X-inactivation (also called lyonization) is a process by which one of
the copies of the
X chromosome present in female mammals is
inactivated. The inactive
X chromosome is silenced by it being
packaged in such a way that it has a transcriptionally inactive
structure called heterochromatin. As nearly all female mammals have
two X chromosomes,
X-inactivation prevents them from having twice as
X chromosome gene products as males, who only possess a single
copy of the
X chromosome (see dosage compensation). The choice of
X chromosome will be inactivated is random in placental mammals
such as humans, but once an
X chromosome is inactivated it will remain
inactive throughout the lifetime of the cell and its descendants in
the organism. Unlike the random
X-inactivation in placental mammals,
inactivation in marsupials applies exclusively to the paternally
derived X chromosome.
2.2 Selection of one active X chromosome
2.3 Expression of X-Linked Disorders in
2.4 Chromosomal component
2.7 Barr bodies
2.7.1 Expressed genes on the inactive X chromosome
3 Uses in experimental biology
4 See also
6 Further reading
Susumu Ohno showed that the two X-chromosomes of mammals were
different: one appeared similar to the autosomes; the other was
condensed and heterochromatic. This finding suggested,
independently to two groups of investigators, that one of the
X-chromosomes underwent inactivation. In 1961, Mary Lyon proposed the
random inactivation of one female
X chromosome to explain the mottled
phenotype of female mice heterozygous for coat color genes. The
Lyon hypothesis also accounted for the findings that one copy of the X
chromosome in female cells was highly condensed, and that mice with
only one copy of the
X chromosome developed as infertile females. This
suggested to Ernest Beutler, studying heterozygous females for
Glucose-6-phosphate dehydrogenase (G6PD) deficiency, that there were
two red cell populations of erythrocytes in such heterozygotes:
deficient cells and normal cells, depending on whether the
X chromosome contains the normal or defective G6PD allele.
All mouse cells undergo an early, imprinted inactivation of the
X chromosome in two-cell or four-cell stage
embryos. The extraembryonic tissues (which give rise to the
placenta and other tissues supporting the embryo) retain this early
imprinted inactivation, and thus only the maternal
X chromosome is
active in these tissues.
In the early blastocyst, this initial, imprinted
reversed in the cells of the inner cell mass (which give rise to the
embryo), and in these cells both X chromosomes become active again.
Each of these cells then independently and randomly inactivates one
copy of the X chromosome. This inactivation event is irreversible
during the lifetime of the cell, so all the descendants of a cell
which inactivated a particular
X chromosome will also inactivate that
same chromosome. This phenomenon, which can be observed in the
coloration of tortoiseshell cats when females are heterozygous for the
X-linked gene, should not be confused with mosaicism, which is a term
that specifically refers to differences in the genotype of various
cell populations in the same individual; X-inactivation, which is an
epigenetic change that results in a different phenotype, is not a
change at the genotypic level. For an individual cell or lineage the
inactivation is therefore skewed or 'non-random', and this can give
rise to mild symptoms in female 'carriers' of
X-inactivation is reversed in the female germline, so that all oocytes
contain an active X chromosome.
Selection of one active X chromosome
Normal females possess two X chromosomes, and in any given cell one
chromosome will be active (designated as Xa) and one will be inactive
(Xi). However, studies of individuals with extra copies of the X
chromosome show that in cells with more than two X chromosomes there
is still only one Xa, and all the remaining X chromosomes are
inactivated. This indicates that the default state of the X chromosome
in females is inactivation, but one
X chromosome is always selected to
It is understood that X-chromosome inactivation is a random process,
occurring at about the time of gastrulation in the epiblast (cells
that will give rise to the embryo). The maternal and paternal X
chromosomes have an equal probability of inactivation. This would
suggest that women would be expected to suffer from
approximately 50% as often as men (because women have two X
chromosomes, while men have only one); however, in actuality, the
occurrence of these disorders in females is much lower than that. One
explanation for this disparity is that 12–20%  of genes on the
X chromosome remain expressed, thus providing women with
added protection against defective genes coded by the X-chromosome.
Some[who?] suggest that this disparity must be evidence of
preferential (non-random) inactivation. Preferential inactivation of
the paternal X-chromosome occurs in both marsupials and in cell
lineages that form the membranes surrounding the embryo, whereas
in placental mammals either the maternally or the paternally derived
X-chromosome may be inactivated in different cell lines.
The time period for X-chromosome inactivation explains this disparity.
Inactivation occurs in the epiblast during gastrulation, which gives
rise to the embryo. Inactivation occurs on a cellular level,
resulting in a mosaic expression, in which patches of cells have an
inactive maternal X-chromosome, while other patches have an inactive
paternal X-chromosome. For example, a female heterozygous for
X-linked disease) would have about half of her liver
cells functioning properly, which is typically enough to ensure normal
blood clotting. Chance could result in significantly more
dysfunctional cells; however, such statistical extremes are unlikely.
