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X-inactivation (also called Lyonization, after English geneticist
Mary Lyon Mary Mason Lyon (; February 28, 1797 – March 5, 1849) was an American pioneer in women's education. She established the Wheaton College (Massachusetts), Wheaton Female Seminary in Norton, Massachusetts, (now Wheaton College (Massachusetts), Whe ...
) is a process by which one of the copies of the
X chromosome The X chromosome is one of the two sex-determining chromosome A chromosome is a long DNA Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecul ...

X chromosome
is inactivated in
theria Theria (; Greek#REDIRECT Greek Greek may refer to: Greece Anything of, from, or related to Greece Greece ( el, Ελλάδα, , ), officially the Hellenic Republic, is a country located in Southeast Europe. Its population is approximatel ...
n
female Female (symbol: ♀) is the sex Sex is either of two divisions, typically male Male (♂) is the sex of an organism that produces the gamete known as sperm. A male gamete can fuse with a larger female gamete, or ovum, in the process of ...

female
mammal Mammals (from Latin Latin (, or , ) is a classical language A classical language is a language A language is a structured system of communication Communication (from Latin ''communicare'', meaning "to share" or "to be i ...
s. The inactive X chromosome is silenced by it being packaged into a transcriptionally inactive structure called
heterochromatin Heterochromatin is a tightly packed form of DNA The structure of part of a DNA double helix Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, whi ...
. As nearly all female mammals have two X chromosomes, X-inactivation prevents them from having twice as many X chromosome
gene product A gene product is the biochemical material, either RNA Ribonucleic acid (RNA) is a polymer A polymer (; Greek '' poly-'', "many" + '' -mer'', "part") is a substance or material consisting of very large molecule File:Pentacene on Ni( ...
s as
male Male (symbol: ♂) is the sex of an organism that produces the gamete (sex cell) known as sperm, which fuses with the larger female gamete, or ovum, in the process of fertilization. A male organism cannot sexual reproduction, reproduce sexually ...

male
s, who only possess a single copy of the X chromosome (see
dosage compensation Dosage compensation is the process by which organisms equalize the expression of genes between members of different biological sexes. Across species, different sexes Sex is either of two divisions, typically male Male (♂) is the sex of an ...

dosage compensation
). The choice of which X chromosome will be inactivated is random in
placental mammals Placentalia is one of the three extant subdivisions of the class of animals Mammalia; the other two are Monotremata and Marsupial Marsupials are any members of the mammal Mammals (from Latin language, Latin , 'breast') are a group ...

placental mammals
such as
human Humans (''Homo sapiens'') are the most abundant and widespread species In biology, a species is the basic unit of biological classification, classification and a taxonomic rank of an organism, as well as a unit of biodiversity. A speci ...

human
s, but once an X chromosome is inactivated it will remain inactive throughout the lifetime of the cell and its descendants in the organism (its cell line). X-inactivation that is unevenly distributed across cell lines within one organism (
skewed X-inactivation Skewed X-chromosome inactivation (skewed X-inactivation) occurs when the X-inactivation and calico cats is a visible manifestation of X-inactivation. The black and orange alleles of a fur coloration gene reside on the X chromosome. For any give ...
) commonly occurs. Unlike the random X-inactivation in placental mammals, inactivation in
marsupial Marsupials are any members of the mammal Mammals (from Latin Latin (, or , ) is a classical language A classical language is a language A language is a structured system of communication Communication (from Latin ' ...
s applies exclusively to the paternally-derived X chromosome.


Mechanism


Cycle of X-chromosome activation in rodents

The paragraphs below have to do only with rodents and do not reflect XI in the majority of mammals. X-inactivation is part of the activation cycle of the X chromosome throughout the female life. The egg and the fertilized zygote initially use maternal transcripts, and the whole embryonic genome is silenced until zygotic genome activation. Thereafter, all mouse cells undergo an early, imprinted inactivation of the paternally-derived X chromosome in 4–8 cell stage
embryo An embryo is the early stage of development of a multicellular organism A multicellular organism is an organism In biology, an organism () is any organic, life, living system that functions as an individual entity. All organisms ar ...

embryo
s. The extraembryonic tissues (which give rise to the
placenta The placenta is a temporary fetal organ Organ may refer to: Biology * Organ (anatomy) An organ is a group of Tissue (biology), tissues with similar functions. Plant life and animal life rely on many organs that co-exist in organ systems. ...

