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Mosaicism in health and disease — clones picking up speed

Key Points

  • An adult human body is likely to contain as many versions of the genome as the number of somatic cells. This is a result of the fact that every cell division is coupled with risk for new mutations. The implications of this variation are still largely unexplored, but physiological and pathological consequences should be considered.

  • Somatic mosaicism is often defined as the presence of a genotypic variant in some but not all cells of an individual that are derived from the same zygote. It can occur through many types of mutations in somatic cells during or after the first mitotic division of the zygote and is called post-zygotic variation.

  • A related common phenomenon, akin to mosaicism, is called microchimerism and refers to the persistent presence of a small number of cells stemming from another person; for instance, cells migrating through the placenta from a mother into the soma of a child, and vice versa.

  • Recent studies have shown that aberrant clonal expansions (ACEs) of apparently normal cells in blood and other organs are common in the ageing population. ACE is defined as a clone of non-cancerous cells carrying an acquired aberration (or aberrations) that provide them with a mild proliferative advantage. ACEs can have a dynamic nature, involving expansions followed by contractions of the number of aberrant cells.

  • Post-zygotic variation and microchimerism represent promising avenues for future research and might be important confounders in current medical genetic testing. To fully explore their potential implications, expanded analyses of sorted cells and single cells from multiple tissue types will be required.

Abstract

Post-zygotic variation refers to genetic changes that arise in the soma of an individual and that are not usually inherited by the next generation. Although there is a paucity of research on such variation, emerging studies show that it is common: individuals are complex mosaics of genetically distinct cells, to such an extent that no two somatic cells are likely to have the exact same genome. Although most types of mutation can be involved in post-zygotic variation, structural genetic variants are likely to leave the largest genomic footprint. Somatic variation has diverse physiological roles and pathological consequences, particularly when acquired variants influence the clonal trajectories of the affected cells. Post-zygotic variation is an important confounder in medical genetic testing and a promising avenue for research: future studies could involve analyses of sorted and single cells from multiple tissue types to fully explore its potential.

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Figure 1: The sum of genetic variation in the human body.
Figure 2: The possible effects of somatic mutations and their relation to fitness of the affected cells.
Figure 3: The origins of genetic variation in the human soma.

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Acknowledgements

The authors thank L. Feuk and C. Rasi for critical evaluation of the manuscript. The study was sponsored by funding from the Olle Enqvist Byggmästare Foundation and Young Investigator Award from the European Research Council to L.A.F. and by the Swedish Cancer Society, the Swedish Research Council, the Swedish Heart-Lung Foundation, Torsten Söderberg's Foundation and Sci-Life-Lab-Uppsala and Uppsala University to J.P.D. D.G. is supported by grants from the Swedish Research Council, the Swedish Cancer Society, the Swedish Childhood Cancer Society, the Gunnar Nilsson Cancer Foundation, the Crafoord Foundation and the Strategic Cancer Research Program BioCARE.

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Correspondence to Lars A. Forsberg, David Gisselsson or Jan P. Dumanski.

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Competing interests

Grants or support for research (J.P.D., D.G. and L.A.F.). Owning stock in or directorship of companies (J.P.D. and L.A.F.). Patents — holders and applicants (J.P.D. and L.A.F.). J.P.D. and L.A.F. are co-founders and shareholders in Cray Innovation AB.

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Glossary

Soma

The community of cells outside the germ line that makes up a multicellular organism. Because monozygotic twins are derived from the same zygote, they can be regarded as a single soma from a genetic point of view.

Zygote

A diploid cell resulting from the fusion of two haploid germ cells. Most multicellular organisms are derived from a single founder zygote. Organisms that are made of cells from more than one zygote are chimaeras. Distinct individuals derived from the same zygote are monozygotic twins.

Microchimerism

The persistent presence in an individual of a small number of cells stemming from another person; for instance, cells originating from a mother in the soma of a child, and vice versa.

Bulk DNA

DNA isolated from a tissue sample that contains a mixture of different cell types and usually a very large number (many thousands or millions) of cells.

