Mosaic (genetics)
Encyclopedia
In genetic
medicine
, a mosaic or mosaicism denotes the presence of two populations of cells
with different genotype
s 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.
s) or tissue or somatic mosaicism.
Another form of somatic mosaicism is chimerism
, where two or more genotypes arise from the fusion of more than one fertilized zygote
in the early stages of embryonal
development.
In rare cases, intersex
conditions can be caused by mosaicism where some cells in the body have XX
and others XY chromosomes.
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'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.
Around 30% of Turner's syndrome cases demonstrate mosaicism, while complete monosomy (45 XO) occurs in about 50–60% of cases.
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
.
in Drosophila in 1936. The process involves exchange of genetic material between chromatids of homologous chromosomes. It occurs much less often than meiotic recombination. The amount of tissue which is mosaic depends on where, in the tree of cell division, the exchange takes place.
is a special form of mosaicism, where some gametes, i.e. either sperm or oocytes, 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 gonadal tissue.
This can cause only some children to be affected, even for a dominant disease.
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
("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, now a group leader at Janelia Farm. 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.
http://research.amnh.org/entomology/social_insects/ants/publications/8214/8214.pdf
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
medicine
Medicine
Medicine is the science and art of healing. It encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness....
, a mosaic or mosaicism denotes the presence of two populations of cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
with different genotype
Genotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...
s in one individual who has developed from a single fertilized egg. Mosaicism may result from a mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
during development
Morphogenesis
Morphogenesis , is the biological process that causes an organism to develop its shape...
which is propagated to only a subset of the adult cells.
Types
Different types of mosaicism exist, such as gonadal mosaicism (restricted to the gameteGamete
A gamete is a cell that fuses with another cell during fertilization in organisms that reproduce sexually...
s) or tissue or somatic mosaicism.
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.Another form of somatic mosaicism is chimerism
Chimera (genetics)
A chimera or chimaera is a single organism that is composed of two or more different populations of genetically distinct cells that originated from different zygotes involved in sexual reproduction. If the different cells have emerged from the same zygote, the organism is called a mosaic...
, where two or more genotypes arise from the fusion of more than one fertilized zygote
Zygote
A zygote , or zygocyte, is the initial cell formed when two gamete cells are joined by means of sexual reproduction. In multicellular organisms, it is the earliest developmental stage of the embryo...
in the early stages of embryonal
Embryo
An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
development.
In rare cases, intersex
Intersex
Intersex, in humans and other animals, is the presence of intermediate or atypical combinations of physical features that usually distinguish female from male...
conditions can be caused by mosaicism where some cells in the body have XX
Sex-determination system
A sex-determination system is a biological system that determines the development of sexual characteristics in an organism. Most sexual organisms have two sexes. In many cases, sex determination is genetic: males and females have different alleles or even different genes that specify their sexual...
and others XY chromosomes.
The most common form of mosaicism found through prenatal diagnosis involves trisomies
Trisomy
A trisomy is a type of polysomy in which there are three copies, instead of the normal two, of a particular chromosome. A trisomy is a type of aneuploidy .-Description and causes:...
. Although most forms of trisomy
Trisomy
A trisomy is a type of polysomy in which there are three copies, instead of the normal two, of a particular chromosome. A trisomy is a type of aneuploidy .-Description and causes:...
are due to problems in meiosis
Meiosis
Meiosis is a special type of cell division necessary for sexual reproduction. The cells produced by meiosis are gametes or spores. The animals' gametes are called sperm and egg cells....
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
Nondisjunction
Nondisjunction is the failure of chromosome pairs to separate properly during meiosis stage 1 or stage 2. This could arise from a failure of homologous chromosomes to separate in meiosis I, or the failure of sister chromatids to separate during meiosis II or mitosis. The result of this error is a...
event in an early mitosis, resulting in a loss of a chromosome from some trisomic cells. Generally this leads to a milder phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
than in non-mosaic patients with the same disorder.
An example of this is one of the milder forms of Klinefelter's syndrome
Klinefelter's syndrome
Klinefelter syndrome, 46/47, XXY, or XXY syndrome is a condition in which human males have an extra X chromosome. While females have an XX chromosomal makeup, and males an XY, affected individuals have at least two X chromosomes and at least one Y chromosome...
, 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.
Around 30% of Turner's syndrome cases demonstrate mosaicism, while complete monosomy (45 XO) occurs in about 50–60% of cases.
