Mosaicism or genetic mosaicism is a condition in

multicellular organism A multicellular organism is an organism that consists of more than one cell, in contrast to unicellular organism. All species of animals, land plants and most fungi are multicellular, as are many algae, whereas a few organisms are partially uni ...

s in which a single

organism In biology, an organism () is any living system that functions as an individual entity. All organisms are composed of cells ( cell theory). Organisms are classified by taxonomy into groups such as multicellular animals, plants, and fu ...

possesses more than one genetic line as the result of genetic

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...

. This means that various genetic lines resulted from a single

fertilized Fertilisation or fertilization (see spelling differences), also known as generative fertilisation, syngamy and impregnation, is the fusion of gametes to give rise to a new individual organism or offspring and initiate its development. Proc ...

egg. Genetic mosaics may often be confused with chimerism, in which two or more

genotype The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a ...

s arise in one individual similarly to mosaicism. In chimerism, though, the two genotypes arise from the fusion of more than one fertilized

zygote A zygote (, ) is a eukaryotic cell formed by a fertilization event between two gametes. The zygote's genome is a combination of the DNA in each gamete, and contains all of the genetic information of a new individual organism. In multicell ...

in the early stages of

embryo An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...

nic development, rather than from a mutation or

chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins ar ...

loss. Genetic mosaicism can result from many different mechanisms including chromosome nondisjunction,

anaphase lag Anaphase lag is a consequence of an event during cell division where sister chromatids do not properly separate from each other because of improper spindle formation. The chromosome or chromatid does not properly migrate during anaphase and the da ...

, and

endoreplication Endoreduplication (also referred to as endoreplication or endocycling) is replication of the nuclear genome in the absence of mitosis, which leads to elevated nuclear gene content and polyploidy. Endoreplication can be understood simply as a vari ...

. Anaphase lagging is the most common way by which mosaicism arises in the preimplantation embryo. Mosaicism can also result from a

in one cell during development, in which case the mutation will be passed on only to its daughter cells (and will be present only in certain adult cells). Somatic mosaicism is not generally inheritable as it does not generally affect germ cells.

History

In 1929,

Alfred Sturtevant Alfred Henry Sturtevant (November 21, 1891 – April 5, 1970) was an American geneticist. Sturtevant constructed the first genetic map of a chromosome in 1911. Throughout his career he worked on the organism ''Drosophila melanogaster'' with ...

studied mosaicism in ''

Drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many speci ...

'', a genus of fly. Muller in 1930 demonstrated that mosaicism in ''Drosophila'' is always associated with

chromosomal rearrangements A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...

and Schultz in 1936 showed that in all cases studied these rearrangements were associated with heterochromatic inert regions, several hypotheses on the nature of such mosaicism were proposed. One hypothesis assumed that mosaicism appears as the result of a break and loss of chromosome segments. Curt Stern in 1935 assumed that the structural changes in the chromosomes took place as a result of ''somatic crossing'', as a result of which mutations or small chromosomal rearrangements in somatic cells. Thus the inert region causes an increase in mutation frequency or small chromosomal rearrangements in active segments adjacent to inert regions. In the 1930s, Stern demonstrated that

genetic recombination Genetic recombination (also known as genetic reshuffling) is the exchange of genetic material between different organisms which leads to production of offspring with combinations of traits that differ from those found in either parent. In eukaryo ...

, normal in

meiosis Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately ...

, can also take place in

mitosis In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is maintai ...

.Stern, C. and K. Sekiguti 1931. Analyse eines Mosaikindividuums bei ''Drosophila melanogaster''. ''Bio. Zentr.'' 51, 194199.Stern C. 1936. "Somatic crossing-over and segregation in ''Drosophila melanogaster''". ''Genetics'' 21, 625730. When it does, it results in somatic (body) mosaics. These organisms contain two or more genetically distinct types of tissue.Stern, Curt 1968. "Genetic mosaics in animals and man". pp27129, in Stern, C. ''Genetic Mosaics and Other Essays''. Harvard University Press, Cambridge, MA. The term ''somatic mosaicism'' was used by CW Cotterman in 1956 in his seminal paper on antigenic variation. In 1944, Belgovskii proposed that mosaicism could not account for certain mosaic expressions caused by chromosomal rearrangements involving heterochromatic inert regions. The associated weakening of biochemical activity led to what he called a '' genetic chimera''.

Types

Germline mosaicism

Germline or gonadal mosaicism is a particular form of mosaicism wherein some

gametes A gamete (; , ultimately ) is a haploid cell that fuses with another haploid cell during fertilization in organisms that reproduce sexually. Gametes are an organism's reproductive cells, also referred to as sex cells. In species that produce ...