Genetic differences on the chromosome may also render one X-chromosome
more likely to undergo inactivation. Also, if one X-chromosome has a
mutation hindering its growth or rendering it non viable, cells which
randomly inactivated that X will have a selective advantage over cells
which randomly inactivated the normal allele. Thus, although
inactivation is initially random, cells that inactivate a normal
allele (leaving the mutated allele active) will eventually be
overgrown and replaced by functionally normal cells in which nearly
all have the same X-chromosome activated.
It is hypothesized[by whom?] that there is an autosomally-encoded
'blocking factor' which binds to the
X chromosome and prevents its
inactivation. The model postulates that there is a limiting blocking
factor, so once the available blocking factor molecule binds to one X
chromosome the remaining X chromosome(s) are not protected from
inactivation. This model is supported by the existence of a single Xa
in cells with many X chromosomes and by the existence of two active X
chromosomes in cell lines with twice the normal number of
Sequences at the X inactivation center (XIC), present on the X
chromosome, control the silencing of the X chromosome. The
hypothetical blocking factor is predicted to bind to sequences within
Expression of X-Linked Disorders in
It’s easy to see the effect of female X heterozygosity in localized
traits, such as the unique coat pattern of a calico cat. It can be
more difficult, however, to fully understand the expression of
un-localized traits in these females, such as the expression of
Since males only have one copy of the X chromosome, all expressed
X-chromosomal genes (or alleles, in the case of multiple variant forms
for a given gene in the population) are located on that copy of the
chromosome. Females, however, will primarily express the genes or
alleles located on the X-chromosomal copy that remains active.
Considering the situation for one gene or multiple genes causing
individual differences in a particular phenotype (i.e., causing
variation observed in the population for that phenotype), in
homozygous females it doesn’t particularly matter which copy of the
chromosome is inactivated, as the alleles on both copies are the same.
However, in females that are heterozygous at the causal genes, the
inactivation of one copy of the chromosome over the other can have a
direct impact on their phenotypic value. Because of this phenomenon,
there is an observed increase in phenotypic variation in females that
are heterozygous at the involved gene or genes than in females that
are homozygous at that gene or those genes. There are many
different ways in which the phenotypic variation can play out. In many
cases, heterozygous females may be asymptomatic or only present minor
symptoms of a given disorder, such as with X-linked
The differentiation of phenotype in heterozygous females is furthered
by the presence of
X-inactivation skewing. Typically, each
X-chromosome is silenced in half of the cells, but this process is
skewed when preferential inactivation of a chromosome occurs. It is
thought that skewing happens either by chance or by a physical
characteristic of a chromosome that may cause it to be silenced more
or less often, such as an unfavorable mutation.
On average, each
X chromosome is inactivated in half of the cells,
however 5-20% of "apparently normal" women display X-inactivation
skewing. In cases where skewing is present, a broad range of
symptom expression can occur, resulting in expression varying from
minor to severe depending on the skewing proportion. An extreme case
of this was seen where monozygotic female twins had extreme variance
in expression of Menkes disease (an
X-linked disorder) resulting in
the death of one twin while the other remained asymptomatic.
It’s thought that
X-inactivation skewing could be caused by issues
in the mechanism that causes inactivation, or by issues in the
chromosome itself. However, the link between phenotype and
skewing is still being questioned, and should be examined on a
case-by-case basis. A study looking at both symptomatic and
asymptomatic females who were heterozygous for Duchenne and Becker
muscular dystrophies (DMD) found no apparent link between transcript
expression and skewed X-Inactivation. The study suggests that both
mechanisms are independently regulated, and there are other unknown
factors at play.
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X-inactivation center (or simply XIC) on the
X chromosome is
necessary and sufficient to cause X-inactivation. Chromosomal
translocations which place the XIC on an autosome lead to inactivation
of the autosome, and X chromosomes lacking the XIC are not
The XIC contains four non-translated
RNA genes, Xist, Tsix, Jpx and
Ftx, which are involved in X-inactivation. The XIC also contains
binding sites for both known and unknown regulatory proteins.
Main article: Xist
The X-inactive specific transcript (Xist) gene encodes a large
RNA that is responsible for mediating the specific
silencing of the
X chromosome from which it is transcribed. The
X chromosome is coated by
Xist RNA, whereas the Xa is not
(See Figure to the right). X chromosomes which lack the
cannot be inactivated. Artificially placing and expressing the
Xist gene on another chromosome leads to silencing of that
Prior to inactivation, both X chromosomes weakly express
Xist gene. During the inactivation process, the future Xa ceases
to express Xist, whereas the future Xi dramatically increases
production. On the future Xi, the
RNA progressively coats the
chromosome, spreading out from the XIC; the
RNA does not
localize to the Xa. The silencing of genes along the Xi occurs soon
after coating by
Like Xist, the
Tsix gene encodes a large
RNA which is not believed to
encode a protein. The
RNA is transcribed antisense to Xist,
meaning that the
Tsix gene overlaps the
Xist gene and is transcribed
on the opposite strand of
DNA from the
Tsix is a
negative regulator of Xist; X chromosomes lacking
Tsix expression (and
thus having high levels of
Xist transcription) are inactivated much
more frequently than normal chromosomes.
