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Somatic Mosaicism and Chromosomal Disorders

By: Heidi Chial, Ph.D. (Write Science Right) © 2008 Nature Education 
Citation: Chial, H. (2008) Somatic mosaicism and chromosomal disorders. Nature Education 1(1):69
Could two pieces of a stone mosaic ever be identical? Of course, the answer is no--and each stone’s variation subtly contributes value to the finished work. Why should your cells be any different?
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If made from stones, could two pieces of a mosaic ever be exactly the same? Of course, the answer is no: although certain pieces of the mosaic may appear similar from a distance, a closer look would reveal that no two stones composing the mosaic were exactly the same.

Like stones in a mosaic, our cells may vary. Specifically, they may undergo changes during development such that one group of cells differs from a neighboring group. This phenomenon is known as mosaicism, and it can be caused by spontaneous DNA mutations, spontaneous reversion of an existing DNA mutation, epigenetic changes in chromosomal DNA, and chromosomal abnormalities. Furthermore, mosaicism can be associated with changes in either nuclear or mitochondrial DNA. The phenotypes associated with mosaicism depend on the extent of the mosaic cell population. Mosaicism has important consequences with respect to human disease, and it also results in variations among all humans at the molecular level, even among identical twins.

Germ Line Mosaicism versus Somatic Mosaicism

Two pedigree diagrams are shown above results from molecular analyses. The pedigree in panel A shows the inheritance of café-au-lait skin spots in a single family over the course of three generations and is an example of somatic mosaicism producing a disease phenotype. Only one individual in generation two carries the mutation. The pedigree in panel B shows the inheritance of the disease tuberous sclerosis in a single family over the course of two generations and is an example of germ-line mosaicism producing a disease phenotype. Two siblings, one male and one female, carry the mutation in generation two. The molecular analyses below the pedigree diagrams are a comparison of wild-type and mutant DNA in blood, normal skin, and abnormal skin in panel A and in blood and sperm in panel B.
© 2002 Nature Publishing Group Youssoufian, H. et al. Mechanisms and consequences of somatic mosaicism in humans. Nature Reviews Genetics 3, 750 (2002). All rights reserved. View Terms of Use
As previously described, mosaicism refers to the presence of a genetically distinct cell population within an organism (Youssoufian & Pyeritz, 2002). Mosaicism can exist in both somatic cells and germ line cells; however, the distinction between germ line mosaicism and somatic mosaicism can be somewhat tricky. As their names imply, somatic and germ line mosaicism refer to the presence of genetically distinct groups of cells within somatic and germ line tissues, respectively.

If the event leading to mosaicism occurs during development, it is possible that both somatic and germ line cells will become mosaic. In this case, both somatic and germ line tissue populations would be affected, and an individual could transmit the mosaic genotype to his or her offspring. Conversely, if the triggering event occurs later in life, it could affect either a germ line or a somatic cell population. If the mosaicism occurs only in a somatic cell population, the phenotypic effect will depend on the extent of the mosaic cell population; however, there would be no risk of passing on the mosaic genotype to offspring. On the other hand, if the mosaicism occurs only in a germ line cell population, the individual would be unaffected, but his or her offspring could be affected.

Figure 1a shows how pedigrees and molecular analyses can be combined to determine whether somatic mosaicism or germ line mosaicism is responsible for disease phenotypes. The first three-generation pedigree shows the inheritance of café au lait spots associated with neurofibromatosis type I, which is typically an autosomal dominant disorder associated with mutations in the NF1 gene. As you can see, two unaffected parents have one son with a café au lait skin lesion. The affected male does not pass on the disorder to any of his four offspring. Molecular analysis of blood and normal skin samples show that these samples carry a wild-type copy of the NF1 gene, whereas the café au lait skin lesion of the affected male contains a wild-type and a mutant copy of the NF1 gene, which is suggestive of a somatic mosaic mutation in this population of skin cells.

