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 its 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
placental mammals, inactivation in marsupials applies exclusively to
the paternally derived X chromosome.
* 1 History
* 2 Mechanism
* 2.1 Timing
* 2.2 Selection of one active
* 2.3 Expression of X-Linked Disorders in
* 2.4 Chromosomal component
* 2.6 Silencing
* 2.7 Barr bodies
* 2.7.1 Expressed genes on the inactive
* 3 Uses in experimental biology
* 4 See also
* 5 References
* 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
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
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 over 25% of genes on the
X chromosome remain expressed, thus providing women with
added protection against defective genes coded by the X-chromosome.
Some suggest that this disparity must be proof 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 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 autosomes.
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 HETEROZYGOUS FEMALES
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.
This section DOES NOT CITE ANY SOURCES . Please help improve this
section by adding citations to reliable sources . Unsourced material
may be challenged and removed . (October 2014) (Learn how and when to
remove this template message )
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
Tsix , Jpx and
Ftx , which are involved in X-inactivation. The XIC also contains
binding sites for both known and unknown regulatory proteins .
XIST AND TSIX RNAS
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 chromosome.
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
RNA production. On the future Xi, the
coats the chromosome, spreading out from the XIC; the
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.
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
Xist , all of which are associated with gene silencing.
Additionally, a histone variant called macroH2A (
H2AFY ) is
exclusively found on nucleosomes along the Xi.
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
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
not known, but silenced and escape regions have been shown to have
distinct chromatin marks. It has been suggested that escape from
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 origin.
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:
Epileptic Encephalopathy, Early Infantile, 9
* ^ Gartler SM, Varadarajan KR, Luo P, Canfield TK, Traynor J,
Francke U, Hansen RS (2004). "Normal histone modifications on the
X chromosome in ICF and Rett syndrome cells: implications for
methyl-/2/21/figure/F1 Figure 1". BMC Biology. 2: 21. PMC 521681 .
PMID 15377381 . doi :10.1186/1741-7007-2-21 .
* ^ A B Björn Reinius, Chengxi Shi, Liu Hengshuo, Kuljeet Singh
Sandhu, Katarzyna J. Radomska, Glenn D. Rosen, Lu Lu, Klas Kullander,
Robert W. Williams and Elena Jazin (November 2010). "Female-biased
expression of long non-coding RNAs in domains that escape
X-inactivation in mouse" . BMC Genomics. 11: 614. PMC 3091755 .
PMID 21047393 . doi :10.1186/1471-2164-11-614 . CS1 maint: Multiple
names: authors list (link )
* ^ Ohno S, Kaplan WD, Kinosita R (1959). "Formation of the sex
chromatin by a single X-chromosome in liver cells of rattus
norvegicus". Exp Cell Res. 18 (2): 415–9. PMID 14428474 . doi
* ^ Lyon MF (1961). "
Gene Action in the X-chromosome of the Mouse
(Mus musculus L.)". Nature . 190 (4773): 372–3. PMID 13764598 . doi
* ^ Beutler, E (January 2008). "Glucose-6-phosphate dehydrogenase
deficiency: a historical perspective". Blood. 111 (1): 16–24. PMID
18156501 . doi :10.1182/blood-2007-04-077412 .
* ^ Beutler E, Yeh M, Fairbanks VF (January 1962). "The normal
human female as a mosaic of X-chromosome activity: Studies using the
genre for g-6-pd-deficiency as a marker" . Proc. Natl. Acad. Sci.
U.S.A. 48 (1): 9–16. PMC 285481 . PMID 13868717 . doi
* ^ Takagi N, Sasaki M (1975). "Preferential inactivation of the
X chromosome in the extraembryonic membranes of the
mouse". Nature. 256 (5519): 640–2. PMID 1152998 . doi
* ^ Cheng MK, Disteche CM (2004). "Silence of the fathers: early X
BioEssays . 26 (8): 821–4. PMID 15273983 . doi
* ^ A B Okamoto I, Otte A, Allis C, Reinberg D, Heard E (2004).
