In medicine (genetics), a mosaic or mosaicism denotes the presence of two populations of cells with different genotypes in one individual, who has developed from a single fertilized egg. Mosaicism may result from a mutation during development which is propagated to only a subset of the adult cells.
Although the two can have some common symptoms, mosaicism is distinctly different from chimerism. In the latter, the two or more genotypes arise from more than one zygote, while in mosaics, these genotypes arise from only a single cell.
In rare cases, intersex conditions can be caused by mosaicism where some cells in the body have XX and others XY chromosomes.[1]
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 only occurs in a selection of the cells. This is usually due to a nondisjunction event in an early mitosis. 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's 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 47 total chromosomes.
Mosaicism also sometimes occurs when a different barr body is expressed in different cells, such as in calico cats.
Gonadal mosaicism
Gonadal mosaicism is a special form of mosaicism, where some gametes, i.e. either sperm or oocytes, carry a mutation, but the rest are normal[2].
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 lead to that only some children are 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" 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, 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 (pronounced mark-em) system, which stands for "Mosaic Analysis with a Repressible Cell Marker" and was developed by Liqun Luo, a professor at Stanford University. In this system the GAL4/UAS system is used to globally express GFP. However the gene GAL80 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, GAL4 is allowed to function, and GFP turns on. This results in the cells of interest being marked brightly in a dark background. [3]
Chimera genetics
zoology, a chimera is an animal that has two or more different populations of genetically distinct cells that originated in different zygotes; if the different cells emerged from the same zygote, it is called a mosaicism. Chimerism is rare in human beings: there have been only about 40 reported cases.
Chimeras are formed from four parent cells (two fertilized eggs or early embryos fuse together) or from three parent cells (a fertilized egg is fused with an unfertilized egg or a fertilized egg is fused with an extra sperm). Each population of cells keeps its own character and the resulting animal is a mixture of mis-matched parts. An analogy is two jigsaw puzzles cut using an identical cutter, but with different pictures. A single puzzle can be made out of the mis-matched parts, but the completed puzzle will show parts of both pictures.
This condition is either inherited, or it is acquired through the infusion of allogeneic hematopoietic cells during transplantation or transfusion. In fraternal twins, chimerism occurs by means of blood-vessel anastomoses. The likelihood of a child being a chimera is increased if the child is created via in vitro fertilization. Chimeras can often breed, but the fertility and type of offspring depends on which cell line gave rise to the ovaries or testes.Tetragametic chimerism
Tetragametic chimerism is a less common cause of congenital chimerism. It occurs through the fertilization of two ova by two sperm, followed by the fusion of the zygotes and the development of an organism with intermingled cell lines. This happens at a very early stage of development, such as that of the blastocyst. Such an organism is called a tetragametic chimera as it is formed from four gametes — two eggs and two sperm. Put another way, the chimera is formed from the merger of two fraternal twins in a very early (zygote or blastocyst) phase. As such, they can be male, female, or hermaphroditic.
As the organism develops, the resulting chimera can come to possess organs that have different sets of chromosomes. For example, the chimera may have a liver composed of cells with one set of chromosomes and have a kidney composed of cells with a second set of chromosomes. This has occurred in humans, and at one time was thought to be extremely rare, though more recent evidence suggests that it is not as rare as previously believed. Most will go through life without realizing they are chimeras. The difference in phenotypes may be minute, or completely undetectable (eg: having a hitchhiker's thumb and a straight thumb, eyes of slightly different colors, differential hair growth on opposite sides of the body, etc). Another telltale of a person being a chimera is visible Blaschko's lines.
Affected persons are identified by the finding of two populations of red cells or, if the zygotes are of opposite sex, ambiguous genitalia and hermaphroditism alone or in combination; such persons sometimes also have patchy skin, hair, or eye pigmentation (heterochromia). If the blastocysts are of the same sex, it can only be detected through DNA testing, although this is a rare procedure. If the blastocysts are of opposite sex, genitals of both sexes are often formed, either ovary and testis, or combined ovotestes, in one rare form of intersexuality, a condition previously known as true hermaphroditism. As of 2003, there were about 30-40 documented human cases in the literature, according to New Scientist.[1] Since hermaphroditic chimeras would be expected to be half of all chimeras, with purely male and purely female chimeras being one-quarter each, this would suggest that the condition is not particularly common.