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 The blastocyst is a structure formed in the early development of mammal Mammals (from Latin Latin (, or , ) is a classical language belonging to the Italic branch of the Indo-European languages. Latin was originally spoken in th ...

blastocyst
, this initial, imprinted X-inactivation is reversed in the cells of the
inner cell mass In early embryogenesis of most eutherian mammals, the inner cell mass (ICM; also known as the embryoblast or pluriblast) is the mass of cells inside the primordial embryo that will eventually give rise to the definitive structures of the fetus. T ...
(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 individual, with the exception of the germline. In the female
germline In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechanisms ...
before meiotic entry, X-inactivation is reversed, so that after meiosis all haploid
oocyte An oocyte (, ), oöcyte, ovocyte, or rarely ocyte, is a female gametocyte A gametocyte is a eukaryotic germ cell that divides by mitosis into other gametocytes or by meiosis into gametids during gametogenesis. Male gametocytes are called ''sperm ...
s contain a single active X chromosome.


Overview

The Xi marks the inactive, Xa the active X chromosome. XP denotes the paternal, and XM to denotes the maternal X chromosome. When the egg (carrying XM), is fertilized by a sperm (carrying a Y or an XP) a diploid zygote forms. From zygote, through adult stage, to the next generation of eggs, the X chromosome undergoes the following changes: # XiP XiM zygote → undergoing zygotic genome activation, leading to: # XaP XaM → undergoing imprinted (paternal) X-inactivation, leading to: # XiP XaM → undergoing X-activation in the early
blastocyst The blastocyst is a structure formed in the early development of mammal Mammals (from Latin Latin (, or , ) is a classical language belonging to the Italic branch of the Indo-European languages. Latin was originally spoken in th ...

blastocyst
stage, leading to: # XaP XaM → undergoing random X-inactivation in the embryonic lineage (inner cell mass) in the blastocyst stage, leading to: # XiP XaM OR XaP XiM → undergoing X-reactivation in primordial germ cells before
meiosis Meiosis (; , because it is a reductional division) is a special type of of in organisms used to produce the , such as or . It involves two rounds of division that ultimately result in four cells with only one copy of each (). Additionall ...

meiosis
, leading to: # XaM XaP diploid germ cells in meiotic arrest. As the meiosis I only completes with
ovulation Ovulation is the release of egg An egg is the organic vessel containing the in which an develops until it can survive on its own, at which point the animal hatches. An egg results from of an . Most s, (excluding s), and lay eggs, alth ...

ovulation
, human germ cells exist in this stage from the first weeks of development until puberty. The completion of meiosis leads to: # XaM AND XaP haploid germ cells (eggs). The X activation cycle has been best studied in mice, but there are multiple studies in humans. As most of the evidence is coming from mice, the above scheme represents the events in mice. The completion of the meiosis is simplified here for clarity. Steps 1–4 can be studied in in vitro fertilized embryos, and in differentiating stem cells; X-reactivation happens in the developing embryo, and subsequent (6–7) steps inside the female body, therefore much harder to study.


= Timing

= The timing of each process depends on the species, and in many cases the precise time is actively debated. he whole part of the human timing of X-inactivation in this table is highly questionable and should be removed until properly substantiated by empirical data


= Inheritance of inactivation status across cell generations

= The descendants of each cell which inactivated a particular X chromosome will also inactivate that same chromosome. This phenomenon, which can be observed in the coloration of
tortoiseshell cat Tortoiseshell is a cat The cat (''Felis catus'') is a domestic Domestic may refer to: In the home * Anything relating to the human home A home, or domicile, is a space used as a permanent or semi-permanent residence for an in ...

tortoiseshell cat
s when females are
heterozygous Zygosity (the noun, zygote, is from the Greek zygotos "yoked," from zygon "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an or ...

heterozygous
for the X-linked gene, should not be confused with
mosaicism Mosaicism or genetic mosaicism is a condition in multi- cellular organisms in which a single organism possesses more than one genetic line as the result of genetic mutation. This means that various genetic lines resulted from a single fertilized eg ...
, which is a term that specifically refers to differences in the
genotype The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a specific ...
of various cell populations in the same individual; X-inactivation, which is an
epigenetic In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechani ...
change that results in a different phenotype, is ''not'' a change at the
genotypic Here the relation between genotype and phenotype is illustrated, using a Punnett square, for the character of petal colour in a pea plant. The letters B and b represent alleles for colour and the pictures show the resultant flowers. The punnet s ...
level. For an individual cell or lineage the inactivation is therefore
skewed In probability theory and statistics, skewness is a measure of the asymmetry of the probability distribution of a real number, real-valued random variable about its mean. The skewness value can be positive, zero, negative, or undefined. For ...
or '
non-random In common parlance, randomness is the apparent or actual lack of pattern or predictability in events. A random sequence of events, symbols or steps often has no :wikt:order, order and does not follow an intelligible pattern or combination. ...
', and this can give rise to mild symptoms in female 'carriers' of
X-linked Sex linked describes the sex-specific patterns of Heredity, inheritance and Phenotype, presentation when a gene mutation (allele) is present on a sex chromosome (allosome) rather than a non-sex chromosome (autosome). In humans, these are termed ...
genetic disorders.