"Epigenetic dynamics of imprinted X inactivation during early mouse
development". Science. 303 (5658): 644–9. PMID 14671313 . doi
* ^ Puck, J; Willard, HF (1998). "X Inactivation in Females with
X-Linked Disease". N. Engl. J. Med. 338 (5): 325–8. PMID 9445416 .
doi :10.1056/NEJM199801293380611 .
* ^ Graves JA (1996). "Mammals that break the rules: genetics of
marsupials and monotremes". Annual Review of Genetics. 30: 233–260.
PMID 8982455 . doi :10.1146/annurev.genet.30.1.233 .
* ^ Lyon, Mary F. (1972-01-01). "X-Chromosome Inactivation and
Developmental Patterns in Mammals". Biological Reviews. 47 (1):
1–35. PMID 4554151 . doi :10.1111/j.1469-185X.1972.tb00969.x .
* ^ Migeon, B (2010). "
X chromosome inactivation in human cells".
The Biomedical & Life Sciences Collection.
http://hstalks.com/?t=BL0132567): Henry Stewart Talks, Ltd. pp.
1–54. Retrieved 15 December 2013.
* ^ A B Gartler, Stanley M; Goldman, Michael A (2001).
"X-Chromosome Inactivation" (PDF). Encyclopedia of Life Sciences.
www.els.net: Nature Publishing Group. pp. 1–2. Retrieved 10 November
* ^ Connallon, Tim; Clark, Andrew G (2013). "Sex-Differential
Selection and the Evolution of X Inactivation Strategies".
Encyclopedia of Life Sciences. www.plosgenetics.org: PLOS Genetics.
pp. 1–12. Retrieved 15 December 2013.
* ^ Barakat, Tahsin Stefan. "X Chromosome Inactivation and
Embryonic Stem Cells".
* ^ Li Ma; Gabriel Hoffman; Alon Keinan (25 March 2015).
"X-Inactivation Informs Variance-based Testing for X-linked
Association of a Quantitative Trait". BMC Genomics. 16: 241. PMC
4381508 . PMID 25880738 . doi :10.1186/s12864-015-1463-y .
Retrieved 8 February 2017.
* ^ Habekost , Troller Clarissa, Santos Pereira Fernanda, Regla
Vargas Carmen, Moura Coelho Daniella, Torrez Vitor, Pierre Oses Jean,
Valmor Portela Luis, Schestatsky Pedro, Torres Felix Vitor, Matte
Ursula, Leotti Torman Vanessa, Bannach Jardim Laura (2015).
"Progression Rate of Myelopathy in
Heterozygotes". Metabolic Brain Disease Metab Brain Dis. 30 (5):
1279–284. doi :10.1007/s11011-015-9672-2 . CS1 maint: Multiple
names: authors list (link )
* ^ A B C Belmont JW (1996). "Genetic Control of X Inactivation and
Processes Leading to X-Inactivation Skewing". American Journal of
Human Genetics. 5 (8): 1101–108.
* ^ A B Holle Jennifer R.; Marsh Rebecca A.; Maria Holdcroft Anna;
Davies Stella M.; Wang Lijun; Zhang Kejian; Jordan Michael B. (2015).
"Hemophagocytic Lymphohistiocytosis in a
Female Patient Due to a
Heterozygous XIAP Mutation and Skewed X Chromosome Inactivation".
Pediatric Blood & Cancer Pediatr Blood Cancer. 62 (7): 1288–290. doi
* ^ Burgemeister , Lena Anna, Zirn Birgit, Oeffner Frank, Kaler
Stephen G., Lemm Gunther, Rossier Eva, Büttel Hans-Martin (2015).
