Mosaicism is the presence, within an organism or tissue, of two or more populations of cells with different genetic compositions that descend from a single fertilized egg. Differences may involve a small change in DNA, an alteration in chromosome structure, or the gain or loss of an entire chromosome. Mosaicism can arise during embryonic development or later in life and does not necessarily cause disease. (genome.gov)
Origin and development
Genetic mosaicism generally develops when a mutation or chromosomal alteration occurs after fertilization. When an altered cell undergoes cell division, its descendants can inherit that alteration, while other cell lineages retain a different genetic composition. Consequently, a variant may occur in only part of a tissue or in several tissues rather than throughout the body. (medlineplus.gov)
The distribution of an alteration depends partly on when it arises and which developmental lineage contains it. Early embryonic mutations can be distributed widely, whereas later mutations may remain restricted to a smaller population. The abundance of a variant can also change as particular cell populations expand. Research on normal human tissues has documented extensive, tissue-dependent patterns of mutation accumulation and clonal expansion. (nature.com)
Mosaicism differs from chimerism. In the strict genetic distinction, mosaic cell populations originate from one fertilized egg, whereas chimeric populations originate from different fertilized eggs. Genetic differences between cells therefore do not, by themselves, establish whether an organism is a mosaic or a chimera; their developmental origin matters. (genome.gov)
Principal forms
Mosaicism can be classified by the cells involved or by the nature of the alteration. These classifications overlap rather than describe mutually exclusive categories.
- Somatic mosaicism affects non-reproductive cells. A variant may be confined to one region or distributed among several tissues, with or without observable effects. (medlineplus.gov)
- Germline mosaicism, also called gonadal mosaicism, occurs when some reproductive cells carry a variant and others do not. A person may therefore transmit a variant that is undetectable in their blood cells. Its transmission probability depends on the proportion of reproductive cells carrying it, which is not necessarily reflected by other tissues. (ncbi.nlm.nih.gov)
- Combined somatic and germline mosaicism involves both body cells and reproductive lineages. (ncbi.nlm.nih.gov)
- Chromosomal mosaicism involves differences in chromosome number or structure. Examples include mosaic forms of Down syndrome and Turner syndrome; chromosome-number differences are a form of aneuploidy. (medlineplus.gov)
- Revertant mosaicism occurs when a subsequent genetic event reverses or compensates for an existing pathogenic alteration in some cells, potentially restoring gene function in that population. (ncbi.nlm.nih.gov)
The placenta can also contain genetically distinct populations. Research has demonstrated extensive mutation and clonal organization in placental tissue, highlighting that its genetic composition need not be identical to that of other tissues from the same pregnancy. (nature.com)
Genetic and functional mosaicism
Strictly defined genetic mosaicism concerns differences in DNA sequence or chromosome composition. A broader use includes functional or epigenetic mosaicism, in which cells differ in gene activity rather than necessarily in DNA sequence. GeneReviews includes postzygotic methylation abnormalities and X-chromosome inactivation among mechanisms producing mosaic patterns. (ncbi.nlm.nih.gov)
X-chromosome inactivation provides a familiar example. In individuals with two X chromosomes, different cell lineages may inactivate different copies, creating a mosaic of gene expression. In calico cats, this process produces patches expressing different X-linked coat-colour variants. Such patterns illustrate why a mosaic appearance does not necessarily imply a newly acquired DNA mutation. (genome.gov)
Biological and medical significance
Mosaicism is not a single disorder. Its effects depend on the alteration, the tissues involved, and the number and distribution of altered cells. Mosaic forms of a genetic condition may differ from non-mosaic forms, but the proportion detected in one sample does not reliably describe every organ or predict the entire phenotype. (medlineplus.gov)
Germline mosaicism explains some instances in which apparently unaffected parents have more than one child with the same pathogenic variant. When transmitted through an egg or sperm, that variant can be present throughout the child's body rather than remain mosaic as it was in the parent. (ncbi.nlm.nih.gov)
Somatic genetic diversity also occurs in morphologically normal tissues. Although somatic mutations contribute to cancer, finding a mutation or an expanded cell population is not equivalent to establishing malignancy. Studies of normal organs show that mutation accumulation and clonal expansion are widespread biological phenomena. (nature.com)
Detection and limitations
Detection depends on both the sampled tissue and the analytical method. Chromosomal mosaicism can be investigated through cytogenetics, chromosome microarrays, and fluorescence in situ hybridization. Sequence-level alterations can be investigated through DNA sequencing, but standard sequencing depth may miss variants present in only a small fraction of cells. (ncbi.nlm.nih.gov)
A negative blood result does not exclude an alteration confined to another tissue or to reproductive cells. Likewise, the percentage of altered cells may differ among samples from the same person. Mosaicism is therefore a spatially distributed biological property, not simply a single percentage attached to an individual. (ncbi.nlm.nih.gov)
Low-abundance mutations are also difficult to distinguish from technical errors. Error-corrected sequencing methods, including approaches that compare both strands of individual DNA molecules, have enabled research on mutations in small clones and individual cells. These methods expand the study of mosaicism beyond alterations abundant enough to detect by conventional bulk sequencing. (nature.com)
References
- Mosaicismgenome.gov
- What is a gene variant and how do variants occur?: MedlinePlus Geneticsmedlineplus.gov
- Mosaicism: MedlinePlus Medical Encyclopediamedlineplus.gov
- Resources for Genetics Professionals — Mosaicismncbi.nlm.nih.gov
- Learn More (gonadal mosaicism)ncbi.nlm.nih.gov
- Turner syndrome: MedlinePlus Geneticsmedlineplus.gov
- Down syndrome: MedlinePlus Geneticsmedlineplus.gov
- X Chromosomegenome.gov
- A body map of somatic mutagenesis in morphologically normal human tissuesnature.com
- Somatic mutation landscapes at single-molecule resolutionnature.com
- Inherent mosaicism and extensive mutation of human placentasnature.com
- The Somatic Mosaicism across Human Tissues Networknature.com