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 remain active. It is understood that X-chromosome inactivation is a random process, occurring at about the time of
gastrulation Gastrulation is the stage in the early embryonic development of most animals, during which the blastula (a single-layered hollow sphere of Cell (biology), cells) is reorganized into a multilayered structure known as the gastrula. Before gastrulat ...

gastrulation
in the
epiblast In amniote Amniotes (from Greek ἀμνίον ''amnion'', "membrane surrounding the fetus", earlier "bowl in which the blood of sacrificed animals was caught", from ἀμνός ''amnos'', "lamb") are a clade A clade (; from grc, , ''kl ...
(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 X-linked disorders 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 inactivated 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 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 haemophilia (an 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 the XIC.


Expression of X-linked disorders in heterozygous females

The effect of female X heterozygosity is apparent in some 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 disease. Since males only have one copy of the X chromosome, all expressed X-chromosomal
gene In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mecha ...

gene
s (or
allele An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is one of two, or more, forms of a given gene In biology, a gene (from ''genos'' "...Wilhelm Johannsen coined the word gene to describe the Mendelian_inheritance ...
s, 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 In genetics Genetics is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular inter ...
(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 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 Menkes disease (MNK), also known as Menkes syndrome, is an X-linked recessive X-linked recessive inheritance is a mode of inheritance Inheritance is the practice of passing on private property, Title (property), titles, debts, entitlements, ...
(an X-linked disorder) resulting in the death of one twin while the other remained asymptomatic. It is 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.


Chromosomal component

The X-inactivation center (or simply XIC) on the X chromosome is
necessary and sufficient In logic Logic is an interdisciplinary field which studies truth and reasoning. Informal logic seeks to characterize Validity (logic), valid arguments informally, for instance by listing varieties of fallacies. Formal logic represents stateme ...
to cause X-inactivation.
Chromosomal translocation In genetics Genetics is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions ...
s which place the XIC on an autosome lead to inactivation of the autosome, and X chromosomes lacking the XIC are not inactivated. The XIC contains four non-
translated Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transla ...
RNA Ribonucleic acid (RNA) is a polymer A polymer (; Greek ''wikt:poly-, poly-'', "many" + ''wikt:-mer, -mer'', "part") is a Chemical substance, substance or material consisting of very large molecules, or macromolecules, composed of many Re ...

RNA
genes, Xist,
Tsix Tsix is a non-coding RNA A non-coding RNA (ncRNA) is an RNA Ribonucleic acid (RNA) is a polymer A polymer (; Greek '' poly-'', "many" + '' -mer'', "part") is a substance or material consisting of very large molecule File:Pentace ...
, Jpx and Ftx, which are involved in X-inactivation. The XIC also contains binding sites for both known and unknown
regulatory protein Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene product A gene product is the biochemical material, either RNA or protein P ...
s.


Xist and Tsix RNAs

The X-inactive specific transcript ( Xist) gene encodes a large
non-coding RNA A non-coding RNA (ncRNA) is an RNA molecule that is not Translation (genetics), translated into a protein. The DNA sequence from which a functional non-coding RNA is transcribed is often called an RNA gene. Abundant and functionally important li ...
that is responsible for mediating the specific silencing of the X chromosome from which it is transcribed. The inactive X chromosome is coated by Xist RNA, whereas the Xa is not (See Figure to the right). X chromosomes that lack the Xist gene 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 RNA from the Xist gene. During the inactivation process, the future Xa ceases to express Xist, whereas the future Xi dramatically increases Xist RNA production. On the future Xi, the Xist RNA progressively coats the chromosome, spreading out from the XIC; the Xist RNA does not localize to the Xa. The silencing of genes along the Xi occurs soon after coating by Xist RNA. Like Xist, the
Tsix Tsix is a non-coding RNA A non-coding RNA (ncRNA) is an RNA Ribonucleic acid (RNA) is a polymer A polymer (; Greek '' poly-'', "many" + '' -mer'', "part") is a substance or material consisting of very large molecule File:Pentace ...
gene encodes a large RNA which is not believed to encode a protein. The Tsix RNA is transcribed
antisense In molecular biology and genetics Genetics is a branch of biology concerned with the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) Though heredity had been observed for millennia, Gregor Mendel, Moravi ...
to Xist, meaning that the Tsix gene overlaps the Xist gene and is transcribed on the opposite strand of
DNA Deoxyribonucleic acid (; DNA) is a molecule A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an electrically Electricity is the set of physical ...