"Menkes Disease with Discordant Phenotype in
Twins". Am. J. Med. Genet. A. 167 (11): 2826–829. PMID 26239182 .
doi :10.1002/ajmg.a.37276 . CS1 maint: Multiple names: authors list
* ^ Brioschi, Simona, Francesca Gualandi, Chiara Scotton, Annarita
Armaroli, Matteo Bovolenta, Maria S. Falzarano, Patrizia Sabatelli,
Rita Selvatici, Adele D’Amico, Marika Pane, Giulia Ricci, Gabriele
Siciliano, Silvana Tedeschi, Antonella Pini, Liliana Vercelli,
Domenico De Grandis, Eugenio Mercuri, Enrico Bertini, Luciano Merlini,
Tiziana Mongini, and Alessandra Ferlini. "Genetic Characterization in
Female DMD Carriers: Lack of Relationship between
X-inactivation, Transcriptional DMD
Allele Balancing and Phenotype."
BMC Medical Genetics BMC Med Genet 13.1 (2012): 73.
* ^ Hoki Y, Kimura N, Kanbayashi M, Amakawa Y, Ohhata T, Sasaki H,
Sado T (2009). "A proximal conserved repeat in the
Xist gene is
essential as a genomic element for
X-inactivation in mouse".
Development. 136 (1): 139–46. PMID 19036803 . doi
* ^ Ng K, Pullirsch D, Leeb M, Wutz A (2007). "
Xist and the order
of silencing" (Review Article). EMBO Rep. 8 (1): 34–9. PMC 1796754
. PMID 17203100 . doi :10.1038/sj.embor.7400871 . Figure 1
encompasses the X from which it is transcribed.
* ^ Penny GD, Kay GF, Sheardown SA, Rastan S, Brockdorff N (1996).
X chromosome inactivation". Nature. 379
(6561): 116–7. PMID 8538762 . doi :10.1038/379131a0 .
* ^ A B Herzing LB, Romer JT, Horn JM, Ashworth A (1997). "
properties of the X-chromosome inactivation centre". Nature. 386
(6622): 272–5. PMID 9069284 . doi :10.1038/386272a0 .
* ^ Lee JT, Jaenisch R (1997). "Long-range cis effects of ectopic
X-inactivation centres on a mouse autosome". Nature. 386 (6622):
275–9. PMID 9069285 . doi :10.1038/386275a0 .
* ^ Lee JT, Davidow LS, Warshawsky D (1999). "Tisx, a gene
Xist at the
X-inactivation centre". Nat Genet. 21 (4):
400–4. PMID 10192391 . doi :10.1038/7734 .
* ^ Ng K, Pullirsch D, Leeb M, Wutz A (2007). "
Xist and the order of
silencing" (Review Article). EMBO Rep. 8 (1): 34–9. PMC 1796754 .
PMID 17203100 . doi :10.1038/sj.embor.7400871 . Table 1 Features of
the inactive X territory – Originated from;
Chow J, Yen Z, Ziesche S, Brown C (2005). "Silencing of the mammalian
X chromosome". Annu Rev Genomics Hum Genet. 6: 69–92. PMID 16124854
. doi :10.1146/annurev.genom.6.080604.162350 .
Lucchesi JC, Kelly WG, Panning B (2005). "Chromatin remodeling in
dosage compensation". Annu. Rev. Genet. 39: 615–51. PMID 16285873 .
doi :10.1146/annurev.genet.39.073003.094210 . * ^ Costanzi C,
Pehrson JR (1998). "
Histone macroH2A1 is concentrated in the inactive
X chromosome of female mammals". Nature. 393 (6685): 599–601. PMID
9634239 . doi :10.1038/31275 .
* ^ Costanzi C, Stein P, Worrad DM, Schultz RM, Pehrson JR (2000).
Histone macroH2A1 is concentrated in the inactive
X chromosome of
female preimplantation mouse embryos" (pdf). Development. 127 (11):
2283–9. PMID 10804171 .
* ^ Barr ML, Bertram EG (1949). "A Morphological Distinction
between Neurones of the
Male and Female, and the Behaviour of the
Nucleolar Satellite during Accelerated Nucleoprotein Synthesis".
Nature . 163 (4148): 676–7. PMID 18120749 . doi :10.1038/163676a0 .
* ^ Plath K, Mlynarczyk-Evans S, Nusinow D, Panning B (2002). "Xist
RNA and the mechanism of
X chromosome inactivation". Annu Rev Genet.
