Mosaicism

8/3/2019 Mosaicism

http://slidepdf.com/reader/full/mosaicism 1/25

M O S A I C I S MBabak Nami

Department of Medical GeneticsSelçuk University

8/3/2019 Mosaicism


What is the Mosaicism

• A genetic mosaic is a creature whose body is builtof a mixture of cells of two or more differentgenotypes.

• Mosaicism is a condition in which cells within thesame person have a different genetic makeup.• This condition can affect any type of cell,

including:

Blood cells Egg and sperm cells (gametes) Skin cells

8/3/2019 Mosaicism


8/3/2019 Mosaicism


Types

• Somatic Mosaicism:

Somatic mosaicism occurs when the somatic cellsof the body are of more than one genotype. In themore common mosaics, different genotypes arisefrom only a single fertilized egg cell, due to miotic

errors at first cleavage.

8/3/2019 Mosaicism


• In this illustration, the green cell represents a cell with an abnormal chromosome make-up.

• All cells that come from the green cell will sharethe same chromosome change.

• The baby that develops from this embryo will

have some cells in his/her body which have thetypical number of chromosomes and some thathave the chromosome change.

8/3/2019 Mosaicism


Variable manifestations of somatic mosaicismSomatic mosaicism for mitochondrial disorders results from the randomsegregation of mutant and wild-type mitochondria during mitosis, which canresult in daughter cells with different proportions of mitochondrial

mutations

8/3/2019 Mosaicism


Types (con)

• Another form of somatic mosaicism is chimerism, where two or more genotypes arise from thefusion 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.

8/3/2019 Mosaicism


Types (con)

Intersex in Humans and, non-human animals, refers tointermediate or atypical combinations of physical featuresthat usually distinguish female from male.

This is usually understood to becongenital, involving chromosomal,morphologic, genital and/or gonadal anomalies, such as diversion fromtypical XX-female or XY-malepresentations, e.g., sex reversal (XY-female, XX-male), genital ambiguity,sex developmental differences.

8/3/2019 Mosaicism


Types (con)

• The most common form of mosaicism foundthrough prenatal diagnosis involves trisomies. Although most forms of trisomies are due to

problems in meiosis and affect all cells of theorganism, there are cases where the trisomy occurs in only a selection of the cells.

• This may be caused by a nondisjunction event inan early mitosis, resulting in a loss of achromosome from some trisomic cells.

• Generally this leads to a milder phonotype than in

non-mosaic patients with the same disorder.

8/3/2019 Mosaicism


Types (con)

• True mosaicism should not be mistaken for thephenomenon of X-inactivation, where all cells inan organism have the same genotype, but a

different copy of the X chromosome is expressedin different cells, such as in calico cats.

8/3/2019 Mosaicism


Types (con)

• Gonadal mosaicism

Gonadal mosaicism or germinal mosaicism is aspecial form of mosaicism, where some gametes,

i.e. either sperm or oocytes, carry a mutation, butthe rest are normal.

The cause is usually a mutation that occurred inan 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.

8/3/2019 Mosaicism


Types (con)

• A study of semen samples from 100 men foundlow-level germline mosaicism in one third of infertile men, with increased incidence with

advancing paternal age.

8/3/2019 Mosaicism


Mechanisms of Occurrence

• In mammals they arise by several differentmechanisms:

1.The fusion of two different zygotes, or early embryos, into one.

• The resulting animal is called a chimera (after themonster in Greek mythology with a lion's head, goat's

body, and serpent's tail).• The tetraparental mouse is a chimera formed this way.

• But on rare occasions, the same process can occurspontaneously in humans (especially those usingIVF).

8/3/2019 Mosaicism



2. The sharing of blood supplies by separateembryos.

• This occurs with the occasional fraternal cattle

twins and also less often with human fraternaltwins who have shared the same placenta.

• Blood stem cells of each twin seed the bonemarrow of the other.

• Only their blood cells are mosaic.

8/3/2019 Mosaicism



• During early development, errors during mitosis can produce stem cells that go on to populate atissue or organ with, for example, a chromosomalaberration (e.g., aneuploid).

8/3/2019 Mosaicism


• Two Notes:

1. All female mammals are mosaic for the genes onthe X chromosome because of the random

inactivation of one or the other X chromosome inall their somatic cells.

2. Anyone unlucky enough to have a cancer is agenetic mosaic because all cancers are made up of

the descendants of cells carrying a suite of mutations not found in normal cells.

8/3/2019 Mosaicism


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 arederived 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 thechromosomes. This produces a cell with 47chromosomes. All cells that are derived from that cell also

have 47 chromosomes. The rest of the cells will have 46chromosomes.In both cases the result is a baby with two different cell

lines, one cell line with 46 chromosomes and one with 47chromosomes.

8/3/2019 Mosaicism


The Tetragametic Human

• A report by Yu, et. al. in the May 16, 2002 issue of The New England Journal of Medicinedocuments 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 tissuetyping results.

8/3/2019 Mosaicism


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

8/3/2019 Mosaicism


• She had two brothers, one who inherited 1 fromtheir father and 3 from their mother.

• The other who inherited 2 from their father and 3from 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 didthe 2 come from?

8/3/2019 Mosaicism


• 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

maternity.)

• A clue came from typing other tissues.

• DNA analysis of her skin cells, hair follicles,thyroid cells, bladder cells, and cells scraped frominside her mouth revealed not only 1 and 3 butalso 2 and 4.

• It is not clear why her bone marrow was anexception containing only 1,3 stem cells.

• How were these results possible?

8/3/2019 Mosaicism


• 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 cellsparticipated in constructing her various organs includingher oogonia(is an immature ovum) (but not, apparently,

the blood stem cells in her bone marrow).

8/3/2019 Mosaicism


8/3/2019 Mosaicism


• Although she was a mosaic for the HLA (andother) genes on chromosome 6, all her cells wereXX.

• So both the father's successful sperm cells had

carried his X chromosome.

• However, tetraparental humans have been foundthat were mosaic for sex chromosomes as well;

that is, some of their cells were XX; the other XY.

8/3/2019 Mosaicism


• So what are her chances for finding a suitable

kidney donor?

THANK U

Documents

Mosaicism