True mosaicism should not be mistaken for the phenomenon of X-inactivation
X-inactivation
X-inactivation is a process by which one of the two copies of the X chromosome present in female mammals is inactivated. The inactive X chromosome is silenced by packaging into transcriptionally inactive heterochromatin...
, 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
Calico cats
Calico cats are domestic cats with a spotted or parti-colored coat, usually predominantly white with orange and black patches. Outside of North America the pattern is more usually called tortoiseshell-and-white. In the province of Quebec, they are unofficially considered a breed by the...
.
Mitotic recombination
One basic mechanism which can produce mosaic tissue is mitotic recombination or somatic crossing-over. It was first discovered by Curt SternCurt Stern
Curt Stern was a German-born American geneticist.Curt Jacob Stern was born in Hamburg, Germany. He studied zoology at the University of Berlin and received his PhD in 1923 at the age of 21...
in Drosophila in 1936. The process involves exchange of genetic material between chromatids of homologous chromosomes. It occurs much less often than meiotic recombination. The amount of tissue which is mosaic depends on where, in the tree of cell division, the exchange takes place.
Gonadal mosaicism
Gonadal mosaicism or germline mosaicismGermline Mosaicism
Germline mosaicism, also known as gonadal mosaicism, is a condition in which the precursor cells to ova and spermatazoa are a mixture of two or more genetically different cell lines....
is a special form of mosaicism, where some gametes, i.e. either sperm or oocytes, 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 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
Blastula
The blastula is a hollow sphere of cells formed during an early stage of embryonic development in animals . The blastula is created when the zygote undergoes the cell division process known as cleavage. The blastula is preceded by the morula and is followed by the gastrula in the developmental...
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
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
, where they are created through mitotic recombination. Mosaics were originally created by irradiating flies heterozygous for a particular allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
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
Transgene
A transgene is a gene or genetic material that has been transferred naturally or by any of a number of genetic engineering techniques from one organism to another....
incorporated into the Drosophila
Drosophila
Drosophila is a genus of small flies, belonging to the family Drosophilidae, whose members are often called "fruit flies" or more appropriately pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species to linger around overripe or rotting fruit...
genome has made the system far more flexible. The Flip Recombinase (or FLP)
FLP-FRT Recombination
In genetics, FLP-FRT recombination is a site-directed recombination technology used to manipulate an organism's DNA under controlled conditions in vivo. It is analogous to Cre-Lox recombination...
is a gene from the commonly studied yeast Saccharomyces cerevisiae
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
which recognizes "Flip Recombinase Target" sites, which are short sequences of DNA, and induces recombination
Genetic recombination
Genetic recombination is a process by which a molecule of nucleic acid is broken and then joined to a different one. Recombination can occur between similar molecules of DNA, as in homologous recombination, or dissimilar molecules, as in non-homologous end joining. Recombination is a common method...
between them. FRT sites have been inserted transgenically near the centromere
Centromere
A centromere is a region of DNA typically found near the middle of a chromosome where two identical sister chromatids come closest in contact. It is involved in cell division as the point of mitotic spindle attachment...
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
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 was developed by Andrea Brand and Norbert Perrimon in 1993 and is considered a powerful technique for studying the expression of genes...
. The resulting clones can be identified either negatively or positively.
In negatively marked clones the fly is transheterozygous
Transheterozygote
The term transheterozygote is used in modern genetics periodicals in two different ways. In the first, the transheterozygote has one mutant and one wildtype allele at each of two different genes . In the second, the transheterozygote carries two different mutated alleles of the same gene...
for a gene encoding a visible marker (commonly the green fluorescent protein, GFP
Green fluorescent protein
The green fluorescent protein is a protein composed of 238 amino acid residues that exhibits bright green fluorescence when exposed to blue light. Although many other marine organisms have similar green fluorescent proteins, GFP traditionally refers to the protein first isolated from the...
) 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
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. This technique relies on recombination during mitosis mediated by FLP-FRT Recombination...
("Mosaic Analysis with a Repressible Cell Marker", pronounced mark-em) system, developed by Liqun Luo, a professor at Stanford University
Stanford University
The Leland Stanford Junior University, commonly referred to as Stanford University or Stanford, is a private research university on an campus located near Palo Alto, California. It is situated in the northwestern Santa Clara Valley on the San Francisco Peninsula, approximately northwest of San...
and his post-doc, Tzumin Lee, now a group leader at Janelia Farm. This system builds on the GAL4/UAS
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 was developed by Andrea Brand and Norbert Perrimon in 1993 and is considered a powerful technique for studying the expression of genes...
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.