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Mosaicism can result from various mechanisms including chromosome non-disjunction, anaphase lagging and endoreplication. Anaphase lagging appears to be the main process by which mosaicism arises in the preimplantation embryo. Mosaicism may also result from a mutation during development which is propagated to only a subset of the adult cells.
Different types of mosaicism exist, such as gonadal mosaicism (restricted to the gametes) or tissue or somatic mosaicism.
Somatic mosaicism occurs when the somatic cells of the body are of more than one genotype. In the more common mosaics, different genotypes arise from a single fertilized egg cell, due to mitotic errors at first or later cleavages.
The most common form of mosaicism found through prenatal diagnosis involves trisomies. Although most forms of trisomy are due to problems in meiosis and affect all cells of the organism, there are cases where the trisomy occurs in only a selection of the cells. This may be caused by a nondisjunction event in an early mitosis, resulting in a loss of a chromosome from some trisomic cells. Generally this leads to a milder phenotype than in non-mosaic patients with the same disorder.
An example of this is one of the milder forms of Klinefelter syndrome, called 46/47 XY/XXY mosaic wherein some of the patient's cells contain XY chromosomes, and some contain XXY chromosomes. The 46/47 annotation indicates that the XY cells have the normal number of 46 total chromosomes, and the XXY cells have a total of 47 chromosomes.
But mosaicism need not necessarily be deleterious. Revertant somatic mosaicism is a rare recombination event in which there is a spontaneous correction of a mutant, pathogenic allele. In revertant mosaicism, the healthy tissue formed by mitotic recombination can outcompete the original, surrounding mutant cells in tissues like blood and epithelia that regenerate often. In the skin disorder ichthyosis with confetti, normal skin spots appear early in life and increase in number and size over time.
Other endogenous factors can also lead to mosaicism including mobile elements, DNA polymerase slippage, and unbalanced chromosomal segregation. Exogenous factors include nicotine and UV radiation. Somatic mosaics have been created in Drosophila using x‑ray treatment and the use of irradiation to induce somatic mutation has been a useful technique in the study of genetics.
True mosaicism should not be mistaken for the phenomenon of X‑inactivation, where all cells in an organism have the same genotype, but a different copy of the X chromosome is expressed in different cells (such as in calico cats). However, all multicellular organisms are likely to be somatic mosaics to some extent. Since the human intergenerational mutation rate is approximately 10−8 per position per haploid genome and there are 1014 cells in the human body, it is likely that during the course of a lifetime most humans have had many of the known genetic mutations in our somatic cells  and thus humans, along with most multicellular organisms, are all somatic mosaics to some extent. To extend the definition, the ends of chromosomes, called telomeres, shorten with every cell division and can vary from cell to cell, thus representing a special case of somatic mosaicism.
Somatic mutation leading to mosaicism is prevalent in the beginning and end stages of human life. Somatic mosaics are common in embryogenesis due to retrotransposition of L1 and Alu transposable elements. In early development, DNA from undifferentiated cell types may be more susceptible to mobile element invasion due to long, un-methylated regions in the genome. Further, the accumulation of DNA copy errors and damage over a lifetime lead to greater occurrences of mosaic tissues in aging humans. As our longevity has increased dramatically over the last century, our genome may not have had time to adapt to cumulative effects of mutagenesis. Thus, cancer research has shown that somatic mutations are increasingly present throughout a lifetime and are responsible for most leukemia, lymphomas, and solid tumors.
One basic mechanism which can produce mosaic tissue is mitotic recombination or somatic crossover. It was first discovered by Curt Stern in Drosophila in 1936. The amount of tissue which is mosaic depends on where in the tree of cell division the exchange takes place.
The cause is usually a mutation that occurred in an early stem cell that gave rise to all or part of the gonadal tissue.
This can cause only some children to be affected, even for a dominant disease.
Use in experimental biology
Genetic mosaics can be extraordinarily useful in the study of biological systems, and can be created intentionally in many model organisms in a variety of ways. They often allow for the study of genes that are important for very early events in development, making it otherwise difficult to obtain adult organisms in which later effects would be apparent. Furthermore they can be used to determine the tissue or cell type in which a given gene is required and to determine whether a gene is cell autonomous. That is, whether or not the gene acts solely within the cell of that genotype, or if it affects neighboring cells which do not themselves contain that genotype, but take on that phenotype due to environmental differentiation.
The earliest examples of this involved transplantation experiments (technically creating chimeras) where cells from a blastula stage embryo from one genetic background are aspirated out and injected into a blastula stage embryo of a different genetic background.
Genetic mosaics are a particularly powerful tool when used in the commonly studied fruit fly, where they are created through mitotic recombination. Mosaics were originally created by irradiating flies heterozygous for a particular allele with X-rays, inducing double-strand DNA breaks which, when repaired, could result in a cell homozygous for one of the two alleles. After further rounds of replication, this cell would result in a patch, or "clone" of cells mutant for the allele being studied.
More recently the use of a transgene incorporated into the Drosophila genome has made the system far more flexible. The Flip Recombinase (or FLP) is a gene from the commonly studied yeast Saccharomyces cerevisiae which recognizes "Flip Recombinase Target" (FRT) sites, which are short sequences of DNA, and induces recombination between them. FRT sites have been inserted transgenically near the centromere of each chromosome arm of Drosophila melanogaster. The FLP gene can then be induced selectively, commonly using either the heat shock promoter or the GAL4/UAS system. The resulting clones can be identified either negatively or positively.
In negatively marked clones the fly is transheterozygous for a gene encoding a visible marker (commonly the green fluorescent protein or GFP) and an allele of a gene to be studied (both on chromosomes bearing FRT sites). After induction of FLP expression, cells that undergo recombination will have progeny that are homozygous for either the marker or the allele being studied. Therefore the cells that do not carry the marker (which are dark) can be identified as carrying a mutation.
It is sometimes inconvenient to use negatively marked clones, especially when generating very small patches of cells, where it is more difficult to see a dark spot on a bright background than a bright spot on a dark background. It is possible to create positively marked clones using the so-called MARCM ("Mosaic Analysis with a Repressible Cell Marker", pronounced [mark-em]) system, developed by Liqun Luo, a professor at Stanford University, and his post-doc Tzumin Lee who now leads a group at Janelia Farm Research Campus. This system builds on the GAL4/UAS system, which is used to express GFP in specific cells. However a globally expressed GAL80 gene is used to repress the action of GAL4, preventing the expression of GFP. Instead of using GFP to mark the wild-type chromosome as above, GAL80 serves this purpose, so that when it is removed by mitotic recombination, GAL4 is allowed to function, and GFP turns on. This results in the cells of interest being marked brightly in a dark background.
The phenomenon was discovered by Curt Stern. In the 1930s, he demonstrated that genetic recombination, normal in meiosis, can also take place in mitosis. When it does, it results in somatic (body) mosaics. These are organisms which contain two or more genetically distinct types of tissue. The term "somatic mosaicism" was used by C. W. Cotterman in 1956 in his seminal paper on antigenic variation.
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