Mosaicism

In genetics, mosaicism is a condition in which an individual who has developed from a single fertilized egg (zygote) has two or more cell populations with different genetic constitutions. This genetic variation arises from an error during cell division that occurs after fertilization, in the early stages of embryonic development.

The term is derived from the artistic practice of creating a mosaic, where a single image is formed from many different individual tiles. Similarly, an individual with mosaicism is composed of genetically different "tiles" or cell lines. The effects of mosaicism can range from being clinically undetectable to causing the full spectrum of symptoms associated with a specific genetic disorder.

Mechanisms

Mosaicism is the result of a post-zygotic event, meaning the error is not present in the original zygote but occurs later in a single cell. All descendants of that cell will carry the genetic change, creating a distinct cell line from the rest of the body's cells.

• Chromosomal Nondisjunction: This is the most common cause of mosaicism involving an abnormal number of chromosomes (aneuploidy). During a mitotic division in the developing embryo, a pair of chromosomes fails to separate correctly. This error produces one daughter cell with an extra chromosome (trisomy) and another with a missing chromosome (monosomy). Often, the monosomic cell line is not viable and dies off, leaving the individual with a mixture of normal cells and trisomic cells. The earlier this event happens, the greater the proportion of abnormal cells.
• Anaphase Lag: This is another error in cell division where a chromosome is "left behind" during anaphase and is not incorporated into either of the new daughter cells. This results in a monosomic cell line.
• Somatic Mutation: A change can occur in the DNA sequence of a single gene within a single somatic (body) cell. This creates a mosaic population of cells containing the mutation and is a key mechanism in the development of many cancers.

Types and Clinical Examples

Mosaicism can involve any chromosome and its clinical significance is highly variable. The outcome depends on which tissues are affected and the proportion of abnormal cells.

Autosomal Mosaicism

This involves the non-sex chromosomes.

• Mosaic Down Syndrome: The most common form of autosomal mosaicism. Individuals have a mixture of two cell lines: one with the normal 46 chromosomes, and another with 47 chromosomes, including an extra copy of chromosome 21 (Trisomy 21). The physical and developmental features can be milder and more variable than in non-mosaic Down syndrome, where every cell is affected.

Sex Chromosome Mosaicism

This affects the X and Y chromosomes.

• Mosaic Turner's Syndrome: Affected females have a mixture of cell lines, most commonly one with a single X chromosome (45,X) and another with a normal female complement (46,XX). Depending on the percentage of normal cells, individuals may have much milder features of Turner syndrome and may even have preserved fertility.
• Mosaic Klinefelter's Syndrome: Affected males have a mix of cells, typically a normal male line (46,XY) and a line with an extra X chromosome (47,XXY). The symptoms can be less severe than in non-mosaic Klinefelter's syndrome.

Distinction from Chimerism

Mosaicism is fundamentally different from chimerism, another condition involving genetically distinct cell populations.

• Mosaicism: Arises from one zygote. The genetic differences are introduced after fertilization due to a mitotic error or mutation.
• Chimerism: Arises from the fusion of two or more distinct zygotes. The cell lines originated from separate individuals. This is extremely rare in humans but is the principle behind a bone marrow transplant, where the recipient becomes a chimera.