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Mosaic (genetics)

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Tulip flower with one side red and one side yellow.
Tulip flower showing mosaicism

Mosaicismorgenetic mosaicismis a condition in which amulticellular organismpossesses more than onegenetic lineas the result of geneticmutation.[1][2]This means that various genetic lines resulted from a singlefertilizedegg.Mosaicism is one of several possible causes ofchimerism,where in a single organism is composed of cells with more than one distinctgenotype.

Genetic mosaicism can result from many different mechanisms including chromosomenondisjunction,anaphase lag,andendoreplication.[3]Anaphase lagging is the most common way by which mosaicism arises in the preimplantation embryo.[3]Mosaicism can also result from amutationin one cell duringdevelopment,in which case the mutation will be passed on only to its daughter cells (and will be present only in certain adult cells).[4]Somatic mosaicism is not generally inheritable as it does not generally affect germ cells.[2]

History[edit]

In 1929,Alfred Sturtevantstudied mosaicism inDrosophila,a genus of fruit fly.[5]Muller in 1930 demonstrated that mosaicism inDrosophilais always associated withchromosomal rearrangementsand Schultz in 1936 showed that in all cases studied these rearrangements were associated withheterochromaticinert 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 Sternin 1935 assumed that the structural changes in the chromosomes took place as a result ofsomatic 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.[6]

In the 1930s, Stern demonstrated thatgenetic recombination,normal inmeiosis,can also take place inmitosis.[7][8]When it does, it results in somatic (body) mosaics. These organisms contain two or more genetically distinct types of tissue.[9]The termsomatic mosaicismwas used by CW Cotterman in 1956 in his seminal paper onantigenic variation.[10]

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 agenetic chimera.[6]

Types[edit]

Germline mosaicism[edit]

Main article:Germline mosaicism

Germline or gonadal mosaicism is a particular form of mosaicism wherein somegametes—i.e.,spermoroocytes—carry a mutation, but the rest are normal.[11][12]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[edit]

Somatic mosaicism (also known as clonal mosaicism) occurs when thesomatic cellsof the body are of more than one genotype. In the more common mosaics, different genotypes arise from a single fertilized egg cell, due tomitoticerrors at first or later cleavages.

Somatic mutation leading to mosaicism is prevalent in the beginning and end stages of human life.[10]Somatic mosaics are common inembryogenesisdue toretrotranspositionoflong interspersed nuclear element-1(LINE-1 or L1) andAlutransposable elements.[10]In early development, DNA from undifferentiated cell types may be more susceptible to mobile element invasion due to long,unmethylatedregions in the genome.[10]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 ofmutagenesis.[10]Thus,cancer researchhas shown that somatic mutations are increasingly present throughout a lifetime and are responsible for mostleukemia,lymphomas,and solid tumors.[13]

Trisomies, monosomies, and related conditions[edit]

The most common form of mosaicism found through prenatal diagnosis involvestrisomies.Although most forms of trisomy are due to problems inmeiosisand 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.[14]Generally, this leads to a milderphenotypethan in nonmosaic patients with the same disorder.

In rare cases,intersexconditions can be caused by mosaicism where some cells in the body haveXXand others XY chromosomes (46, XX/XY).[15][16]In the fruit flyDrosophila 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, orgynandromorphs.[5][17]Likewise, a loss of theY chromosomecan result in XY/X mosaic males.[18]

An example of this is one of the milder forms ofKlinefelter 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.

Alsomonosomiescan present with some form of mosaicism. The only non-lethal full monosomy occurring in humans is the one causingTurner'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.[19]In revertant mosaicism, the healthy tissue formed by mitotic recombination can outcompete the original, surrounding mutant cells in tissues such asbloodandepitheliathat regenerate often.[19]In the skin disorderichthyosis with confetti,normal skin spots appear early in life and increase in number and size over time.[19]

Other endogenous factors can also lead to mosaicism, includingmobile elements,DNA polymeraseslippage, and unbalancedchromosome segregation.[10]Exogenous factors includenicotineandUV radiation.[10]Somatic mosaics have been created inDrosophilausing X‑ray treatment and the use ofirradiationto induce somatic mutation has been a useful technique in the study of genetics.[20]

True mosaicism should not be mistaken for the phenomenon ofX-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 incalico cats). However, allmulticellular organismsare likely to be somatic mosaics to some extent.[21]

Gonosomal mosaicism[edit]

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.[1][22]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.[22]

Brain cell mosaicism[edit]

See also:Human somatic variation § Human somatic variations in brain

A frequent type of neuronal genomic mosaicism iscopy number variation.Possible sources of such variation were suggested to be incorrectrepairs of DNA damageandsomatic recombination.[23]

Mitotic recombination[edit]

One basic mechanism that can produce mosaic tissue ismitotic recombinationorsomatic crossover.It was first discovered byCurt SterninDrosophilain 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 inDrosophilais 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 inDrosophila.another example of mitotic recombination is the Bloom's syndrome, which happens due to the mutation in theblmgene. 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.[24][25]

Use in experimental biology[edit]

Genetic mosaics are a particularly powerful tool when used in the commonly studiedfruit fly,where specially selected strains frequently lose an X[17]or a Y[18]chromosome in one of the first embryonic cell divisions. These mosaics can then be used to analyze such things as courtship behavior,[17]and female sexual attraction.[26]

More recently, the use of atransgeneincorporated into theDrosophilagenome has made the system far more flexible. Theflip recombinase (orFLP)is a gene from the commonly studied yeastSaccharomyces cerevisiaethat recognizes "flip recombinase target" (FRT) sites, which are short sequences of DNA, and inducesrecombinationbetween them. FRT sites have been inserted transgenically near thecentromereof each chromosome arm ofD. melanogaster.TheFLPgene can then be induced selectively, commonly using either the heat shock promoter or theGAL4/UAS system.The resulting clones can be identified either negatively or positively.