Like Xist, prior to inactivation, both X chromosomes weakly express
RNA from the
Tsix gene. Upon the onset of X-inactivation, the
future Xi ceases to express
RNA (and increases
whereas Xa continues to express
Tsix for several days.
Rep A is a long non coding
RNA that works with another long non coding
RNA, Xist, for X inactivation. Rep A inhibits the function of Tsix,
the antisense of Xist, in conjunction with eliminating expression of
Xite. It promotes methylation of the
Tsix region by attracting PRC2
and thus inactivating one of the X chromosomes.
X chromosome does not express the majority of its genes,
unlike the active X chromosome. This is due to the silencing of the Xi
by repressive heterochromatin, which compacts the Xi
DNA and prevents
the expression of most genes.
Compared to the Xa, the Xi has high levels of
DNA methylation, low
levels of histone acetylation, low levels of histone H3 lysine-4
methylation, and high levels of histone H3 lysine-9 methylation and H3
lysine-27 methylation mark which is placed by the PRC2 complex
recruited by Xist, all of which are associated with gene
silencing. Additionally, a histone variant called macroH2A (H2AFY)
is exclusively found on nucleosomes along the Xi.
Main article: Barr body
DNA packaged in heterochromatin, such as the Xi, is more condensed
DNA packaged in euchromatin, such as the Xa. The inactive X forms
a discrete body within the nucleus called a Barr body. The Barr
body is generally located on the periphery of the nucleus, is late
replicating within the cell cycle, and, as it contains the Xi,
contains heterochromatin modifications and the
Expressed genes on the inactive X chromosome
A fraction of the genes along the
X chromosome escape inactivation on
the Xi. The
Xist gene is expressed at high levels on the Xi and is not
expressed on the Xa. Many other genes escape inactivation; some
are expressed equally from the Xa and Xi, and others, while expressed
from both chromosomes, are still predominantly expressed from the
Xa. Up to one quarter of genes on the human Xi are capable
of escape. Studies in the mouse suggest that in any given cell
type, 3% to 15% of genes escape inactivation, and that escaping gene
identity varies between tissues.
Many of the genes which escape inactivation are present along regions
X chromosome which, unlike the majority of the X chromosome,
contain genes also present on the Y chromosome. These regions are
termed pseudoautosomal regions, as individuals of either sex will
receive two copies of every gene in these regions (like an autosome),
unlike the majority of genes along the sex chromosomes. Since
individuals of either sex will receive two copies of every gene in a
pseudoautosomal region, no dosage compensation is needed for females,
so it is postulated that these regions of
DNA have evolved mechanisms
to escape X-inactivation. The genes of pseudoautosomal regions of the
Xi do not have the typical modifications of the Xi and have little
The existence of genes along the inactive X which are not silenced
explains the defects in humans with abnormal numbers of the X
chromosome, such as
Turner syndrome (X0) or Klinefelter syndrome
X-inactivation should eliminate the differences
in gene dosage between affected individuals and individuals with a
normal chromosome complement. In affected individuals, however,
X-inactivation is incomplete and the dosage of these non-silenced
genes will differ as they escape X-inactivation, similar to an
The precise mechanisms that control escape from
X-inactivation are not
known, but silenced and escape regions have been shown to have
distinct chromatin marks. It has been suggested that escape
X-inactivation might be mediated by expression of long non-coding
RNA (lncRNA) within the escaping chromosomal domains.
Uses in experimental biology
Stanley Michael Gartler used
X chromosome inactivation to demonstrate
the clonal origin of cancers. Examining normal tissues and tumors from
females heterozygous for isoenzymes of the sex-linked G6PD gene
demonstrated that tumor cells from such individuals express only one
form of G6PD, whereas normal tissues are composed of a nearly equal
mixture of cells expressing the two different phenotypes. This pattern
suggests that a single cell, and not a population, grows into a
cancer. However, this pattern has been proven wrong for many
cancer types, suggesting that some cancers may be polyclonal in
Besides, measuring the methylation (inactivation) status of the
polymorphic human androgen receptor (HUMARA) located on X-chromosome
is considered the most accurate method to assess clonality in female
cancer biopsies. A great variety of tumors was tested by this
method, some, such as renal cell carcinoma, found monoclonal while
others (e.g. mesothelioma) were reported polyclonal.
Researchers have also investigated using X-chromosome inactivation to
silence the activity of autosomal chromosomes. For example, Jiang et
al. inserted a copy of the
Xist gene into one copy of chromosome 21 in
stem cells derived from an individual with trisomy 21 (Down's
syndrome). The inserted
Xist gene induces
Barr body formation,
triggers stable heterochromatin modifications, and silences most of
the genes on the extra copy of chromosome 21. In these modified stem
cells, the Xist-mediated gene silencing seems to reverse some of the
defects associated with Down's syndrome.
Developmental disorders thought to be related to X-inactivation:
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