Mosaic (genetics)

Germline or gonadal mosaicism is a special form of mosaicism wherein some gametes—i.e., sperm or oocytes—carry a mutation, but the rest are normal.[10][11] 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 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.

In rare cases, intersex conditions can be caused by mosaicism where some cells in the body have XX and others XY chromosomes (46, XX/XY).[12][13] In the fruit fly Drosophila melanogaster, 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.[4][14] Likewise, a loss of the Y chromosome can result in XY/X mosaic males.[15]

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, 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.[16] Generally, this leads to a milder phenotype than in nonmosaic patients with the same disorder.

An example of this is one of the milder forms of Klinefelter syndrome, 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.[17] In revertant mosaicism, the healthy tissue formed by mitotic recombination can outcompete the original, surrounding mutant cells in tissues such as blood and epithelia that regenerate often.[17] In the skin disorder ichthyosis with confetti, normal skin spots appear early in life and increase in number and size over time.[17]

Other endogenous factors can also lead to mosaicism, including mobile elements, DNA polymerase slippage, and unbalanced chromosomal segregation.[9] Exogenous factors include nicotine and UV radiation.[9] 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.[18]

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 in calico cats). However, all multicellular organisms are likely to be somatic mosaics to some extent.[19]

Somatic mutation leading to mosaicism is prevalent in the beginning and end stages of human life.[9] Somatic mosaics are common in embryogenesis due to retrotransposition of L1 and Alu transposable elements.[9] In early development, DNA from undifferentiated cell types may be more susceptible to mobile element invasion due to long, unmethylated regions in the genome.[9] 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.[9] Thus, cancer research has shown that somatic mutations are increasingly present throughout a lifetime and are responsible for most leukemia, lymphomas, and solid tumors.[20]

A frequent type of neuronal genomic mosaicism is copy number variation. Possible sources of such variation were suggested to be incorrect repair of DNA damages and somatic recombination.[21]

One basic mechanism that 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 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.[22][23]