Editing X-inactivation (section)

===Selection of one active X chromosome===
Typical 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 [[X chromosome#Role in disease|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.<ref name="Tallaksen2023">{{cite journal | vauthors = Tallaksen HB, Johannsen EB, Just J, Viuff MH, Gravholt CH, Skakkebæk A | title = The multi-omic landscape of sex chromosome abnormalities: current status and future directions | journal = Endocrine Connections | volume = 12 | issue = 9 | date = August 2023 | pmid = 37399516 | pmc = 10448593 | doi = 10.1530/EC-23-0011 }}</ref>

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 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% <ref>{{cite journal | vauthors = Balaton BP, Cotton AM, Brown CJ | title = Derivation of consensus inactivation status for X-linked genes from genome-wide studies | journal = Biology of Sex Differences | volume = 6 | issue = 35 | pages = 35 | date = 30 December 2015 | pmid = 26719789 | pmc = 4696107 | doi = 10.1186/s13293-015-0053-7 | doi-access = free }}</ref> of genes on the inactivated X chromosome remain expressed, thus providing women with added protection against defective genes coded by the X-chromosome. Some{{who|date=October 2014}} 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,<ref>{{cite journal | vauthors = Graves JA | title = Mammals that break the rules: genetics of marsupials and monotremes | journal = Annual Review of Genetics | volume = 30 | pages = 233–60 | year = 1996 | pmid = 8982455 | doi = 10.1146/annurev.genet.30.1.233 }}</ref> whereas in placental mammals either the maternally or the paternally derived X-chromosome may be inactivated in different cell lines.<ref>{{cite journal | vauthors = Lyon MF | title = X-chromosome inactivation and developmental patterns in mammals | journal = Biological Reviews of the Cambridge Philosophical Society | volume = 47 | issue = 1 | pages = 1–35 | date = January 1972 | pmid = 4554151 | doi = 10.1111/j.1469-185X.1972.tb00969.x | s2cid = 39402646 }}</ref>

The time period for X-chromosome inactivation explains this disparity. Inactivation occurs in the epiblast during gastrulation, which gives rise to the embryo.<ref>{{cite journal| vauthors = Migeon, B |title=X chromosome inactivation in human cells|url=http://hstalks.com/main/view_talk.php?t=1676&r=494&c=252|journal=The Biomedical & Life Sciences Collection|publisher=Henry Stewart Talks, Ltd|access-date=15 December 2013 |pages=1–54|year=2010}}</ref> 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.<ref name="Gartler_2001">{{cite journal | last1 = Gartler | first1 = Stanley M | last2 = Goldman | first2 = Michael A | name-list-style = vanc | title = X-Chromosome Inactivation | url = http://web.udl.es/usuaris/e4650869/docencia/segoncicle/genclin98/recursos_classe_(pdf)/revisionsPDF/XChromoInac.pdf | journal = Encyclopedia of Life Sciences | publisher = Nature Publishing Group | pages = 1–2 | year=2001 }}</ref><ref name="Connallon_2013">{{cite journal | vauthors = Connallon T, Clark AG | title = Sex-differential selection and the evolution of X inactivation strategies | journal = PLOS Genetics | volume = 9 | issue = 4 | pages = e1003440 | date = April 2013 | pmid = 23637618 | pmc = 3630082 | doi = 10.1371/journal.pgen.1003440 | doi-access = free }}</ref> 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.<ref name="Gartler_2001"/>

It is hypothesized that there is an autosomally-encoded 'blocking factor' which binds to the X chromosome and prevents its inactivation.<ref>{{Cite journal |last1=Avner |first1=Philip |last2=Heard |first2=Edith |date=January 2001 |title=X-chromosome inactivation: counting, choice and initiation |url=https://www.nature.com/articles/35047580 |journal=Nature Reviews Genetics |language=en |volume=2 |issue=1 |pages=59–67 |doi=10.1038/35047580 |pmid=11253071 |s2cid=5234164 |issn=1471-0064|url-access=subscription }}</ref> 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.<ref>{{cite book | first1 = Tahsin Stefan | last1 = Barakat | first2 = Joost | last2 = Gribnau | name-list-style = vanc | chapter = X Chromosome Inactivation and Embryonic Stem Cells | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK45037/ | title = The Cell Biology of Stem Cells | editor-first1 = Eran | editor-last1 = Meshorer | editor-first2 = Kathrin | editor-last2 = Plath | year = 2010 | publisher = Landes Bioscience and Springer Science+Business Media }}</ref>

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.