Abstract
Diversity is the basis of fitness selection. Although the genome of an individual is considered to be largely stable, there is theoretical and experimental evidence — both in model organisms and in humans — that genetic mosaicism is the rule rather than the exception. The continuous generation of cell variants, their interactions and selective pressures lead to life-long tissue dynamics. Individuals may thus enjoy 'clonal health', defined as a clonal composition that supports healthy morphology and physiology, or suffer from clonal configurations that promote disease, such as cancer. The contribution of mosaicism to these processes starts during embryonic development. In this Opinion article, we argue that the road to cancer might begin during these early stages.
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Acknowledgements
The authors thank G. Morata, Y. Fujita, F. Notta, L. Pérez-Jurado, A. Toll and E. Wagner for valuable comments on the manuscript. Work in the authors' laboratories was supported by grants BFU2012-31086 and ISCIII-RD12/0019/0005 (ISCIII) to M.T., SAF2011-29530, ISCIII-RD12-0036-0034 and ONCOBIO Consolíder to F.X.R., and the CEL-DD programme from the Comunidad Autónoma de Madrid (to M.T. and F.X.R.). The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Government of Spain through the Ministry of Economy and Competitiveness (MINECO) and the Pro-CNIC Foundation. L.C.F. was the recipient of a Marie Curie training grant (FP7-PEOPLE-2010-IEF, project 274946).
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Glossary
- Age-related clonal haematopoiesis
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(ARCH). Defined by comparing genetic findings in blood from patients with leukaemia and from healthy individuals. Mutations found in leukaemia could also be demonstrated at low frequency in DNA from leukocytes of individuals without leukaemia. The prevalence of these mutations increases with age and reflects the expansion of founder clones that only infrequently acquire additional genetic alterations to become leukaemic.
- Blaschko's lines
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Lines that identify pathways of embryonic cell migration. Skin diseases caused by mosaicism are often characterized by a distribution along Blaschko's lines; these lines cannot be seen in the absence of such lesions.
- Cellular heterogeneity
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Phenotypic cellular diversity that occurs widely in tissues. Genetic mosaicism is only one of the mechanisms contributing to cellular heterogeneity. Epigenetic and cell-specific transcriptional programmes confer cellular identity through different mechanisms. Many other processes (for example, protein glycosylation) can also contribute to cellular heterogeneity.
- Epigenetic mosaicism
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A form of mosaicism in which a stable epigenetic modification is clonally transmitted. Epigenetic mosaicism can occur in differentiated cells and can contribute to field cancerization and tumour development. Females are naturally epigenetically mosaic: one X chromosome is active and the second is epigenetically silenced. Clonal selection may favour X inactivation disequilibrium in association with ageing.
- Field cancerization
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The occurrence of genetic alterations in histologically normal or abnormal — but non-neoplastic — tissues that are shared with an adjacent primary tumour. It is also often used to describe seemingly unrelated patches of cells harbouring genetic changes when they are found in non-neoplastic tissue.
- Gonadal mosaicism
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The occurrence of two or more genetically distinct cell populations present in the gonads; this phenomenon can give rise to de novo mutations in the human population as determined in blood or tissue DNA from the progeny. It comprises conditions that generally behave with an autosomal dominant pattern of inheritance, the parents being either unaffected or with a mild phenotype.
- Guthrie cards
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Pre-printed cards used to collect blood spots from newborns to allow testing for phenylketonuria, among other metabolic conditions.
- Metazoans
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Pluricellular animals composed of cells that have functional specialization.
- Neutral drift
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A shift in the genetic composition of a cell group (or individual) that originates solely from random fluctuations in the clonal contribution of the progenitor pool. The smaller the founder population, the stronger the effects of neutral drifts.
- Selfish clonal expansion
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Unequal preferential expansion of genetic clones in tissues or whole organisms at the expense of the surrounding cells.
- Somatic mosaicism
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The occurrence of two or more genetically distinct cell populations exclusively in somatic cells. Mutations that occur after the first division of the zygote are called postzygotic. When it can be demonstrated that they have occurred during embryonic development, because they give rise to a congenital lesion or because they affect tissues from more than one germ layer (an event that is thought not to take place in vivo after gastrulation), they are considered embryonic. When mosaicism is detected only in cells from adult tissues, it is often impossible to determine when the genetic event leading to mosaicism occurred.
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Fernández, L., Torres, M. & Real, F. Somatic mosaicism: on the road to cancer. Nat Rev Cancer 16, 43–55 (2016). https://doi.org/10.1038/nrc.2015.1
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DOI: https://doi.org/10.1038/nrc.2015.1
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