Post-zygotic variation

The presence of a genotypic variant in some but not all cells of an individual that are derived from the same zygote. It occurs through post-zygotic mutations (mosaicism) during or after the first mitotic division of the zygote. If mosaicism is confined to non-germ cells (somatic mosaicism), it represents variation that ceases to exist with the death of the host. If the variant is present in lineages that form germ cells (gonadal mosaicism), the variant can be inherited by the next generation.

Macrochimerism

This very rare phenomenon is synonymous with classical chimerism and refers to the blending of cellular lineages from different zygotes during early embryogenesis of a single individual.

De novo variation

A broad and sometimes not well-defined term, usually referring to a change in DNA that emerges in a family tree for the first time. In typical usage, it comprises germline-transmissible genetic variants caused by a mutation in gonadal cell lineages of the parent, or in the zygote before the first cell division.

Gonadal mosaicism

Genetic variation emerging in cells that develop into gonads (ovaries and testicles), leading to variation in a pool of different germ cells of an individual; it is one cause of de novo variation in the next generation. Gonadal mosaicism is closely related to gonosomal mosaicism, which refers to mosaic variants that are present in both somatic and germline lineages.

Mitochondrial heteroplasmy

The presence of more than one mitochondrial genome in a cell or individual.

Structural variants

Chromosomal changes affecting regions of at least 1 kb. Structural variation can include balanced alterations (in which copy number remains unchanged), such as translocations, inversions or copy-number-neutral loss-of-heterozygosity (CNNLOH; also called uniparental isodisomy). In addition, structural variation includes unbalanced changes, such as deletions and duplications, which are collectively referred to as copy-number variants (CNVs).

Polyploidy

An increase in chromosome number in steps of one or several complete haploid sets. Normal human germ cells are haploid (23 chromosomes), whereas somatic cells are diploid (46 chromosomes). Examples of human polyploidy are triploidy (69 chromosomes) and tetraploidy (92 chromosomes).

Aneuploidy

Any change in chromosome number that does not occur in steps of one or several complete haploid sets.

Merotelic

The situation when one kinetochore of a chromosome is attached to microtubules emanating from two spindle poles.

Mitotic checkpoint slippage

When a cell exits mitosis even if its chromosomes are not properly oriented and the spindle assembly control machinery is still active.

Cryptic mosaicism

Mosaicism occurring at a level so low that it will not be detected by genetic screening of bulk DNA by current routine methods. Because the sensitivity of screening techniques is ever increasing, the level below which variation is considered cryptic versus detectable must remain flexible and depends on the methodological context.

Aberrant clonal expansions

(ACEs). Clones of non-cancerous cells (which can occur in any tissue) harbouring acquired post-zygotic mutations or chromosomal aberrations that provide the affected cells with a mild proliferative advantage, relative to unaffected cells. This phenomenon is also referred to as 'detectable clonal mosaicism' or 'clonal haematopoiesis'.

Exome

The part of the genome that is transcribed and retained in the mature RNA after splicing: that is, the exons. The exome constitutes about 1% of the human genome and includes all DNA sequences that are transcribed into mature RNA in all cells in the soma, in contrast to the transcriptome, which is the RNA transcribed in a specific cell type.

Proband

The first individual to be investigated in the genetic study of a family.

Uniparental disomy

When two copies of a chromosome or chromosomal region in a diploid genome come from the same parent, instead of one copy originating from the mother and the other from the father. When the disomy consists of two different homologues from the same parent, it is referred to as uniparental heterodisomy. When it consists of a duplicate of a single copy, it is called uniparental isodisomy.

Turner syndrome

A physical condition of a female lacking one sex chromosome or parts of a sex chromosome, most often having the blood karyotype 45,X.

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Forsberg, L., Gisselsson, D. & Dumanski, J. Mosaicism in health and disease — clones picking up speed. Nat Rev Genet 18, 128–142 (2017). https://doi.org/10.1038/nrg.2016.145

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