DNA
from the Xist gene. 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 Tsix RNA from the Tsix gene. Upon the onset of X-inactivation, the future Xi ceases to express Tsix RNA (and increases Xist expression), 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.Mercer, T.R., Dinger, M.E., Mattick, J.S., (2009). Long non-coding RNAs: insight into functions. Nature Reviews Genetics. (10) 155–159.


Silencing

The inactive 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 Heterochromatin is a tightly packed form of DNA The structure of part of a DNA double helix Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, whi ...
, which compacts the Xi DNA and prevents the expression of most genes. Compared to the Xa, the Xi has high levels of
DNA methylation DNA methylation is a biological process by which methyl group A methyl group is an alkyl derived from methane, containing one carbon atom chemical bond, bonded to three hydrogen atoms — CH3. In chemical formula, formulas, the ...

DNA methylation
, low levels of
histone acetylation Histone acetyltransferases (HATs) are enzymes that acetylation, acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-''N''-acetyllysine. DNA is wrapped around histones, and, by trans ...
, low levels of
histone H3 Histone H3 is one of the five main histones involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and a long N-terminal end, N-terminal tail, H3 is involved with the structure of the nucleosomes of the 'be ...
lysine-4
methylation In the chemical sciences, methylation denotes the addition of a methyl group A methyl group is an alkyl derived from methane, containing one carbon atom chemical bond, bonded to three hydrogen atoms — CH3. In chemical formula, fo ...
, 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.
PRC2 PRC2 (polycomb repressive complex 2) is one of the two classes of polycomb-group proteins Polycomb-group proteins (PcG proteins) are a family of protein complexes first discovered in fruit flies that can remodel chromatin Chromatin is a complex ...

PRC2
regulates
chromatin Chromatin is a complex of DNA Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecu ...
compaction and
chromatin remodeling Chromatin remodeling is the dynamic modification of chromatin Chromatin is a complex of DNA Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, w ...
in several processes including the
DNA damage DNA repair is a collection of processes by which a identifies and corrects damage to the molecules that encode its . In human cells, both normal activities and environmental factors such as can cause DNA damage, resulting in tens of thousan ...
response. Additionally, a histone variant called macroH2A (
H2AFY Core histone macro-H2A.1 is a protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendre ...
) is exclusively found on
nucleosome A nucleosome is the basic structural unit of DNA Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon ...

nucleosome
s along the Xi.


Barr bodies

DNA packaged in heterochromatin, such as the Xi, is more condensed than DNA packaged in
euchromatin Image:Diagram human cell nucleus.svg, 350px, The nucleus of a human cell showing the location of euchromatin Euchromatin is a lightly packed form of chromatin (DNA, RNA, and protein) that is enriched in gene, genes, and is often (but not always) und ...
, such as the Xa. The inactive X forms a discrete body within the nucleus called a
Barr body A Barr body (named after discoverer Murray Barr Murray Llewellyn Barr (June 20, 1908 – May 4, 1995) was a Canadians, Canadian physician and medical researcher who discovered with graduate student Ewart George Bertram, in 1948, an import ...
. The Barr body is generally located on the periphery of the
nucleus ''Nucleus'' (plural nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA ...

nucleus
, is late within the
cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication In , DNA replication is the of pro ...

cell cycle
, and, as it contains the Xi, contains heterochromatin modifications and the Xist RNA.


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 of the X chromosome which, unlike the majority of the X chromosome, contain genes also present on the
Y chromosome The Y chromosome is one of two sex chromosome A chromosome is a long DNA molecule with part or all of the genome, genetic material of an organism. Most eukaryotic chromosomes include packaging proteins called histones which, aided by Chaper ...
. 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 The pseudoautosomal regions, PAR1, PAR2, are homologous sequences of nucleotide Nucleotides are organic molecules , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that con ...

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 Xist RNA bound. 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 Turner syndrome (TS), also known as 45,X, or 45,X0, is a genetic condition A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene In biology, a gene ...
(X0) or
Klinefelter syndrome Klinefelter syndrome (KS), also known as 47,XXY, is a syndrome where a male has an additional copy of the X chromosome The X chromosome is one of the two sex-determining chromosome A chromosome is a long DNA Deoxyribonucleic ...
(XXY). Theoretically, 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 autosomal
aneuploidy Aneuploidy is the presence of an abnormal number of chromosome A chromosome is a long DNA molecule with part or all of the genome, genetic material of an organism. Most eukaryotic chromosomes include packaging proteins called histones whic ...
. 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 from X-inactivation might be mediated by expression of
long non-coding RNA Long non-coding RNAs (long ncRNAs, lncRNA) are a type of RNA Ribonucleic acid (RNA) is a polymer A polymer (; Greek ''wikt:poly-, poly-'', "many" + ''wikt:-mer, -mer'', "part") is a Chemical substance, substance or material consisting ...
(lncRNA) within the escaping chromosomal domains.


