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Curt Stern (30 August 1902 – 23 October 1981) was a German-American geneticist. Born in Hamburg, Germany, he studied zoology at the University of Berlin, receiving his PhD in 1923 at the age of 21. He was selected for a fellowship to study at Columbia University, then the site of Thomas Hunt Morgan's famous drosophila fly room. In 1936, he demonstrated that recombination can also take place in mitosis resulting in somatic mosaics, organisms that contain two or more genetically distinct types of tissues. He later demonstrated that there were multiple genes on the Drosophila Y chromosome, and described the mechanism of dosage compensation.
Greek "gyne" female and "andro" male,
For example, an XY cell undergoing mitosis duplicates its chromosomes, becoming XXYY. Usually this cell would divide into two XY cells, but in rare occasions the cell may divide into an X cell and an XYY cell. If this happens early in development, then a large portion of the cells are X and a large portion are XYY. Since X and XYY dictate different sexes, the organism has tissue that is female and tissue that is male
“geep” chimera comprised of goat and sheep cells
Approximately 2-4% of individuals with Down syndrome are mosaic for cells that have three copies of chromosome 21. Neurofibromatosis, in its mosaic form, is termed segmental NF. This means that only one part of the body is affected. This is most likely due to a mutation in the NF gene that arose very early on in development and led to a proportion of affected cells in the same area of the body.
Typically, a person with only germline mosaicism will not be affected with the disorder caused by the mutation because the mutation is not in the other cells of the body. Genetic testing using blood or tissue samples (other than germline tissue) from individuals who only have a germline mutation will be negative for the mutation.
In a normal cell, the concentrations of active (dephosphorylated) merlin are controlled by processes such as cell adhesion (which would indicate the need to restrain cell division).
Proteus syndrome causes an overgrowth of skin, bones, muscles, fatty tissues, and blood and lymphatic vessels.
These include its limited throughput and the fact that both alleles of an autosomal locus are sequenced concurrently and are displayed as analogue electropherograms, from which the often subtle contribution from mosaic alleles cannot be accurately determined (
M. Sc. Microbial Biotechnology
Mahrishi Dayanand University
• GENOME - The genome is the genetic material of an
• MOSAICISM - Mosaicism is a condition in which
cells within the same person have a different
• The phenomenon was discovered by Curt Stern.
• In 1936, he demonstrated that recombination, normal in meiosis, can
also take place in mitosis.
• When it does, it results in somatic (body) mosaics. These are organisms
which contain two or more genetically distinct types of tissue.
• Named after the intricate images created by the craftsman from small pieces of
• The coexistence of two or more genetically distinct cell populations derived origina
lly from a single zygote.
• Mosaics may arise at any stage of development, from the two-
cell stage onward, or in any tissue which actively proliferates thereafter.
• The phenomenon is commonly observed in many species of animals and
plants and may be caused by somatic mutation or chromosomal nondisjunction.
• An individual animal or plant may exhibit mosaicism, or it may occur in a culture
of a single cell- or tissue-type obtained from an individual.
When eye colours vary between the two eyes, or within one or both eyes, the
condition is called heterochromia iridis (= 'different coloured iris').
Changes may take place in the dividing cells leading up to iris formation in
• These females are heterozygous
for the X-linked colour genes: the genes
for their coat colours are carried on the
• X-inactivation causes groups of cells
to carry either one or the other X-
chromosome in an active state.
FEMALE MALE MOSAIC GYNANDROMORPH
• A gynandromorph is an organism that contains both male and female characteristics.
• While the organism is only a few cells large, one of the dividing cells does not split its
sex chromosomes typically.
• This leads to one of the two cells having sex chromosomes that cause male
development and the other cell having chromosomes that cause female development.
• Use of aCGH and SNP chips has allowed detection of events that were missed by karyotyping
• Scientists analyzed the genomes of a bunch of iPSC lines and then compared them to the
“parental” fibroblast cells from which they had been made
CNV arose specifically during the iPSC production process
CNVs varied from one cell to another even though all the cells came from a single
• Mosaicism for small for small intragenic CNV was detected in 10% of 30 molecularly
• Subjects and extensive genomic CNVs have been found in clonal isolates of embryonic
• In addition, varying levels of mosaicism have reported in somatic human tissues
including the skin, Brain, blood and induced pluripotent stem cells
• Mosaicism may result from:
– Unusual events in cell division (mitosis).