—i.e.,

sperm Sperm is the male reproductive cell, or gamete, in anisogamous forms of sexual reproduction (forms in which there is a larger, female reproductive cell and a smaller, male one). Animals produce motile sperm with a tail known as a flagellum, ...

oocyte An oocyte (, ), oöcyte, or ovocyte is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in a female fetus in the ovary during female gametogenesis. The female ...

s—carry a mutation, but the rest are normal. The cause is usually a mutation that occurred in an early stem cell that gave rise to all or part of the gametes.

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. Somatic mutation leading to mosaicism is prevalent in the beginning and end stages of human life. Somatic mosaics are common in

embryogenesis An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...

due to

retrotransposition A transposable element (TE, transposon, or jumping gene) is a nucleic acid sequence in DNA that can change its position within a genome, sometimes creating or reversing mutations and altering the cell's genetic identity and genome size. Tra ...

of long interspersed nuclear element-1 (LINE-1 or L1) and Alu

transposable elements A transposable element (TE, transposon, or jumping gene) is a nucleic acid sequence in DNA that can change its position within a genome, sometimes creating or reversing mutations and altering the cell's genetic identity and genome size. Trans ...

. In early development, DNA from undifferentiated cell types may be more susceptible to mobile element invasion due to long, unmethylated 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 longevity has increased dramatically over the last century, human genome may not have had time to adapt to cumulative effects of

mutagenesis Mutagenesis () is a process by which the genetic information of an organism is changed by the production of a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using lab ...

. Thus,

cancer research Cancer research is research into cancer to identify causes and develop strategies for prevention, diagnosis, treatment, and cure. Cancer research ranges from epidemiology, molecular bioscience to the performance of clinical trials to evaluate an ...

has shown that somatic mutations are increasingly present throughout a lifetime and are responsible for most

leukemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ...

, lymphomas, and solid tumors.

Trisomies, monosomies and related conditions

The most common form of mosaicism found through prenatal diagnosis involves trisomies. Although most forms of trisomy are due to problems in

and affect all cells of the organism, some cases occur 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 In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (biology), morphology or physical form and structure, its Developmental biology, developmental proc ...

than in nonmosaic patients with the same disorder. In rare cases,

intersex Intersex people are individuals born with any of several sex characteristics including chromosome patterns, gonads, or genitals that, according to the Office of the United Nations High Commissioner for Human Rights, "do not fit typical b ...

conditions can be caused by mosaicism where some cells in the body have XX and others XY chromosomes ( 46, XX/XY). In the fruit fly ''

Drosophila melanogaster ''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the " vinegar fly" or "pomace fly". Starting with ...

'', where a fly possessing two X chromosomes is a female and a fly possessing a single X chromosome is a sterile male, a loss of an X chromosome early in embryonic development can result in sexual mosaics, or gynandromorphs. Likewise, a loss of the

Y chromosome The Y chromosome is one of two sex chromosomes (allosomes) in therian mammals, including humans, and many other animals. The other is the X chromosome. Y is normally the sex-determining chromosome in many species, since it is the presence or abs ...

can result in XY/X mosaic males. An example of this is one of the milder forms of

Klinefelter syndrome Klinefelter syndrome (KS), also known as 47,XXY, is an aneuploid genetic condition where a male has an additional copy of the X chromosome. The primary features are infertility and small, poorly functioning testicles. Usually, symptoms are sub ...

, called 46,XY/47,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. Also monosomies can present with some form of mosaicism. The only non-lethal full monosomy occurring in humans is the one causing Turner's syndrome. Around 30% of Turner's syndrome cases demonstrate mosaicism, while complete monosomy (45, X) occurs in about 50–60% of cases. Mosaicism need not necessarily be deleterious, though. Revertant somatic mosaicism is a rare recombination event with a spontaneous correction of a mutant,

pathogenic allele In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...

. In revertant mosaicism, the healthy tissue formed by mitotic recombination can outcompete the original, surrounding mutant cells in tissues such as

blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the cir ...

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 A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to crea ...

slippage, and unbalanced chromosomal segregation. Exogenous factors include

nicotine Nicotine is a naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and '' Duboisia hopwoodii'') and is widely used recreationally as a stimulant and anxiolytic. As a pharmaceutical drug, it is use ...

and

UV radiation Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nm (with a corresponding frequency around 30 PHz) to 400 nm (750 THz), shorter than that of visible light, but longer than X-rays. UV radiatio ...

. Somatic mosaics have been created in ''Drosophila'' using X‑ray treatment and the use of

irradiation Irradiation is the process by which an object is exposed to radiation. The exposure can originate from various sources, including natural sources. Most frequently the term refers to ionizing radiation, and to a level of radiation that will serve ...