In negatively marked clones, the fly istransheterozygousfor a gene encoding a visible marker (commonly thegreen fluorescent protein) and an allele of a gene to be studied (both on chromosomes bearing FRT sites). After induction ofFLPexpression, 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-calledMARCM( "mosaic analysis with a repressible cell marker" system, developed byLiqun Luo,a professor atStanford University,and his postdoctoral student Tzumin Lee, who now leads a group atJanelia Farm Research Campus.This system builds on the GAL4/UAS system, which is used to express GFP in specific cells. However, a globally expressedGAL80gene 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 bymitotic recombination,GAL4 is allowed to function, and GFP turns on. This results in the cells of interest being marked brightly in a dark background.[27]

See also[edit]

References[edit]

  1. ^abCampbell, Ian M.; Shaw, Chad A.; Stankiewicz, Pawel; Lupski, James R. (2015-07-01)."Somatic mosaicism: implications for disease and transmission genetics".Trends in Genetics.31(7): 382–392.doi:10.1016/j.tig.2015.03.013.ISSN0168-9525.PMC4490042.PMID25910407.
  2. ^abForsberg, Lars A.; Gisselsson, David; Dumanski, Jan P. (February 2017)."Mosaicism in health and disease — clones picking up speed".Nature Reviews Genetics.18(2): 128–142.doi:10.1038/nrg.2016.145.ISSN1471-0064.PMID27941868.S2CID44092954.
  3. ^abTaylor, T. H.; Gitlin, S. A.; Patrick, J. L.; Crain, J. L.; Wilson, J. M.; Griffin, D. K. (2014)."The origin, mechanisms, incidence and clinical consequences of chromosomal mosaicism in humans".Human Reproduction Update.20(4): 571–581.doi:10.1093/humupd/dmu016.ISSN1355-4786.PMID24667481.
  4. ^Strachan, Tom; Read, Andrew P. (1999)."Glossary".Human Molecular Genetics(2nd ed.). New York: Wiley–Liss.ISBN978-1-85996-202-2.PMID21089233.[page needed]
  5. ^abSturtevant, A. H. (1929). "The claret mutant type of Drosophila simulans: a study of chromosome elimination and cell-lineage".Zeitschrift für Wissenschaftliche Zoologie.135:323–356.
  6. ^abBelgovskii, ML (1962) [1944]. "K Voprosu o Mekhanizme Osushchestvleniya Mozaichnosti Svyazannoi s Geterokhromaticheskimi Raionami Khromosom" [The Causes of Mosaicism Associated With Heterochromatic Chromosome Regions].Zhurnal Obshchei Biologii.V(6). United States Department of Commerce - Office of Technical Services: 325–356. OTS 61-11476.
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  9. ^Stern, Curt 1968. "Genetic mosaics in animals and man". pp27–129, in Stern, C.Genetic Mosaics and Other Essays.Harvard University Press, Cambridge, MA.
  10. ^abcdefgDe, S. (2011). "Somatic mosaicism in healthy human tissues".Trends in Genetics.27(6): 217–223.doi:10.1016/j.tig.2011.03.002.PMID21496937.
  11. ^"Google Health – Google".health.google.
  12. ^Schwab, Angela L.; et al. (2007). "Gonadal mosaicism and familial adenomatous polyposis".Familial Cancer.7(2): 173–7.doi:10.1007/s10689-007-9169-1.PMID18026870.S2CID20956228.
  13. ^Jacobs, K. B.; et al. (2012)."Detectable Clonal Mosaicism and Its Relationship to Aging and Cancer".Nature Genetics.44(6): 651–U668.doi:10.1038/ng.2270.PMC3372921.PMID22561519.
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  15. ^Marchi, M. De; et al. (2008). "True hermaphroditism with XX/XY sex chromosome mosaicism: Report of a case".Clinical Genetics.10(5): 265–72.doi:10.1111/j.1399-0004.1976.tb00047.x.PMID991437.S2CID6074108.
  16. ^Fitzgerald, P. H.; Donald, R. A.; Kirk, R. L. (1979). "A true hermaphrodite dispermic chimera with 46,XX and 46,XY karyotypes".Clinical Genetics.15(1): 89–96.doi:10.1111/j.1399-0004.1979.tb02032.x.PMID759058.S2CID39280592.
  17. ^abcHotta, Yoshiki; Benzer, Seymour (1972). "Mapping of Behaviour in Drosophila mosaics".Nature.240(5383): 527–535.Bibcode:1972Natur.240..527H.doi:10.1038/240527a0.PMID4568399.S2CID4181921.
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  19. ^abcJongmans, M. C. J.; et al. (2012)."Revertant somatic mosaicism by mitotic recombination in Dyskeratosis Congenita".American Journal of Human Genetics.90(3): 426–433.doi:10.1016/j.ajhg.2012.01.004.PMC3309184.PMID22341970.
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  22. ^abMensa-Vilaró, Anna; et al. (2019-01-01)."Unexpected relevant role of gene mosaicism in patients with primary immunodeficiency diseases".Journal of Allergy and Clinical Immunology.143(1): 359–368.doi:10.1016/j.jaci.2018.09.009.ISSN0091-6749.PMID30273710.
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  27. ^Lee, Tzumin; Luo, Liqun (1999)."Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis".Neuron.22(3): 451–61.doi:10.1016/S0896-6273(00)80701-1.PMID10197526.

Further reading[edit]

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