The genetic information within a person’s body is generally understood to be uniform, with every cell containing the same set of instructions inherited from the fertilized egg. This uniformity is the expected blueprint for development and function in all humans. However, this assumption of a single, identical genetic code in every cell is not always the reality. Sometimes, a variation arises where different populations of cells with distinct genetic makeups coexist within the same individual. This phenomenon, known as mosaicism, introduces genetic variability that can have profound implications for health and development.
Defining Mosaicism in Genetics
Mosaicism describes a condition where an individual possesses two or more genetically distinct cell lines, all originating from a single fertilized egg, or zygote. This means that a person’s body is a mixture of cells with different genotypes. The difference between these cell lines can involve a range of genetic changes, from a single nucleotide variant to the gain or loss of an entire chromosome. One cell line typically represents the original, unaffected genetic makeup, while the others carry the variant. The presence of two or more cell populations distinguishes mosaicism from a constitutional variant, where every cell in the body is affected by the same genetic change. The degree of mosaicism refers to the proportion of cells that carry the variant in a specific tissue.
Mechanisms: How Mosaicism Arises
The origin of mosaicism is rooted in cell division and arises from an error that occurs after fertilization, making it a post-zygotic event. The initial cell, the zygote, divides repeatedly through mitosis to generate all body cells. An error during one of these early mitotic divisions introduces the genetic difference that leads to mosaicism. One primary mechanism is mitotic non-disjunction, the failure of sister chromatids to separate properly, which results in daughter cells having an unequal number of chromosomes. Another mechanism is anaphase lag, where a chromosome is lost because it fails to be incorporated into either daughter nucleus.
Somatic Versus Germline Mosaicism
Mosaicism is categorized based on the type of cell population that harbors the genetic variant, primarily somatic or germline forms. Somatic mosaicism involves non-reproductive cells, meaning the variant is present in body tissues such as the skin, brain, or blood. If the error occurs early in development, the variant may be widespread, affecting multiple organs, but it is generally not passed on to offspring because it does not affect the egg or sperm cells. In contrast, germline mosaicism, also called gonadal mosaicism, is characterized by the presence of the genetic variant only in the reproductive cells. The individual carrying germline mosaicism is often unaffected because their somatic cells are normal. However, the variant can be transmitted to their children, potentially causing a genetic condition in the offspring.
Clinical Manifestations and Variable Severity
The medical relevance of mosaicism depends on which specific cells are affected and to what extent, leading to a wide spectrum of clinical presentations. The proportion of variant cells and their location within the body are the two most significant factors determining the severity of a condition. If the variant cells are confined to an organ that is not immediately life-sustaining, the health impact may be minimal. However, if a high percentage of cells in a critical organ like the brain or heart carry a pathogenic change, a severe disorder can result.
Conditions resulting from mosaicism often present as a milder or atypical version of a full-blown genetic disorder. A well-known example is Mosaic Down syndrome, where an individual has a mixture of cells with the typical 46 chromosomes and cells with an extra copy of chromosome 21 (Trisomy 21). In cases like Trisomy 8 or Trisomy 9, which are typically lethal, the presence of a normal cell line through mosaicism is what allows the individual to survive, sometimes with mild or asymptomatic outcomes. The non-uniform distribution of cell lines presents a diagnostic challenge, often requiring genetic testing on multiple tissues, such as blood and skin, to accurately detect and assess the extent of the mosaicism.