– A gene mutation during development
• De novo pre zygotic mutation
• De novo post zygotic mutation
– A chromosomal mutation during development
– X-inactivation: one X chromosome is randomly switched off in cells of
a female mammal
– Numerical or structural abnormalities of chromosomes
• Chimerism — the presence of two or more cell lines that are derived
from different zygotes in an organism .
• A 52-year-old woman from Boston was told that she was not the
biological mother of her children, after years of raising them.
• The woman who claimed to have given birth to her children had a set
of genes completely different from those of two of her three children.
but the DNA of the children matched their father’s DNA.
• After working for nearly two years on the case, doctors came up with
an answer to the problem: the woman was a “human chimera.”
• Cells in the organism have
same genetic origins
• Nearly all loci are identical in
the different cell populations
as all cells are derived from
the same zygotic genotype
• Somatic mutations make us all
• A single organism composed of
genetically distinct cells.
• In chimerism there are divergent
genotypes all across the
• Chimeras can be artificially
produced: organ transplants,
chimera of diffferent animals
• Heterochromia iridis
• Lines of Blaschko
• Neurofibromatosis type 1
• Proteus syndrome
• Osteogenesis imperfecta type II
• The non-germ cells of the body are heterogeneous: some have a
mutation and some do not.
• The person may or may not be affected by the disorder caused by
• Individuals will express the phenotype depending on how many and
which cells are affected.
• Typically, individuals with somatic mosaicism exhibit a milder
phenotype since only a proportion of cells contain the mutation
and/or because the mutation is confined to a finite segment of the
• Clinical Information on Diseases:
– Down Syndrome
- Lines of Blaschko
• A classic example of somatic mosaicism.
• Cancer arises when cells grow uncontrollably, which can be caused by mutations in
genes that prevent the cell from properly functioning within the cell cycle or
prevent it from cell death at the proper time.
• Most cancers occur sporadically, meaning they are not due to an inherited
• Some inherited cancer syndromes include breast and ovarian cancer (BRCA1/2
genes), colon cancer, retinoblastoma, and thyroid cancer.
• Since these mutations are only present in the cancer cells and not the rest of the
cells in the body, the individual has somatic mosaicism for these mutations.
• Blaschko lines or the lines of Blaschko are thought to represent pathways of
epidermal cell migration and proliferation during the development of the fetus.
• These lines are invisible but many inherited and acquired diseases of skin
manifest themselves according to these patterns creating the visual appearance
of these lines.
• The diploid germ cell precursors in the gonad are heterogeneous: some have a
mutation and some do not.
• A mosaic germline mutation is significant because it can be passed to
• Germline mosaicism can be observed with any inheritance pattern, but it is
most commonly seen with autosomal dominant and X-linked disorders.
• Most individuals are unaware they possess a germline mutation until they have
children that are affected.
• Clinical Information on Diseases:
– Osteogenesis imperfecta
– Ovarian dysgenesis
• Sometimes known as brittle bone disease
• Bone disorder characterized by brittle bones that are prone to fracture.
• People with OI are born with defective connective tissue, or without the
ability to make it, usually because of a deficiency of Type-I collagen.
• Eight types of OI can be distinguished. Most cases are caused by
mutations in the COL1A1 and COL1A2 genes.
• Severe and usually lethal in the perinatal period
• Most cases die within the first year of life due to respiratory
failure or intracerebral hemorrhage
• A combination of germline and somatic mosaicism
• Example is Neurofibromatosis type 2 (NF2) is an autosomal
dominant cancer syndrome
• Symptoms are dizziness; headache; facial weakness, numbness,
or pain; ringing in the ears and progressive hearing loss.
• This disease is caused by inactivating mutations in the NF2
tumour-suppressor gene, located in 22q12, that normally gives
rise to a product called Merlin.
• This peptide is thought to have a tumor-suppressive function
• Merlin's deficiency can result in unmediated progression
through the cell cycle due to the lack of contact-mediated
tumour suppression, sufficient to result in the tumors
characteristic of NF II.