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. The latter is the case in normal (XX) female mammals, although it is not always visible from the phenotype (as it is in

calico cats A calico cat is a domestic cat of any breed with a tri-color coat. The calico cat is most commonly thought of as being typically 25% to 75% white with large orange and black patches (or sometimes cream and grey patches, which is called a mut ...

). However, all

s are likely to be somatic mosaics to some extent.

Gonosomal mosaicism

Gonosomal mosaicism is a type of somatic mosaicism that occurs very early in the organisms development and thus is present within both germline and somatic cells. Somatic mosaicism is not generally inheritable as it does not usually affect germ cells. In the instance of gonosomal mosaicism, organisms have the potential to pass the genetic alteration, including to potential offspring because the altered allele is present in both somatic and germline cells.

Brain cell mosaicism

A frequent type of neuronal genomic mosaicism is

copy number variation Copy number variation (CNV) is a phenomenon in which sections of the genome are repeated and the number of repeats in the genome varies between individuals. Copy number variation is a type of structural variation: specifically, it is a type of ...

. Possible sources of such variation were suggested to be incorrect repair of DNA damages and

somatic recombination Somatic recombination, as opposed to the genetic recombination that occurs in meiosis, is an alteration of the DNA of a somatic cell that is inherited by its daughter cells. The term is usually reserved for large-scale alterations of DNA such as ch ...

Mitotic recombination

One basic mechanism that can produce mosaic tissue is mitotic recombination or somatic crossover. It was first discovered by Curt Stern in ''

'' in 1936. The amount of tissue that is mosaic depends on where in the tree of cell division the exchange takes place. A phenotypic character called "twin spot" seen in ''Drosophila'' is a result of mitotic recombination. However, it also depends on the allelic status of the genes undergoing recombination. Twin spot occurs only if the heterozygous genes are linked in repulsion, i.e. the trans phase. The recombination needs to occur between the centromeres of the adjacent gene. This gives an appearance of yellow patches on the wild-type background in ''Drosophila''. another example of mitotic recombination is the Bloom's syndrome, which happens due to the mutation in the ''blm'' gene. The resulting BLM protein is defective. The defect in RecQ, a helicase, facilitates the defective unwinding of DNA during replication, thus is associated with the occurrence of this disease.

Use in experimental biology

Genetic mosaics are a particularly powerful tool when used in the commonly studied fruit fly, where specially selected strains frequently lose an X or a Y chromosome in one of the first embryonic cell divisions. These mosaics can then be used to analyze such things as courtship behavior, and female sexual attraction. More recently, the use of a

transgene A transgene is a gene that has been transferred naturally, or by any of a number of genetic engineering techniques, from one organism to another. The introduction of a transgene, in a process known as transgenesis, has the potential to change t ...

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 ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have b ...

'' that 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 The centromere links a pair of sister chromatids together during cell division. This constricted region of chromosome connects the sister chromatids, creating a short arm (p) and a long arm (q) on the chromatids. During mitosis, spindle fibers ...

of each chromosome arm of ''D. melanogaster''. The ''FLP'' gene can then be induced selectively, commonly using either the heat shock promoter or the

GAL4/UAS system The GAL4-UAS system is a biochemical method used to study gene expression and function in organisms such as the fruit fly. It is based on the finding by Hitoshi Kakidani and Mark Ptashne, and Nicholas Webster and Pierre Chambon in 1988 that Gal4 ...

. 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 The green fluorescent protein (GFP) is a protein that exhibits bright green fluorescence when exposed to light in the blue to ultraviolet range. The label ''GFP'' traditionally refers to the protein first isolated from the jellyfish '' Aequore ...

) 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 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. Using negatively marked clones is sometimes inconvenient, especially when generating very small patches of cells, where seeing a dark spot on a bright background is more difficult than a bright spot on a dark background. Creating positively marked clones is possible using the so-called

MARCM Mosaic analysis with a repressible cell marker, or MARCM, is a genetics technique for creating individually labeled homozygous cells in an otherwise heterozygous ''Drosophila melanogaster''. It has been a crucial tool in studying the development of ...

("mosaic analysis with a repressible cell marker" system, developed by

Liqun Luo Liqun Luo (; born January 1966) is a neuroscientist in the Department of Biology at Stanford University, where he is the Ann and Bill Swindells Professor in the School of Humanities and Sciences, and an investigator of the Howard Hughes Medical I ...

, a professor at

Stanford University Stanford University, officially Leland Stanford Junior University, is a private research university in Stanford, California. The campus occupies , among the largest in the United States, and enrolls over 17,000 students. Stanford is conside ...

, and his postdoctoral student Tzumin Lee, who now leads a group at

Janelia Farm Research Campus Janelia Research Campus is a scientific research campus of the Howard Hughes Medical Institute that opened in October 2006. The campus is located in Loudoun County, Virginia, near the town of Ashburn. It is known for its scientific research and ...

. 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.