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the condition in which an organism has two or more cell populations that differ in genetic makeup

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/06/02 00:02:58」(JST)

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In genetics, a mosaic or mosaicism denotes the presence of two or more populations of cells with different genotypes in one individual who has developed from a single fertilized egg.^[1]

Mosaicism can result from various mechanisms including chromosome non-disjunction, anaphase lag and endoreplication.^[2] Anaphase lagging appears to be the main process by which mosaicism arises in the preimplantation embryo.^[2] Mosaicism may also result from a mutation during development which is propagated to only a subset of the adult cells.

Mosaics may be contrasted with chimerism, in which two or more genotypes arise from the fusion of more than one fertilized zygote in the early stages of embryonic development.

Mosaicism has been reported to be present in as high as 70% of cleavage stage embryos and 90% of blastocyst-stage embryos derived from in vitro fertilization.^[2]

Types

Different types of mosaicism exist, such as gonadal mosaicism (restricted to the gametes) 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.

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).^[3]^[4]

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.^[5] 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 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 a total of 47 chromosomes.

Around 30% of Turner's syndrome cases demonstrate mosaicism, while complete monosomy (45, X) occurs in about 50–60% of cases.

But mosaicism need not necessarily be deleterious. Revertant somatic mosaicism is a rare recombination event in which there is a spontaneous correction of a mutant, pathogenic allele.^[6] In revertant mosaicism, the healthy tissue formed by mitotic recombination can outcompete the original, surrounding mutant cells in tissues like blood and epithelia that regenerate often.^[6] In the skin disorder ichthyosis with confetti, normal skin spots appear early in life and increase in number and size over time.^[6]

Other endogenous factors can also lead to mosaicism including mobile elements, DNA polymerase slippage, and unbalanced chromosomal segregation.^[7] Exogenous factors include nicotine and UV radiation.^[7] 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.^[8]

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). However, all multicellular organisms are likely to be somatic mosaics to some extent.^[9] Since the human intergenerational mutation rate is approximately 10⁻⁸ per position per haploid genome^[10] and there are 10¹⁴ cells in the human body,^[9] it is likely that during the course of a lifetime most humans have had many of the known genetic mutations in our somatic cells ^[9] and thus humans, along with most multicellular organisms, are all somatic mosaics to some extent. To extend the definition, the ends of chromosomes, called telomeres, shorten with every cell division and can vary from cell to cell, thus representing a special case of somatic mosaicism.^[7]

Somatic mutation leading to mosaicism is prevalent in the beginning and end stages of human life.^[7] Somatic mosaics are common in embryogenesis due to retrotransposition of L1 and Alu transposable elements.^[7] In early development, DNA from undifferentiated cell types may be more susceptible to mobile element invasion due to long, un-methylated regions in the genome.^[7] Further, the accumulation of DNA copy errors and damage over a lifetime lead to greater occurrences of mosaic tissues in aging humans. As our longevity has increased dramatically over the last century, our genome may not have had time to adapt to cumulative effects of mutagenesis.^[7] Thus, cancer research has shown that somatic mutations are increasingly present throughout a lifetime and are responsible for most leukemia, lymphomas, and solid tumors.^[11]

Mitotic recombination

One basic mechanism which 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 which is mosaic depends on where in the tree of cell division the exchange takes place.^[12]

Germline mosaicism

Germline or gonadal mosaicism is a special form of mosaicism, where some gametes—i.e., sperm or oocytes—carry a mutation, but the rest are normal.^[13]^[14]

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 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" (FRT) 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 or 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 who now leads a group at Janelia Farm Research Campus. 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.^[15]

History

The phenomenon was discovered by Curt Stern. In the 1930s, he demonstrated that genetic recombination, normal in meiosis, can also take place in mitosis.^[16]^[17] When it does, it results in somatic (body) mosaics. These are organisms which contain two or more genetically distinct types of tissue.^[18] The term "somatic mosaicism" was used by C. W. Cotterman in 1956 in his seminal paper on antigenic variation.^[7]