Natural chimeras are almost never detected unless the offspring has abnormalities such as male/female or hermaphrodite characteristics or skin discolouring. The most noticeable are some male tortoiseshell cats or animals with ambiguous sex organs or behavioural abnormalities such as confused gender behaviour (where female cells made the brain but male cells made the genitals or vice versa).[citation needed] Recent studies of tortoiseshell male cats and unusually coloured tortoiseshell-like cats suggest that natural chimerism is far more common than previously realised and that it frequently goes undetected.[citation needed]
Chimerism can be detected in DNA testing. The Lydia Fairchild case, for example, was brought to court after DNA testing showed that her children could not be hers, since DNA did not match. The charge against her was dismissed when it became clear that Lydia was a chimera, with the matching DNA being found in her cervical tissue. Another case was that of Karen Keegan.[1]
The tetragametic state has important implications for organ or stem-cell transplantation. Chimeras typically have immunologic tolerance to both cell lines. Thus, for a tetragametic human, a wider array of relatives and other persons may be eligible to be an organ donor.[citation needed]
Microchimerism
Microchimerism is the presence of a small number of cells, genetically distinct from those of the host individual. The most common form is fetomaternal microchimerism (or fetal chimerism) whereby cells from a fetus pass through into the mother. Fetal cells have been documented to persist in maternal circulation for as long as 38 years.[2] Microchimerism had also been shown to exist after blood transfusions to a severely immunocompromised population of patients who suffered trauma.[3]
Microchimerism has been implicated in autoimmune diseases. Two independent scientists (Carol M. Artlett and J. Lee Nelson) published data within a month of each other, suggesting that microchimeric cells of fetal origin may be involved in the pathogenesis of systemic sclerosis.[4][5] Artlett went on to demonstrate that microchimeric cells of maternal origin may be involved in the pathogenesis of a group of autoimmune diseases found in children, juvenile idiopathic inflammatory myopathies (one example would be juvenile dermatomyositis).[6] Microchimerism has now been further implicated in other autoimmune diseases, including systemic lupus erythematosus.[7] A recent alternative hypothesis of the role of microchimeric cells in lesions is that they may be facilitating tissue repair of the damaged organ.[8] However, although these foreign cells are found in the lesions of autoimmune diseases, their role in the cause of disease is yet to be fully uncovered. Microchimeric cells may be mediating damage, facilitating tissue repair, or alternatively, be innocent bystanders.
Parasitic chimerism in anglerfishes
Chimerism occurs naturally in adult Ceratioid anglerfishes and is in fact a natural and essential part of their lifecycle. One or more males attach to a female as parasites (they must do so, as they will never fully mature alone), eventually fusing into a single, hermaphroditic individual with a shared circulatory system. Once fused to a female, the males will reach sexual maturity, developing large testicles as their other organs atrophy.
Zebrafish
Currently, a company named GloFish is selling Zebrafish chimeras. The fish have the DNA of jellyfish. They glow-in-the-dark, and come in green, red, and yellow. They are also trying to create chimeras with other types of fish.
Chimeras in research
In biological research, chimeras are artificially produced by physically mixing cells from two different organisms. Chimeras are not hybrids, which form from the fusion of gametes from two species (such as a donkey and a horse) that form a single zygote that will develop as much as it can (in this case into a live mule if the parents are jackass and mare, or a hinny if the parents are stallion and jenney); in comparison, chimeras are the physical mixing of cells from two independent zygotes: for example, one from the donkey and one from the horse. "Chimera" is a broad term and is often applied to many different types of mixing of cells from two different species.
Some chimeras can result in the eventual development of an adult animal composed of cells from both donors, which may be of different species — for example, in 1984 a chimeric geep was produced by combining embryos from a goat and a sheep[9]. The "geep" has been a very important contributor to answering fundamental questions about development and the techniques used to create it may one day help save endangered species. For example, if one tried to let a goat embryo gestate in a sheep the sheep's immune system would reject the developing embryo and the goat would die; however, if one used a geep that shared markers of immunity with both sheep and goats, the goat embryo may survive. It may be possible to extend this practice for the purpose of preventing the extinction of some endangered animal species.
Such interspecies chimeras such as the "geep" are made in the laboratory and rarely with the purpose of generating living hybrid animals. In addition to the famous geep, there are rat/mouse chimeras and a rabbit/human chimera which was destroyed within a few days for the purpose of harvesting stem cells. Intraspecies chimeras are created by transplanting embryonic cells from an animal with one trait into an embryo of an animal with a different trait. This practice is common in the field of embryology and has been a very important contributor to our current understanding of human and animal biology. For example, by mixing embryonic cells of differently coloured or otherwise genetically distinct mice (of the same species), researchers have been able to see how embryos form and which organs and tissues are related (arise from the similar cell lineages).
