution of chromosomes and mitochondria in daughter cells.

  • Somatic and germ-line mosaicism can coexist in an individual.

  • Several, otherwise lethal, genetic mutations are revealed only in the somatic mosaic state.

  • The Bloom syndrome helicase and the mismatch-repair system are important in the generation of somatic genetic variability.

  • Spontaneous reversions of inherited mutations can occur by homologous recombination, site-specific correction and second-site suppressor mutations.

  • The extent of somatic mosaicism is determined most crucially by selection.

  • Treatment of a genetic disorder can influence the degree of mosaicism and the frequency or maintenance of reverted cell populations.

Abstract

Somatic mosaicism — the presence of genetically distinct populations of somatic cells in a given organism — is frequently masked, but it can also result in major phenotypic changes and reveal the expression of otherwise lethal genetic mutations. Mosaicism can be caused by DNA mutations, epigenetic alterations of DNA, chromosomal abnormalities and the spontaneous reversion of inherited mutations. In this review, we discuss the human disorders that result from somatic mosaicism, as well as the molecular genetic mechanisms by which they arise. Specifically, we emphasize the role of selection in the phenotypic manifestations of mosaicism.

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Figure 1: Variable manifestations of somatic mosaicism.
Figure 2: Diagnostic methods for somatic and germ-line mosaicism.
Figure 3: Model for how new mutations are selected in the generation of mosaic phenotypes.

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Acknowledgements

We dedicate this review to our mentor and friend, Dr Victor A. McKusick. We would like to thank Andrew Shenker and Robert Tanguny for providing the photos in Figure 1a and 1b, respectively

Author information

Authors and Affiliations

  1. Department of Clinical Discovery, Bristol-Myers Squibb Company, Princeton, 08543-4000, New Jersey, USA

    Hagop Youssoufian

  2. Division of Medical Genetics, University of Pennsylvania School of Medicine, Philadelphia, 19104-4283, Pennsylvania, USA

    Reed E. Pyeritz

Authors
  1. Hagop Youssoufian
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  2. Reed E. Pyeritz
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Corresponding author

Correspondence to Hagop Youssoufian.

Related links

Related links

DATABASES

Cancer.gov

colorectal cancer

LocusLink

adenosine deaminase

Aprt

BLM

dystrophin

FAH

FANCA

FANCC

GNAS1

IL2RG

MLH1

Msh2

NEMO

NF1

WASP

OMIM

acute myeloid leukaemia

adenosine deaminase deficiency

Bloom syndrome

DK-phocomelia

Duchenne muscular dystrophy

Fanconi anaemia

hereditary nonpolyposis colorectal cancer

hereditary tyrosinaemia type I

incontinentia pigmenti

McCune–Albright syndrome

neurofibromatosis type I

Proteus syndrome

Rett syndrome

Russell–Silver syndrome

Turner syndrome

Wiskott–Aldrich syndrome

Glossary

EXPRESSIVITY

The extent to which a particular organ or structure is affected by a particular genotype.

MCCUNE–ALBRIGHT SYNDROME

A human syndrome in which polyostotic lesions affect the skeleton and are patchily distributed. Irregular café au lait hyperpigmented macules affect the skin. Several endocrinopathies are typically present, causing variable hypercortisolism, hyperthyroidism, pituitary gigantism and sexual precocity in girls.

HEREDITARY TYROSINAEMIA TYPE I

An autosomal-recessive disorder of tyrosine metabolism that is due to deficiency of the enzyme fumarylacetoacetate hydrolase. The disorder typically causes liver and renal problems early in life and is associated with neurological deterioration and hepatoma.

ALLOGENEIC ORGAN TRANSPLANTATION

The use of an organ or tissue from any human other than self or a monozygotic twin.

SEGMENTAL NEUROFIBROMATOSIS TYPE I

A form of neurofibromatosis type I in which pigmented skin macules, subcutaneous benign tumors (neurofibroma) or large plexiform neurofibroma are limited to one region of the body. Segmental neurofibromatosis type II also occurs, typically with unilateral vestibular schwannoma or meningioma.

TUBEROUS SCLEROSIS

An autosomal-dominant disorder with a varied phenotype. Severely affected individuals have seizures, mental retardation and fatty tumours of the kidneys. Mildly affected individuals might only show small, depigmented skin macules and small nodules under the nails and on the face.

ASCERTAINMENT BIAS

Any tendency for an inference to be non-representative of the true population, because individuals of a particular class are more likely to be sampled.

COMPOUND HETEROZYGOTE

The occurrence of mutations in each of the two alleles of an autosomal gene.

GENE CONVERSION

A non-reciprocal recombination process that results in an alteration of the sequence of a gene to that of its homologue during meiosis.

COMPLEMENTATION GROUP C

Subclassification of cells from Fanconi anaemia patients on the basis of somatic-cell hybrid analysis or mutation analysis.

CHORIONIC VILLUS SAMPLING

A prenatal diagnostic procedure that involves removal of cells from the finger-like projections (villi) of the chorion (the tissue surrounding the fetus) to obtain chromosomes and cell products for diagnosis.

AMNIOCENTESIS

Prenatal diagnosis method in which cells of the amniotic fluid are used to determine the number and kind of chromosomes of the fetus and for biochemical studies.

DK-PHOCOMELIA

A rare condition that is characterized by maldevelopment of the proximal portions of limbs, urogenital defects and failure of closure of the posterior skull (occipital encephalocoele).

PALLISTER–KILLIAN SYNDROME

A severe congenital malformation syndrome that includes mental retardation, postnatal growth deficiency, progressive coarsening of the facial features, and sparse eyebrows and hair over the temples. It is due to tetrasomy of the short arm of human chromosome 12.

ISODISOMY

A euploid cell in which one of the chromosome pairs consists of identical chromosomes inherited from one parent; this is due to non-disjunction in meiosis II in one parent, formation of a triploid zygote and loss of the chromosome provided by the parent in which non-disjunction did not occur.

MULTIPLEX PCR

Simultaneous analysis of multiple genetic loci by PCR.

PROTEUS SYNDROME

A congenital malformation disorder in which overgrowth of any organ or tissue can occur, but invariably in a patchy distribution.

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Youssoufian, H., Pyeritz, R. Mechanisms and consequences of somatic mosaicism in humans. Nat Rev Genet 3, 748–758 (2002). https://doi.org/10.1038/nrg906

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