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Babak Nami
Department of Medical Genetics Seluk University

What is the Mosaicism

A genetic mosaic is a creature whose body is built of a mixture of cells of two or more different genotypes. Mosaicism is a condition in which cells within the same person have a different genetic makeup. This condition can affect any type of cell, including: Blood cells Egg and sperm cells (gametes) Skin cells

a) Normal and abnormal cells are found in most tissues

Skin cells

Blood cells

b) Normal and abnormal cells are confined to specific tissues

Skin cells

Intestine cells

Somatic Mosaicism: Somatic mosaicism occurs when the somatic cells of the body are of more than one genotype. In the more common mosaics, different genotypes arise from only a single fertilized egg cell, due to miotic errors at first cleavage.

In this illustration, the green cell represents a cell with an abnormal chromosome make-up. All cells that come from the green cell will share the same chromosome change. The baby that develops from this embryo will have some cells in his/her body which have the typical number of chromosomes and some that have the chromosome change.

Variable manifestations of somatic mosaicism Somatic mosaicism for mitochondrial disorders results from the random segregation of mutant and wild-type mitochondria during mitosis, which can result in daughter cells with different proportions of mitochondrial mutations

Types (con)
Another form of somatic mosaicism is chimerism, where two or more genotypes arise from the fusion of more than one fertilized zygotes in the early stages of embryonal development. In rare cases, intersex conditions can be caused by mosaicism where some cells in the body have XX and others XY chromosomes.

Types (con)
Intersex in Humans and, non-human animals, refers to intermediate or atypical combinations of physical features that usually distinguish female from male. This is usually understood to be congenital, involving chromosomal, morphologic, genital and/or gonadal anomalies, such as diversion from typical XX-female or XY-male presentations, e.g., sex reversal (XYfemale, XX-male), genital ambiguity, sex developmental differences.

Types (con)
The most common form of mosaicism found through prenatal diagnosis involves trisomies. Although most forms of trisomies are due to problems in meiosis and affect all cells of the organism, there are cases where the trisomy occurs in only a selection of the cells. This may be caused by a nondisjunction event in an early mitosis, resulting in a loss of a chromosome from some trisomic cells. Generally this leads to a milder phonotype than in non-mosaic patients with the same disorder.

Types (con)
True mosaicism should not be mistaken for the phenomenon of X-inactivation, where all cells in an organism have the same genotype, but a different copy of the X chromosome is expressed in different cells, such as in calico cats.

Types (con)
Gonadal mosaicism Gonadal mosaicism or germinal mosaicism is a special form of mosaicism, where some gametes, i.e. either sperm or oocytes, carry a mutation, but the rest are normal. The cause is usually a mutation that occurred in an early stem cell that gave rise to all or part of the gonadal tissue. This can cause only some children to be affected, even for a disease.

Types (con)
A study of semen samples from 100 men found low-level germline mosaicism in one third of infertile men, with increased incidence with advancing paternal age.

Mechanisms of Occurrence
In mammals they arise by several different mechanisms: 1.The fusion of two different zygotes, or early embryos, into one. The resulting animal is called a chimera (after the The tetraparental mouse is a chimera formed this way. But on rare occasions, the same process can occur spontaneously in humans (especially those using IVF).
monster in Greek mythology with a lion's head, goat's body, and serpent's tail).

Mechanisms of Occurrence
2. The sharing of blood supplies by separate embryos. This occurs with the occasional fraternal cattle twins and also less often with human fraternal twins who have shared the same placenta. Blood stem cells of each twin seed the bone marrow of the other. Only their blood cells are mosaic.

Mechanisms of Occurrence
During early development, errors during mitosis can produce stem cells that go on to populate a tissue or organ with, for example, a chromosomal aberration (e.g., aneuploid).

Two Notes: 1.All female mammals are mosaic for the genes on the X chromosome because of the random inactivation of one or the other X chromosome in all their somatic cells. 2.Anyone unlucky enough to have a cancer is a genetic mosaic because all cancers are made up of the descendants of cells carrying a suite of mutations not found in normal cells.

How does trisomy mosaicism occur?

Trisomy mosaicism can occur in one of two ways:
1. In an abnormal fertilized egg with 47 chromosomes, one of

the cells may lose the extra chromosome at cell division, leaving 46 chromosomes in that cell. All cells that are derived from that cell will have 46 chromosomes. The rest of the cells will have 47 chromosomes. 2.In a typical zygote with 46 chromosomes, at cell division one of the cells may retain a duplicated copy of one of the chromosomes. This produces a cell with 47 chromosomes. All cells that are derived from that cell also have 47 chromosomes. The rest of the cells will have 46 chromosomes. In both cases the result is a baby with two different cell lines, one cell line with 46 chromosomes and one with 47 chromosomes.

The Tetragametic Human

A report by Yu, et. al. in the May 16, 2002 issue of The New England Journal of Medicine documents the discovery of a woman that derived from four different gametes, not just two. She came to the doctors' attention because she needed a kidney transplant. Doctors was surprised after reading the her tissue typing results.

Tissue typing, which is done with blood cells, showed her to have inherited the "1" HLA region of her father (who was 1,2) and the "3" region of her mother (who was 3,4):

She had two brothers, one who inherited 1 from their father and 3 from their mother. The other who inherited 2 from their father and 3 from their mother. Her husband typed 5,6 Of her three sons, One was 1,6 which was to be expected. the other two were both 2,5. the 5 they got from their father But the question is: where did the 2 come from?

The first thought was that she could not have been their mother, but clearly she knew better. (Paternity may sometimes be in doubt, but not

A clue came from typing other tissues. DNA analysis of her skin cells, hair follicles, thyroid cells, bladder cells, and cells scraped from inside her mouth revealed not only 1 and 3 but also 2 and 4. It is not clear why her bone marrow was an exception containing only 1,3 stem cells. How were these results possible?

The most reasonable explanation is that: 1. Her mother had simultaneously ovulated two eggs: one containing a chromosome 6 with HLA 3; the other with HLA 4. 1. Her father would, of course, have produced equal numbers of 1-containing and 2-containing sperm. A 1-sperm fertilized the 3-egg A 2-sperm fertilized the 4-egg. 1. Soon thereafter the resulting early embryos fused into a single embryo. As this embryo developed into a fetus, both types of cells participated in constructing her various organs including her oogonia(is an immature ovum) (but not, apparently, the blood stem cells in her bone marrow).

Although she was a mosaic for the HLA (and other) genes on chromosome 6, all her cells were XX. So both the father's successful sperm cells had carried his X chromosome. However, tetraparental humans have been found that were mosaic for sex chromosomes as well; that is, some of their cells were XX; the other XY.

So what are her chances for finding a suitable kidney donor?