References

^ Strachan, Tom; Read, Andrew P. (1999). "Glossary". Human Molecular Genetics (2nd ed.). New York: Wiley–Liss. ISBN 1-85996-202-5. PMID 21089233. ^{[page needed]}
^ ^a ^b ^c Taylor, 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. ISSN 1355-4786.
^ 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. PMID 991437.
^ 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. PMID 759058.
^ Strachan, Tom; Read, Andrew P. (1999). "Chromosome abnormalities". Human Molecular Genetics (2nd ed.). New York: Wiley–Liss. ISBN 1-85996-202-5. PMID 21089233. ^{[page needed]}
^ ^a ^b ^c Jongmans, 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.
^ ^a ^b ^c ^d ^e ^f ^g ^h De, S. (2011). "Somatic mosaicism in healthy human tissues". Trends in Genetics 27 (6): 217–223. doi:10.1016/j.tig.2011.03.002. |accessdate= requires |url= (help)
^ Blair, S. S. "Genetic mosaic techniques for studying Drosophila development". Development 130 (21): 5065–5072. doi:10.1242/dev.00774.
^ ^a ^b ^c Hall, J. G. (1988). "Review and hypotheses: Somatic mosaicism, observations related to clinical genetics". American Journal of Human Genetics 43 (4): 355–363.
^ Roach, J. C.; Glusman, G. et al. (2010). "Analysis of genetic inheritance in a family quartet by whole-genome sequencing". Science 328 (5978): 636–639. doi:10.1126/science.1186802. PMC 3037280. PMID 20220176.
^ 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. Check date values in: |accessdate= (help); |accessdate= requires |url= (help)
^ King R. C; Stansfield W. D. and Mulligan P. K. 2006. A Dictionary of Genetics. 7th ed, Oxford University Press. p282
^ https://health.google.com/health/ref/Mosaicism
^ 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. PMID 18026870.
^ 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. PMID 10197526.
^ Stern, C. and K. Sekiguti 1931. Analyse eines Mosaikindividuums bei Drosophila melanogaster. Bio. Zentr. 51, 194–199.
^ Stern C. 1936. "Somatic crossing-over and segregation in Drosophila melanogaster". Genetics 21, 625–730.
^ Stern, Curt 1968. "Genetic mosaics in animals and man". pp27–129, in Stern, C. Genetic Mosaics and Other Essays. Harvard University Press, Cambridge, MA.

UpToDate Contents

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1. 遺伝性疾患の基本原則 basic principles of genetic disease
2. 絨毛膜サンプリング検査：リスク、合併症、および手技 chorionic villus sampling
3. ターナー症候群（性腺発育不全）の臨床症状および診断 clinical manifestations and diagnosis of turner syndrome gonadal dysgenesis
4. 性染色体異常 sex chromosome abnormalities
5. Kindler syndrome

English Journal

Small mosaic deletion encompassing the snoRNAs and SNURF-SNRPN results in an atypical Prader-Willi syndrome phenotype.

Anderlid BM, Lundin J, Malmgren H, Lehtihet M, Nordgren A.Author information Department of Molecular Medicine and Surgery, Clinal Genetic Unit, Centre of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.AbstractGenetic analyses were performed in a male patient with suspected Prader-Willi syndrome who presented with hypogonadism, excessive eating, central obesity, small hands and feet and cognition within the low normal range. However, he had no neonatal hypotonia or feeding problems during infancy. Chromosome analysis showed a normal male karyotype. Further analysis with array-CGH identified a mosaic 847 kb deletion in 15q11-q13, including SNURF-SNRPN, the snoRNA gene clusters SNORD116 (HBII-85), SNORD115, (HBII-52), SNORD109 A and B (HBII-438A and B), SNORD64 (HBII-13), and NPAP1 (C15ORF2). MLPA confirmed the deletion and the results were compatible with a paternal origin. Metaphase-FISH verified the mosaicism with the deletion present in 58% of leukocytes analyzed. Three smaller deletions in this region have previously been reported in patients with Prader-Willi syndrome phenotype. All three deletions included SNORD116, but only two encompassed parts of SNURF-SNRPN, implicating SNORD116 as the major contributor to the Prader-Willi phenotype. Our case adds further information about genotype-phenotype correlation and supports the hypothesis that SNORD116 plays a major role in the pathogenesis of Prader-Willi syndrome. Furthermore, it examplifies diagnostic difficulties in atypical cases and illustrates the need for additional testing methods when Prader-Willi syndrome is suspected. © 2013 Wiley Periodicals, Inc.
American journal of medical genetics. Part A.Am J Med Genet A.2014 Feb;164(2):425-31. doi: 10.1002/ajmg.a.36307. Epub 2013 Dec 5.
Genetic analyses were performed in a male patient with suspected Prader-Willi syndrome who presented with hypogonadism, excessive eating, central obesity, small hands and feet and cognition within the low normal range. However, he had no neonatal hypotonia or feeding problems during infancy. Chromos
PMID 24311433

Somatic and germ-line mosaicism of deletion 15q11.2-q13 in a mother of dyzigotic twins with Angelman syndrome.