The second pedigree (Figure 1b) shows the inheritance of tuberous sclerosis, which is typically an autosomal disorder associated with mutations in the TSC1 or TSC2 gene. In this pedigree, you can see that unaffected parents have one affected son, one affected daughter, and one unaffected son. This pattern of inheritance is consistent with an autosomal recessive disorder in which both parents are carriers, or with germ line mosaicism in one parent. Molecular analysis of blood samples shows that both parents are homozygous for the wild-type TSC1 allele, suggesting that they are not typical heterozygous carriers. Blood samples from the affected children show that both are heterozygous for the mutant TSC1 allele, whereas the unaffected son carries only the wild-type TSC1 allele. Analysis of germ line (sperm) cells from the males in the pedigree shows that the father and the affected son carry the mutant TSC1 allele. Taken together, these results suggest that the father has undergone a germ line mosaic mutation such that some of his sperm cells carry the mutant TSC1 allele.

Mechanisms Leading to Somatic Mosaicism

So, how is somatic mosaicism generated? As previously mentioned, there are many possible answers to this question, including somatic mutations, epigenetic changes in DNA, alterations in chromosome structure and/or number, and spontaneous reversal of inherited mutations. In all of these cases, a given cell and those cells derived from it could exhibit altered function. Epigenetic changes can often be induced by environmental factors (e.g., exposure to a mutagen, trauma, or altered temperature).

Mendelian Disorders and Mosaicism

Some examples of single-gene diseases that are associated with somatic mosaicism are listed in Table 1. Hereditary tyrosinemia type I is caused by mutations in the fumarylacetoacetate hydrolase (FAH) gene; individuals with this disease often have mosaic livers that contain mutant and reverted cell populations. The groups of cells with the FAH reversion form nodules and appear to have a growth advantage.

Bloom syndrome is a single-gene autosomal recessive disorder associated with growth problems, immunodeficiency, and a predisposition for cancer. The gene associated with Bloom syndrome, called BLM, encodes an enzyme called DNA helicase that prevents DNA strands from getting too twisted during DNA replication. Patients with Bloom syndrome show high levels of recombination events between sister chromatids during mitosis.

Fanconi's anemia is associated with growth problems, skeletal abnormalities, loss of bone marrow function, and cancer susceptibility. Somatic mutations in several genes, including FANCA, FANCC, and FANCD2, have been linked with the onset of this disorder. Early evidence for somatic mosaicism in Fanconi's anemia was suggested by the observation that patients had two different populations of lymphocytes: one group of cells was susceptible to chromosome breaks, whereas the other was not.

Classification Disorder
Metabolic Disorders

Tyrosinemia type I



Immune dysfunction

Adenosine deaminase deficiency

Wiskott-Aldrich syndrome

Clotting disorders

Hemophilia A

Hemophilia B

Skeletal Disorders

Marfan syndrome


Muscle Disorders

Duchenne musclar dystrophy

Congenital myotonic dystrophy

Chromosomal instability

Bloom syndrome

Fanconi anemia

Tumor suppressor

Neurofibromatosis type I

Neurofibromatosis type II

Tuberous sclerosis

Skin disorders

Bullous ichthysiform erythroderma

Incontinentia pigmenti

Endocrine disorders Androgen insensitivity
Nervous-system disorders Friedreich ataxia
*Only selected disorders are included.
Table 1: Examples of additional Mendelian disorders associated with mosaicism
Adapted from Youssoufian H. et. al. Human genetics and disease: Mechanisms and consequences of somatic mosaicism in humans. Nature Reviews Genetics 3, 748-758.

Non-Mendelian Disorders Associated with Somatic Mosaicism

Cancer represents one of the most prominent forms of somatic mosaicism, although this disease typically does not follow Mendelian patterns of inheritance. Cancer is often viewed as a multistep process, during which cells progressively accumulate a series of mutations in tumor suppressor genes and oncogenes, eventually leading to unrestrained cell growth and division. Tumor cell populations form a heterogeneous mosaic patch that differs from the adjacent non-tumor cell populations. Mosaicism in cancer cells can be due to both genetic and epigenetic changes.