Hybridomas are not true chimeras as described above because they do not result from the mixture of two cell types but result from fusion of two species' cells into a single cell and artificial propagation of this cell in the laboratory. Hybridomas have been very important tools in biomedical research for decades.
In August 2003, researchers at the Shanghai Second Medical University in China reported that they had successfully fused human skin cells and dead rabbit eggs to create the first human chimeric embryos. The embryos were allowed to develop for several days in a laboratory setting, then destroyed to harvest the resulting stem cells.[7] Because of the high therapeutic potential of human embryonic stem cells and the American moratorium on using discarded embryos from in vitro fertilization clinics as well as other concerns about using human embryos directly for research, scientists are trying to find ways to find alternative paths of research. However, increasingly realizable projects using part-human, part-animal chimeras as living factories for producing cells or organs not only for biopharmaceutical production (see hybridomas) for xenotransplantation raise a host of ethical and safety issues.
During November 2006, UK researchers from Newcastle University and King's College London applied to the Human Fertilisation and Embryology Authority for a three-year license to fuse human DNA with cow eggs. The proposal is to insert human DNA into a cow's egg which has had its genetic material removed and then create an embryo by the same technique that produced Dolly the Sheep. The resulting embryo would be 99.9% human; the only bovine element would be DNA outside the nucleus of the cell.[citation needed] This research was attempted in the United States several years before and failed to yield such an embryo.
In 2007, scientists at the University of Nevada School of Medicine created a sheep that has 15% human cells and 85% animal cells. [8]
Chimeras should not be confused with mosaics, which are organisms with genetically different cell types, but which again originate from a single zygote.
[edit] References
^ "The Twin Inside Me: Extraordinary People" Channel 5 TV, UK, 23:00 9 March 2006
^ Evans PC, Lambert N, Maloney S, Furst DE, Moore JM, Nelson JL (1999). "Long-term fetal microchimerism in peripheral blood mononuclear cell subsets in healthy women and women with scleroderma.". Blood 93 (6): 2033-2037.
^ Reed W, Lee TH, Norris PJ, Utter GH, Busch MP (2007). "Transfusion-associated microchimerism: a new complication of blood transfusions in severely injured patients". Seminars in Hematology 44 (1): 24–31. PMID 17198844 doi:10.1053/j.seminhematol.2006.09.012
^ Evans PC, Lambert N, Maloney S, Furst DE, Moore JM, Nelson JL (1999). "Long-term fetal microchimerism in peripheral blood mononuclear cell subsets in healthy women and women with scleroderma.". Blood 93 (6): 2033-2037.
^ Artlett CM, Smith JB, Jimenez SA (1998). "Identification of fetal DNA and cells in skin lesions from women with systemic sclerosis.". New England Journal of Medicine 338 (17): 1186-1196.
^ Artlett CM, Ramos R, Jimenez SA, Patterson K, Miller FW, Rider LG (2000). "Chimeric cells of maternal origin in juvenile idiopathic inflammatory myopathies. Childhood Myositis Heterogeneity Collaborative Group.". Lancet 356 (9248): 2155-2156.
^ Johnson KL, McAlindon TE, Mulcahy E, Bianchi DW (2001). "Microchimerism in a female patient with systemic lupus erythematosus.". Arthritis Rheum 44 (9): 2107-2111.
^ Gilliam AC (2006). "Microchimerism and skin disease: true-true unrelated?". J. Invest Dermatol 126 (2): 239-241.
^ "It's a Geep", Time, 1984-02-27. Retrieved on 2006-08-02.
^ Lessig, Lawrence (2004). "Chapter 11: Chimera", Free Culture.
References
^ True hermaphroditism with XX/XY sex chromosome mosaicism: report of a case. De Marchi M, Carbonara AO, Carozzi F, Massara F, Belforte L, Molinatti GM, Bisbocci D, Passarino MP, Palestro G.
^ Questions and Answers - From Alexis Poss
^ stanford.edu
vivo.colostate.edu - Mosaicism and Chimerism
medgen.ubc.ca - Chromosomal Mosaicism
www.mc3cb.com/pdf_articles_interest_physiology/2012_10_19_Microchimerism_wiki.pdf