• Recently, a range of disorders has been shown to be caused by
mosaicism for point mutations, primarily using NGS technologies
• Non-overgrowth mosaic disorders like Benign keratinocytic epidermal
nevi, which have been shown to be caused by mutations in fibroblast
growth factor receptor 3 (FGFR3), phosphatidylinositol-4, -
5-bisphosphate 3-kinase and different RAS family members.
• A series of mosaic overgrowth disorders was molecularly delineated,
beginning with Proteus syndrome, which was shown to be due to AKT1
• Causes skin overgrowth and a typical bone development, often
accompanied by tumours over half the body.
• Proteus syndrome results from a mutation in the AKT1 gene.
• The AKT1 gene helps regulate cell growth and division (proliferation) and
• A mutation in this gene disrupts a cell's ability to regulate its own
growth, allowing it to grow and divide abnormally.
• Increased cell proliferation in various tissues and organs leads to the
abnormal growth characteristic of Proteus syndrome.
• Studies suggest that an AKT1 gene mutation is more common in groups
of cells that experience overgrowth than in the parts of the body that
is probably the principal cause
of chromosomal aberration,
which in turn may lead to the d
evelopment of mosaicism.
(such as whole-chromosome
aneuploidy (that is, aneuploidy
of parts of chromosomes) and
structural alterations) have
been historically identified by
• Mosaicism can result when that genetic lesion is completely or partially reverted,
perhaps driven by selective pressure, in a subset of cells in the multicellular organism.
• For example, the phenomenon of revertant mosaicism has recently been described, in
which a mutation was spontaneously directly corrected in a subset of cells in an affected
• This phenomenon has been demonstrated in blood, muscle, liver and skin, of which skin
is most dramatic, as the normal patches can be directly visualized among the abnormal
• Recent technological advances have provided us with tools to
assess mosaicism on a much broader scale, in many disorders
and in diverse tissues, with increasing resolution to detect
• Different approaches used to study mosaicism include
– DNA sequencing
• Cytogenetic analysis by study of banded metaphase chromosomes
or by fluorescence in situ hybridization (FISH) is carried out in a
cell-by-cell manner, and recognition of mosaicism is therefore fairly
• Mosaicism is recognized when cells within an individual are found
to have divergent chromosome contents, such as monosomic or
trisomic chromosomes in the karyotype of one cell and a normal
karyotype in another.
• The cytogenetic detection of low-level mosaicism is challenging, as
a sufficient number of cells must be counted
• Beginning in 2005, microarray-based techniques began to replace cytogenetic
testing, with the introduction first of array-based comparative genomic
hybridization (aCGH), which can analyse genomic copy number variants (CNVs).
• It is followed by genome-wide SNP arrays, which can analyse both SNPs and
• The advantages of array-based testing (which typically analyses DNA extracted
from whole blood) for mosaicism detection include:
– many cells are analysed simultaneously;
– different cell types are analysed;
– cells of all cell cycle phases are analysed;
– samples do not require culturing, which might itself cause mutations
• SNP arrays are much more sensitive than aCGH for mosaicism detection.
• Sanger-based sequencing can be extremely effective for many applications, but
it is a low throughput technique.
• NGS is a high-throughput technique that is massively used nowadays.
• These digital data are more amenable to statistical approaches to distinguish
mosaicism from sequencing errors.
• It also does not require genetic mapping data to identify causative genetic
• For this reason, subtractive informatic approaches — in which two samples are
informatically processed to identify only those positions in the genome that
differ — can be coupled to NGS to identify mosaic alterations.
• The recognition of mosaic disorders is rapidly increasing.
• It can affect somatic tissues, the germ line or both.
• It can arise at various stages of development or adult life and can be
caused by mutation from a normal genotype to a variant genotype or from
a variant genotype to a normal genotype.
• Recent advances in genomic technologies have enhanced our ability to
study the widespread nature of mosaicism in both healthy individuals and
in patients with a wide range of disorders.
• Recent insights include:
– Identification of disease genes for disorders that are seen only as
mosaics as they are lethal when constitutional
– the identification of chimerism by whole-genome tools
– recognition of the changing rates of mosaicism with increasing age
represents a window on the ageing process.
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