Uses in experimental biology

Stanley Michael Gartler Stanley Michael Gartler (born June 9, 1923) is a cell and molecular biologist and human geneticist. He was the first scientist to offer conclusive evidence for the clonality of human cancers. He showed that HeLa cells had contaminated many cell li ...
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 In multicellular organisms Multicellular organisms are organism In biology, an organism (from Ancient Greek, Greek: ὀργανισμός, ''organismos'') is any individual contiguous system that embodies the Life#Biology, properties o ...
derived from an individual with trisomy 21 (
Down syndrome Down syndrome or Down's syndrome, also known as trisomy 21, is a genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome In the fields of molecular biology and genetics Gen ...
). 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 syndrome.


History

In 1959
Susumu Ohno was a Japanese-American geneticist A geneticist is a biologist Francesco Redi, the founder of biology, is recognized to be one of the greatest biologists of all time A biologist is a professional who has specialized knowledge in the field ...
showed that the two X chromosomes of mammals were different: one appeared similar to the
autosomes An autosome is any chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. Most eukaryotic chromosomes include packaging proteins called histones which, aided by chaperone proteins, bind ...
; 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 Mary Mason Lyon (; February 28, 1797 – March 5, 1849) was an American pioneer in women's education. She established the Wheaton College (Massachusetts), Wheaton Female Seminary in Norton, Massachusetts, (now Wheaton College (Massachusetts), Whe ...
proposed the random inactivation of one female X chromosome to explain the mottled phenotype of female mice
heterozygous Zygosity (the noun, zygote, is from the Greek zygotos "yoked," from zygon "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an or ...

heterozygous
for coat color
gene In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mecha ...

gene
s. 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 Ernest Beutler (September 30, 1928 – October 5, 2008) was a German-born American hematologist and biomedical scientist. He made important discoveries about the causes of a number of diseases, including anemias, Gaucher disease, disorders of iron ...
, studying heterozygous females for
glucose-6-phosphate dehydrogenase Glucose-6-phosphate dehydrogenase (G6PD or G6PDH) () is a cytosolic enzyme that catalysis, catalyzes the chemical reaction : Glucose 6-phosphate, D-glucose 6-phosphate + NADP+ + H2O 6-Phosphogluconolactone, 6-phospho-D-glucono-1,5-lactone + NADP ...
(G6PD) deficiency, that there were two red cell populations of erythrocytes in such heterozygotes: deficient cells and normal cells, depending on whether the inactivated X chromosome (in the nucleus of the red cell's precursor cell) contains the normal or defective G6PD allele.


See also

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Sex-determination system A sex-determination system is a biological system that determines the development of sexual characteristics in an organism In biology, an organism (from Ancient Greek, Greek: ὀργανισμός, ''organismos'') is any individual conti ...
*
Dosage compensation Dosage compensation is the process by which organisms equalize the expression of genes between members of different biological sexes. Across species, different sexes Sex is either of two divisions, typically male Male (♂) is the sex of an ...

Dosage compensation
*
Barr body A Barr body (named after discoverer Murray Barr Murray Llewellyn Barr (June 20, 1908 – May 4, 1995) was a Canadians, Canadian physician and medical researcher who discovered with graduate student Ewart George Bertram, in 1948, an import ...
*
Heterochromatin Heterochromatin is a tightly packed form of DNA Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon r ...
*
Epigenetics In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechani ...
*
Skewed X-inactivation Skewed X-chromosome inactivation (skewed X-inactivation) occurs when the X-inactivation and calico cats is a visible manifestation of X-inactivation. The black and orange alleles of a fur coloration gene reside on the X chromosome. For any give ...
*Developmental disorders thought to be related to X-inactivation: ** Early infantile epileptic encephalopathy type 9 **
Frontonasal dysplasia Frontonasal dysplasia (FND) is a congenital malformation of the midface. For the diagnosis of FND, a patient should present at least two of the following characteristics: hypertelorism (an increased distance between the eyes), a wide nasal root, ver ...


References


Further reading

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External links

* * {{DEFAULTSORT:X-Inactivation Molecular genetics Genetics Epigenetics Female Sex-determination systems