36: 233–78. PMID 12429693 . doi
* ^ A B Carrel L, Willard H (2005). "
X-inactivation profile reveals
extensive variability in
X-linked gene expression in females". Nature.
434 (7031): 400–404. PMID 15772666 . doi :10.1038/nature03479 .
* ^ A B C Calabrese JM, Sun W, Song L, Mugford JW, Williams L, Yee
D, Starmer J, Mieczkowski P, Crawford GE, Magnuson T (2012).
"Site-specific silencing of regulatory elements as a mechanism of X
inactivation" . Cell. 151 (5): 951–63. PMC 3511858 . PMID
23178118 . doi :10.1016/j.cell.2012.10.037 .
* ^ A B Yang F, Babak T, Shendure J, Disteche CM (2010). "Global
survey of escape from X inactivation by RNA-sequencing in mouse" .
Genome Research. 20 (5): 614–22. PMC 2860163 . PMID 20363980 .
doi :10.1101/gr.103200.109 .
* ^ Berletch JB, Yang F, Disteche CM (June 2010). "Escape from X
inactivation in mice and humans" . Genome Biology. 11 (6): 213. PMC
2911101 . PMID 20573260 . doi :10.1186/gb-2010-11-6-213 .
* ^ Linder D, Gartler SM (October 1965). "Glucose-6-phosphate
dehydrogenase mosaicism: utilization as a cell marker in the study of
leiomyomas". Science. 150 (3692): 67–9. PMID 5833538 . doi
* ^ Parsons, BL (2008). "Many different tumor types have polyclonal
tumor origin:evidence and implications". Mutat Res. 659 (3):
232–247. PMID 18614394 . doi :10.1016/j.mrrev.2008.05.004 .
* ^ Chen, GL; Prchal, JT (2007). "
X-linked clonality testing:
interpretation and limitations" . Blood. 110 (5): 1411–1419. PMC
1975831 . PMID 17435115 . doi :10.1182/blood-2006-09-018655 .
* ^ Petersson; et al. (2014). "The leiomyomatous stroma in renal
cell carcinomas is polyclonal and not part of the neoplastic process".
Virchows Arch. 465 (1): 89–96. PMID 24838683 . doi
* ^ Comertpay; et al. (2014). "Evaluation of clonal origin of
malignant mesothelioma" . Journal of Translational Medicine. 12: 301.
PMC 4255423 . PMID 25471750 . doi :10.1186/s12967-014-0301-3 .
* ^ Jiang; et al. (2013). "Translating dosage compensation to
trisomy 21" . Nature. 500 (7462): 296–300. PMC 3848249 . PMID
23863942 . doi :10.1038/nature12394 .
* Huynh KD, Lee JT (2005). "X-chromosome inactivation: a hypothesis
linking ontogeny and phylogeny". Nature Reviews Genetics. 6 (5):
410–18. PMID 15818384 . doi :10.1038/nrg1604 .
X-inactivation as a possible cause for autoimmunity
* Goto T, Monk M (1 June 1998). "Regulation of X-Chromosome
Inactivation in Development in Mice and Humans" (Review Article).
Microbiol Mol Biol Rev. 62 (2): 362–78. PMC 98919 . PMID 9618446
. access-date= requires url= (help )
* Lyon M (2003). "The Lyon and the LINE hypothesis". Semin Cell Dev
Biol (Review Article)format= requires url= (help ). 14 (6): 313–8.
PMID 15015738 . doi :10.1016/j.semcdb.2003.09.015 .
* Ng K, Pullirsch D, Leeb M, Wutz A (2007). "
Xist and the order of
silencing" (Review Article). EMBO Rep. 8 (1): 34–9. PMC 1796754 .
PMID 17203100 . doi :10.1038/sj.embor.7400871 .
* Cerase A, Pintacuda G, Tattermusch A, Avner P (2015). "Xist
localization and function: new insights from multiple levels." .
Genome Biology. 16: 166. PMC 4539689 . PMID 26282267 . doi
Wikimedia Commons has media related to X CHROMOSOME INA