Sánchez J, Fernández R, Madruga M, Bernabeu-Wittel J, Antiñolo G, Borrego S.Author information Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío, CSIC, University of Seville, Seville, Spain.AbstractAngelman syndrome (AS, OMIM105830) is a neurogenetic disorder caused by different genetic mechanisms. Determining the genetic mechanism is essential to establish the recurrence risk and the accuracy of genetic/reproductive counseling. The majority of AS patients present with a deletion of the 15q11.2-q13 region on the maternally derived chromosome. The other genetic mechanisms are: paternal disomy of chromosome 15, imprinting center defects, and mutations in the ubiquitin-protein ligase E3A gene (UBE3A). Different recurrence risks are associated with each specific genetic mechanism involved. We report on the study of dizygotic twins with classic phenotypic AS due to deletion of the same maternally derived chromosome 15. The mother presented with hypopigmented macular lesions on the inner side of both arms. Fibroblast culture studies of the maternal hypopigmented skin areas from both arms showed mosaicism for a normal cell line and for a second cell line with a 15q11.2-q13 deletion. This family represents the first demonstrated case of maternal somatic and germ line mosaicism for 15q11.2-q13 deletion as the cause of AS. © 2013 Wiley Periodicals, Inc.
American journal of medical genetics. Part A.Am J Med Genet A.2014 Feb;164(2):370-6. doi: 10.1002/ajmg.a.36281. Epub 2013 Dec 5.
Angelman syndrome (AS, OMIM105830) is a neurogenetic disorder caused by different genetic mechanisms. Determining the genetic mechanism is essential to establish the recurrence risk and the accuracy of genetic/reproductive counseling. The majority of AS patients present with a deletion of the 15q11.
PMID 24311297

Waardenburg syndrome type 4: Report of two new cases caused by SOX10 mutations in Spain.

Fernández RM, Núñez-Ramos R, Enguix-Riego MV, Román-Rodríguez FJ, Galán-Gómez E, Blesa-Sánchez E, Antiñolo G, Núñez-Núñez R, Borrego S.Author information Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain.AbstractShah-Waardenburg syndrome or Waardenburg syndrome type 4 (WS4) is a neurocristopathy characterized by the association of deafness, depigmentation and Hirschsprung disease. Three disease-causing genes have been identified so far for WS4: EDNRB, EDN3, and SOX10. SOX10 mutations, found in 45-55% of WS4 patients, are inherited in autosomal dominant way. In addition, mutations in SOX10 are also responsible for an extended syndrome involving peripheral and central neurological phenotypes, referred to as PCWH (peripheral demyelinating neuropathy, central dysmyelinating leucodystrophy, Waardenburg syndrome, Hirschsprung disease). Such mutations are mostly private, and a high intra- and inter-familial variability exists. In this report, we present a patient with WS4 and a second with PCWH due to SOX10 mutations supporting again the genetic and phenotypic heterogeneity of these syndromes. Interestingly, the WS4 family carries an insertion of 19 nucleotides in exon 5 of SOX10, which results in distinct phenotypes along three different generations: hypopigmentation in the maternal grandmother, hearing loss in the mother, and WS4 in the proband. Since mosaicism cannot explain the three different related-WS features observed in this family, we propose as the most plausible explanation the existence of additional molecular events, acting in an additive or multiplicative fashion, in genes or regulatory regions unidentified so far. On the other hand, the PCWH case was due to a de novo deletion in exon 5 of the gene. Efforts should be devoted to unravel the mechanisms underlying the intrafamilial phenotypic variability observed in the families affected, and to identify new genes responsible for the still unsolved WS4 cases. © 2013 Wiley Periodicals, Inc.
American journal of medical genetics. Part A.Am J Med Genet A.2014 Feb;164(2):542-7. doi: 10.1002/ajmg.a.36302. Epub 2013 Dec 5.
Shah-Waardenburg syndrome or Waardenburg syndrome type 4 (WS4) is a neurocristopathy characterized by the association of deafness, depigmentation and Hirschsprung disease. Three disease-causing genes have been identified so far for WS4: EDNRB, EDN3, and SOX10. SOX10 mutations, found in 45-55% of WS4
PMID 24311220