Non-Mendelian Disorders Associated with Mitochondrial Mosaicism

In addition to a nuclear genome, our cells also contain a mitochondrial genome; each mitochondrion maintains dozens of copies of its own circular genome, and most human cells contain numerous mitochondria. As a result, these cells contain several thousand copies of their mitochondrial genome. In human cells, mitochondria are always inherited from the mother. Furthermore, mitochondrial populations are often heterogeneous, due to an innately higher mutation rate for the mitochondrial genome.

When a cell divides, its mitochondria are distributed to the two daughter cells. However, mitochondrial segregation occurs randomly and is not nearly as organized as the highly regulated process of mitotic chromosome segregation. Therefore, cells will receive similar, but not identical, mitochondrial DNA populations. Mitochondria rely on their own set of genes, as well as on nuclear-encoded genes, in order to carry out their function as the ATP-generating powerhouses of the cell. Therefore, mitochondrial mutations can lead to profound effects on cellular metabolism and function, especially in tissues that have high energy demands, such as that of the brain, skeletal muscle, cardiac muscle, and retina (Figure 2).

Chromosomal Mosaicism

Chromosomal mosaicism is due to alterations in chromosome number or structure within a given cell population. Only three forms of autosomal trisomy are compatible with life, including trisomy 13 (Patau syndrome), trisomy 18 (Edwards syndrome), and trisomy 21 (Down syndrome), all of which can occur in a somatic mosaic manner. In most cases in which individuals with these conditions also exhibit mosaicism, it is believed that the zygote is initially trisomic but can lose the extra chromosome within a cell or cells that continue to divide throughout development. In addition, females with Turner's syndrome, which is associated with a karyotype that includes 44 autosomes and a single X chromosome (called 45,X), are sometimes somatic mosaic with some cell populations with two X chromosomes (46,XX).

The Role of Somatic Mosaicism in Lethal Disorders

Many conditions that are usually incompatible with life are due to somatic mosaic mechanisms. For example, nearly every patient with trisomy 8 is somatic mosaic. Here, the original zygote does not start out trisomic; rather, the zygote begins with two copies of chromosome 8, but gains an extra copy later in development due to a problem in chromosome segregation during mitosis (Karadima et al., 1998; Robinson et al., 1995).

Rett's syndrome, an X chromosome-associated disorder that is linked to mutations in the MECP2 gene, is usually lethal during development in males. The rare males who survive development are typically mosaic for the MECP2 mutation (Armstrong et al., 2001). The MECP2 gene is located on the X chromosome, which is subject to X inactivation in females. Therefore, if a female is heterozygous for an MECP2 mutation, only a fraction of her cells will express the mutant gene. Males, on the other hand, are XY and therefore inherit only one copy the mutant MECP2 gene; their only hope for survival is to become mosaic for a reverse mutation so that some of their cells have a wild-type copy of the MECP2 gene.

Are Identical Twins Really Identical?

Although identical (monozygotic) twins are likely to contain identical chromosomal DNA sequences at the time the embryo splits into two, they are not truly identical. If they are females, one way in which they will certainly differ is through the random process of X chromosome inactivation. Of course, no matter the gender of identical twins, their cells will also undergo random somatic mutations throughout their lifetime. As they age, their cells are also subjected to epigenetic changes that will certainly differ between twins. Therefore, it is safe to say that no two people could possibly be exactly alike at the molecular level.

References and Recommended Reading

Armstrong, J., et al. Classic Rett syndrome in a boy as a result of somatic mosaicism for a MECP2 mutation. Annals of Neurology 50, 692 (2001)

Karadima, G., et al. Origin of nondisjunction in trisomy 8 and trisomy 8 mosaicism. European Journal of Human Genetics 6, 432–438 (1998)

Robinson, W. P., et al. Molecular studies of chromosomal mosaicism: Relative frequency of chromosome gain or loss and possible role of cell selection. American Journal of Human Genetics 56, 444–451 (1995)

Youssoufian, H., & Pyeritz, R. E. Mechanisms and consequences of somatic mosaicism in humans. Nature Reviews Genetics 3, 748–758 (2002) doi:10.1038/nrg906 (link to article)


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